Artykuły w czasopismach: „IGF-2 Binding Protein-2 (IGF2BP3)”

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Cao, Junguo, Qingchun Mu i Haiyan Huang. "The Roles of Insulin-Like Growth Factor 2 mRNA-Binding Protein 2 in Cancer and Cancer Stem Cells". Stem Cells International 2018 (2018): 1–15. http://dx.doi.org/10.1155/2018/4217259.

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RNA-binding proteins (RBPs) mediate the localization, stability, and translation of the target transcripts and fine-tune the physiological functions of the proteins encoded. The insulin-like growth factor (IGF) 2 mRNA-binding protein (IGF2BP, IMP) family comprises three RBPs, IGF2BP1, IGF2BP2, and IGF2BP3, capable of associating with IGF2 and other transcripts and mediating their processing. IGF2BP2 represents the least understood member of this family of RBPs; however, it has been reported to participate in a wide range of physiological processes, such as embryonic development, neuronal differentiation, and metabolism. Its dysregulation is associated with insulin resistance, diabetes, and carcinogenesis and may potentially be a powerful biomarker and candidate target for relevant diseases. This review summarizes the structural features, regulation, and functions of IGF2BP2 and their association with cancer and cancer stem cells.

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Palanichamy, Jayanth Kumar, Tiffany Tran, Jorge Contreras, Thilini R. Fernando i Dinesh S. Rao. "Role Of Insulin Like Growth Factor mRNA Binding Protein-3 (IGF2BP3) In Mixed Lineage Leukemia (MLL) Positive B-Cell Lymphomas". Blood 122, nr 21 (15.11.2013): 3816. http://dx.doi.org/10.1182/blood.v122.21.3816.3816.

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Abstract Oncogenic transformation of early B-cell progenitors leads to the human disease of B-acute lymphoblastic leukemia or B-ALL, which affects both children and adults. Among the different subtypes of B-ALL, defined by particular cytogenetic anomalies, there are two which are difficult to treat and have a dismal prognosis. These are B-ALL with chromosomal translocation t (9; 22)/BCR-ABL and MLL gene rearrangements, which show distinctive gene expression profiles. Gene expression is now known to be significantly regulated by post-transcriptional mechanisms. These involve RNA binding proteins and microRNAs. Deregulation of microRNAs as well as RNA binding protein expression is associated with numerous cancers. Here, we hypothesized that RNA binding proteins may be important in regulating gene expression in MLL rearranged leukemias. To examine this hypothesis, we undertook a microarray study examining the expression of both protein-coding and non-coding genes in B-ALL, including MLL translocations. A total of 44 samples were used for the microarray. Supervised class prediction was carried out using the R library of prediction analysis for microarrays (PAM). One of the most significantly differentially expressed genes was Insulin Like Growth Factor mRNA Binding Protein-3 (IGF2BP3). The expression of IGF2BP3 was highest in the MLL rearranged B-ALL group. IGF2BP3 is an oncofetal protein known to be highly expressed in a number of epithelial malignancies such as glioblastomas. IGF2BP3 has been known to bind to the 5’-UTR and stabilize mRNAs like CD44 the expression of which correlates with epithelial tumors metastasis. IGF2BP3 has been shown to bind to the Insulin like Growth Factor-2 (IGF-2) mRNA and enhance translation in glioblastomas. We confirmed the expression of IGF2BP3 and CD44 in these 44 tumor samples and 90 other B-cell lymphoma samples by RT-qPCR. This corroborated with our previous data showing that the expression of both these genes is significantly higher in the group with MLL translocations. In the MLL rearranged leukemias, there was a significant correlation between the expression of CD44 and IGF2BP3. Interestingly however, there was no significant difference in the expression of IGF2 mRNA between these different subsets, indicating either that IGF2BP3 might be acting on IGF-2 mRNA at the translational level or that IGF-2 regulation may be cell-type specific. To evaluate whether IGF2BP3 affects the growth of B-ALL cells, we used NALM6, a B-ALL cell line which expresses IGF2BP3. We generated microRNA-155 formatted siRNAs against human IGF2BP3 and subcloned them into pHAGE6 based lentiviral vectors. Our preliminary data demonstrates that these vectors are capable of knocking down IGF2BP3 in the NALM6 cell line. In addition, cells with knockdown showed a dramatic decrease in their growth rates, as measured by the MTS assay. The IGF-2 paracrine signaling system is thought to be important in the maintenance of HSCs as well as in lymphocyte development. We separated different precursors of B-cells (Hardy fractions) from murine bone marrow using FACS and measured the mRNA expression of CD44 and IGF2BP3 in these different subsets. The expression of both these genes correlated well with each other and showed a dynamic expression pattern with the highest expression seen in the Hardy Fraction C (late pro-B cells). This indicates that the IGF2BP3/CD44 axis might play a role in regulating normal B-cell development and this may be dysregulated in MLL-translocated B-ALL. To examine whether IGF2BP3 overexpression causes leukemia, we cloned the murine and human IGF2BP3 coding regions in a murine retroviral expression vector, MIG (MSCV-IGF2BP3-IRES-GFP). Retroviral packaging was done using 293T cell line, virus was collected and used to infect 7Oz/3, a murine pre-B ALL cell line. Western blot and qPCR confirmed overexpression of IGF2BP3. We have infected bone marrow cells from CD 45.2 positive wild type donor mice with the virus and transferred them into irradiated CD 45.1 recipient mice. We have confirmed engraftment in these mice using flowcytometry for CD 45.1/2 and are presently following the mice for the development of leukemia. In summary, IGF2BP3 is dysregulated in MLL-rearranged leukemia, and its knockdown can cause decreased growth rates in B-ALL cell lines. The current study explores whether IGF2BP3 is oncogenic and the mechanisms of action of IGF2BP3 in B-cell development and neoplasia. Disclosures: No relevant conflicts of interest to declare.

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Yin, Huadong, Haorong He, Xiaoxu Shen, Jing Zhao, Xinao Cao, Shunshun Han, Can Cui i in. "miR-9-5p Inhibits Skeletal Muscle Satellite Cell Proliferation and Differentiation by Targeting IGF2BP3 through the IGF2-PI3K/Akt Signaling Pathway". International Journal of Molecular Sciences 21, nr 5 (28.02.2020): 1655. http://dx.doi.org/10.3390/ijms21051655.

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MicroRNAs are evolutionarily conserved, small non-coding RNAs that play critical post-transcriptional regulatory roles in skeletal muscle development. We previously found that miR-9-5p is abundantly expressed in chicken skeletal muscle. Here, we demonstrate a new role for miR-9-5p as a myogenic microRNA that regulates skeletal muscle development. The overexpression of miR-9-5p significantly inhibited the proliferation and differentiation of skeletal muscle satellite cells (SMSCs), whereas miR-9-5p inhibition had the opposite effect. We show that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is a target gene of miR-9-5p, using dual-luciferase assays, RT-qPCR, and Western Blotting, and that it promotes proliferation and differentiation of SMSCs. In addition, we found that IGF2BP3 regulates IGF-2 expression, using overexpression and knockdown studies. We show that Akt is activated by IGF2BP3 and is essential for IGF2BP3-induced cell development. Together, our results indicate that miR-9-5p could regulate the proliferation and differentiation of myoblasts by targeting IGF2BP3 through IGF-2 and that this activity results in the activation of the PI3K/Akt signaling pathway in skeletal muscle cells.

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Wächter, Kristin, Marcel Köhn, Nadine Stöhr i Stefan Hüttelmaier. "Subcellular localization and RNP formation of IGF2BPs (IGF2 mRNA-binding proteins) is modulated by distinct RNA-binding domains". Biological Chemistry 394, nr 8 (1.08.2013): 1077–90. http://dx.doi.org/10.1515/hsz-2013-0111.

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Abstract The IGF2 mRNA-binding protein family (IGF2BPs) directs the cytoplasmic fate of various target mRNAs and controls essential cellular functions. The three IGF2BP paralogues expressed in mammals comprise two RNA-recognition motifs (RRM) as well as four KH domains. How these domains direct IGF2BP paralogue-dependent protein function remains largely elusive. In this study, we analyze the role of KH domains in IGF2BPs by the mutational GXXG-GEEG conversion of single KH domain loops in the context of full-length polypeptides. These analyses reveal that all four KH domains of IGF2BP1 and IGF2BP2 are essentially involved in RNA-binding in vitro and the cellular association with RNA-binding proteins (RBPs). Moreover the KH domains prevent the nuclear accumulation of these two paralogues and facilitate their recruitment to stress granules. The role of KH domains appears less pronounced in IGF2BP3, because GxxG-GEEG conversion in all four KH domains only modestly affects RNA-binding, subcellular localization and RNA-dependent protein association of this paralogue. These findings indicate paralogue-dependent RNA-binding properties of IGF2BPs which likely direct distinct cellular functions. Our findings suggest that IGF2BPs contact target RNAs via all four KH domains. This implies significant structural constraints, which presumably allow the formation of exceedingly stable protein-RNA complexes.

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Wang, Peng-Fei, Xiaoyu Wang, Min Liu, Zheng Zeng, Caiji Lin, Wenwen Xu, Wenqing Ma i in. "The Oncogenic Functions of Insulin-like Growth Factor 2 mRNA-Binding Protein 3 in Human Carcinomas". Current Pharmaceutical Design 26, nr 32 (24.09.2020): 3939–54. http://dx.doi.org/10.2174/1381612826666200413080936.

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IGF2BP3 (also known as IMP3, KOC), a member of the insulin-like growth factor mRNA-binding protein family (IMPs), has been a research target in recent studies of promoting embryo development and exacerbating cancer. IGF2BP3 is ubiquitously expressed in early embryogenesis stages but limited in postembryonic stages, which is important in many physiological aspects such as stem cell renewal, morphological development and metabolism. A large number of studies show that IGF2BP3 interacts with many kinds of non-coding RNAs and proteins to promote cancer cell proliferation and metastasis and inhibit cancer cell apoptosis. As IGF2BP3 is highly expressed in advanced cancers and associated with poor overall survival rates of patients, it may be a potential molecular marker in cancer diagnosis for the detection of cancerous tissues and an indicator of cancer stages. Therefore, anti-IGF2BP3 drugs or monoclonal antibodies are expected as new therapeutic methods in cancer treatment. This review summarizes recent findings among IGF2BP3, RNA and proteins in cancer processes, with a focus on its cancer-promoting mechanisms and potential application as a new biomarker for cancer diagnosis and treatment.

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Panebianco, Federica, Lindsey M. Kelly, Pengyuan Liu, Shan Zhong, Sanja Dacic, Xiaosong Wang, Aatur D. Singhi i in. "THADA fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer". Proceedings of the National Academy of Sciences 114, nr 9 (13.02.2017): 2307–12. http://dx.doi.org/10.1073/pnas.1614265114.

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Thyroid cancer development is driven by known point mutations or gene fusions found in ∼90% of cases, whereas driver mutations in the remaining tumors are unknown. The insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays an important role in cancer, yet the mechanisms of its activation in cancer cells remain poorly understood. Using whole-transcriptome and whole-genome analyses, we identified a recurrent fusion between the thyroid adenoma-associated (THADA) gene on chromosome 2 and the LOC389473 gene on chromosome 7 located 12 kb upstream of the IGF2BP3 gene. We show that THADA fusion to LOC389473 and other regions in the vicinity does not result in the formation of a chimeric protein but instead leads to strong overexpression of the full-length IGF2BP3 mRNA and protein, increased IGF2 translation and IGF1 receptor (IGF1R) signaling via PI3K and MAPK cascades, and promotion of cell proliferation, invasion, and transformation. THADA fusions and IGF2BP3 overexpression are found in ∼5% of thyroid cancers that lack any other driver mutations. We also find that strong IGF2BP3 overexpression via gene fusion, amplification, or other mechanisms occurs in 5 to 15% of several other cancer types. Finally, we provide in vitro and in vivo evidence that growth of IGF2BP3-driven cells and tumors may be blocked by IGF1R inhibition, raising the possibility that IGF2BP3 overexpression in cancer cells may predict an anti-IGF1R benefit.

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Zhang, Haotian, Junjie Tang, Xiaowei Gong i Chenjun Huang. "Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Suppresses Ferroptosis in Non-Small Cell Lung Cancer via Stabilizing m6A Modification of Fanconi Anemia Group D2 Protein". Journal of Biomedical Nanotechnology 19, nr 8 (1.08.2023): 1390–99. http://dx.doi.org/10.1166/jbn.2023.3643.

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This study investigated the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) in non-small cell lung cancer (NSCLC) and its association with N6-methyladenosine (m6A) modification. The study analyzes the expression levels and stability of IGF2BP3, as well as its impact on NSCLC cell functions. The findings indicate that IGF2BP3 is upregulated in NSCLC patients and cell lines. Knocking down IGF2BP3 reduces cell proliferation and promotes ferroptosis in A549 and H1299 cells. Additionally, the study reveals that IGF2BP3 regulates the m6A modification of the fanconi anemia group D2 protein (FANCD2) and influences its mRNA stability. Overexpressing FANCD2 counteracts the effects of IGF2BP3 silencing and increases the aggressiveness of NSCLC. Furthermore, treatment with celastrol induces ferroptosis in NSCLC cells and inhibits tumor growth in vivo. In conclusion, these findings suggest that IGF2BP3 acts as an oncogene in NSCLC. Its interaction with FANCD2 through m6A modification suppresses ferroptosis in NSCLC cells. Thus, the IGF2BP3/FANCD2 signaling pathway may serve as a potential therapeutic target for NSCLC.

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de Vasconcellos, Jaira F., Colleen Byrnes, Y. Terry Lee, Pauline C. Xu, Antoinette Rabel i Jeffery L. Miller. "IGF2BP3 Moderately Increases Fetal Hemoglobin Levels in Human Adult Erythroblasts". Blood 128, nr 22 (2.12.2016): 2464. http://dx.doi.org/10.1182/blood.v128.22.2464.2464.

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Abstract Recent studies demonstrated that IGF2BP1 over-expression (IGF2BP1-OE) in adult erythroblasts has robust effects on fetal hemoglobin (HbF; >65% of the total globin levels), accompanied by reversal of the beta-like globin expression patterns to a fetal-like phenotype. Here we investigated if another member of the insulin-like growth factor 2 mRNA-binding protein family, IGF2BP3, also has potential for HbF regulation that may be useful for therapeutic application among patients with beta-hemoglobin disorders. The developmental pattern and expression levels for IGF2BP3 were initially determined in cord blood versus adult blood CD34(+) samples cultivated ex vivo in erythropoietin-supplemented serum-free media for 21 days. RNA samples were collected at culture day 14 and expression levels were measured by qRT-PCR. IGF2BP3 showed a developmentally regulated expression pattern similar to IGF2BP1 (IGF2BP1: cord blood: 1.3.E+03 ± 4.3.E+02 and adult blood: below detection limits; IGF2BP3: cord blood: 5.8.E+02 ± 2.4.E+02 and adult blood: below detection limits). These results were confirmed in vivo by comparing human fetal liver to adult bone marrow samples (IGF2BP1: fetal liver: 3.5.E+02 ± 5.7.E+01, adult bone marrow: below detection limits and IGF2BP3: fetal liver: 2.0.E+01 ± 2.7.E+00, adult bone marrow: below detection limits). To investigate the effects of IGF2BP3 upon erythropoiesis and globin expression, a lentiviral construct was designed for expression of IGF2BP3 driven by the erythroid-specific gene promoter region of the human SPTA1 gene (IGF2BP3-OE), with a matched empty vector control. Transductions were performed in CD34(+) cells from four adult healthy volunteers cultivated ex vivo in erythropoietin-supplemented serum-free media for 21 days. Over-expression of IGF2BP3 was confirmedby qRT-PCR and Western blot analyses at culture day 14. IGF2BP3-OE cells maintained their ability to differentiate and enucleate ex vivo compared to donor-matched controls. The expression levels of globin genes were evaluated at culture day 14 by qRT-PCR and showed that IGF2BP3-OE caused significantly increased gamma-globin expression levels compared to control transductions (control: 7.7.E+05 ± 1.7.E+05; IGF2BP3-OE: 8.4.E+06 ± 3.2.E+06; p=0.018). Consistent with increased gamma-globin, HbF rose to moderately high levels upon IGF2BP3-OE (control: 4.0 ± 2.1%; IGF2BP3-OE: 18.6 ± 1.0%; p=0.0021). In addition, the expression pattern of the erythroid transcription factor BCL11A was investigated by qRT-PCR at culture day 14 and no significant changes were observed (control: 5.6.E+02 ± 2.7.E+02; IGF2BP3-OE: 6.7.E+02 ± 3.5.E+02; p=0.694). However, minor decreases in BCL11A protein levels were detected by Western analysis. These results demonstrate that IGF2BP3 is developmentally regulated in human erythroid tissues with silencing during the fetal-to-adult transition. However, the effects of IGF2BP3-OE on HbF levels were less robust when compared to IGF2BP1-OE in cultured adult erythroblasts. Disclosures No relevant conflicts of interest to declare.

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Zhang, Jing, Fanghui Ding, Dan Jiao, Qiaozhi Li i Hong Ma. "The Aberrant Expression of MicroRNA-125a-5p/IGF2BP3 Axis in Advanced Gastric Cancer and Its Clinical Relevance". Technology in Cancer Research & Treatment 19 (1.01.2020): 153303382091733. http://dx.doi.org/10.1177/1533033820917332.

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RNA-binding proteins have been associated with cancer development. The overexpression of a well-known RNA-binding protein, insulin-like growth factor 2 messenger RNA–binding protein 3, has been identified as an indicator of poor prognosis in patients with various types of cancer. Although gastric cancer is a relatively frequent and potentially fatal malignancy, the mechanism by which insulin-like growth factor 2 messenger RNA–binding protein 3 regulates the development of this cancer remains unclear. This study aimed to investigate the role and regulatory mechanism of insulin-like growth factor 2 messenger RNA–binding protein 3 in gastric cancer. An analysis of IGF2BP3 expression patterns reported in 4 public gastric cancer–related microarray data sets from the Gene Expression Omnibus and The Cancer Genome Atlas-Stomach Adenocarcinoma revealed strong expression of this gene in gastric cancer tissues. Insulin-like growth factor 2 messenger RNA–binding protein 3 expression in gastric cancer was further confirmed via quantitative reverse transcription polymerase chain reaction and immunohistochemistry, respectively, in an in-house gastric cancer cohort (n = 30), and the association of insulin-like growth factor 2 messenger RNA–binding protein 3 expression with clinical parameters and prognosis was analyzed. Notably, stronger IGF2BP3 expression significantly correlated with poor prognosis, and significant changes in insulin-like growth factor 2 messenger RNA–binding protein 3 expression were only confirmed in patients with advanced-stage gastric cancer in an independent cohort. The effects of insulin-like growth factor 2 messenger RNA–binding protein 3 on cell proliferation were confirmed through in vitro experiments involving the HGC-27 gastric cancer cell line. MicroR-125a-5p, a candidate microRNA that target on insulin-like growth factor 2 messenger RNA–binding protein 3, decreased in advanced-stage gastric cancer. Upregulation of microR-125a-5p inhibited insulin-like growth factor 2 messenger RNA–binding protein 3, and dual-luciferase report assay indicated that microR-125a-5p inhibited the translation of IGF2BP3 by directly targeting the 3′ untranslated region. These results indicate that the microR-125a-5p/insulin-like growth factor 2 messenger RNA–binding protein 3 axis contributes to the oncogenesis of advanced gastric cancer.

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Liu, Xin, Jiayu Chen, Wenliang Chen, Yangtao Xu, Yang Shen i Ximing Xu. "Targeting IGF2BP3 in Cancer". International Journal of Molecular Sciences 24, nr 11 (29.05.2023): 9423. http://dx.doi.org/10.3390/ijms24119423.

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RNA-binding proteins (RBPs) can regulate multiple pathways by binding to RNAs, playing a variety of functions, such as localization, stability, and immunity. In recent years, with the development of technology, researchers have discovered that RBPs play a key role in the N6-methyladenosine (m6A) modification process. M6A methylation is the most abundant form of RNA modification in eukaryotes, which is defined as methylation on the sixth N atom of adenine in RNA. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is one of the components of m6A binding proteins, which plays an important role in decoding m6A marks and performing various biological functions. IGF2BP3 is abnormally expressed in many human cancers, often associated with poor prognosis. Here, we summarize the physiological role of IGF2BP3 in organisms and describe its role and mechanism in tumors. These data suggest that IGF2BP3 may be a valuable therapeutic target and prognostic marker in the future.

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Zhu, Lin, Xing Gao, Yun Du, Min Tang, Xiaofei Guo, Zhigang Chen, Yulong Liu i Yimin Lu. "Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 and Its Related Molecules as Potential Biomarkers in Small-Cell Lung Cancer". BioMed Research International 2022 (7.07.2022): 1–14. http://dx.doi.org/10.1155/2022/5774339.

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Background. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays a key role in tumorigenesis and tumor progression. Lung cancer is the leading cause of cancer-related death in men and women all over the world. However, the relationship between IGF2BP3 and small-cell lung cancer (SCLC) has not been reported yet. Methods. SCLC and normal samples (GSE19945 and GSE149507) were obtained in the Gene Expression Omnibus (GEO) dataset. Differential genes were screened by R software, and functional analysis and signal pathway enrichment analysis were carried out. In addition, we used the survival analysis database to analyze the relationship between prognosis and gene expression. Besides, immunohistochemistry (IHC) and quantitative real-time PCR (qPCR) were used for further research. Results. Five differentially expressed miRNAs and 9 differentially expressed mRNAs were selected by using R software. Survival analysis database results show that C7, CLIC5, PRDX1, IGF2BP3, and LDB2 were related the overall survival of patients with SCLC. Furthermore, multivariate analysis included that IGF2BP3 was independent risk factors for SCLC patients. Besides, gene function and signal pathway enrichment analysis showed that differentially expressed miRNAs were involved in the process of tumorigenesis and development. Furthermore, IHC and qPCR outcomes showed that the expression level of hsa-miR-182, hsa-miR-183, and IGF2BP3 was differentially expressed in normal lung tissues (NLTs) and SCLC tissues (SCLCTs). Conclusions. Our results concluded that hsa-miR-182, hsa-miR-183, and IGF2BP3 may take part in the development of SCLC.

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Wu, Tao, Xuan Zhang, Lu Xing, Dingguo Pan, Ping Liu, Rong Ding, Renfang Yang, Xudong Yang i Yunfeng Li. "Abnormal Expression of N6-Methyladenosine RNA Methylation Regulator IGF2BP3 in Colon Cancer Predicts a Poor Prognosis". Disease Markers 2022 (30.05.2022): 1–27. http://dx.doi.org/10.1155/2022/5883101.

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The value of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an N6-methyladenosine (m6A) RNA methylation regulatory factor, in the prognosis of colon cancer was still unclear. High levels of IGF2BP3 were expressed in colon adenocarcinoma (COAD) samples and in human colon cancer tissues, which was associated with poorer overall survival (OS). We validated IGF2BP3 as an independent prognostic risk biomarker in COAD patients. Moreover, functional enrichment analysis suggested that differentially expressed genes (DEGs) of groups with high versus low IGF2BP3 expression were related to immune- and cancer-related pathways. Furthermore, the tumor microenvironments of high- versus low-IGF2BP3 expression groups showed significant differences and IGF2BP3 predicted the efficiency of immunotherapy. Finally, protein-protein interaction network analysis suggested that there was a direct or indirect interaction among IGF2BP3, WNT7B, VANGL2, NKD1, AXIN2, RNF43, and CDKN2A. In brief, IGF2BP3 was confirmed as an independent prognostic signature in COAD patients and might be a therapeutic target in this study. Moreover, IGF2BP3 could be used in personalized immunotherapy for COAD.

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Mäkinen, Artturi, Atte Nikkilä, Teppo Haapaniemi, Laura Oksa, Juha Mehtonen, Matti Vänskä, Merja Heinäniemi, Timo Paavonen i Olli Lohi. "IGF2BP3 Associates with Proliferative Phenotype and Prognostic Features in B-Cell Acute Lymphoblastic Leukemia". Cancers 13, nr 7 (25.03.2021): 1505. http://dx.doi.org/10.3390/cancers13071505.

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The oncofetal protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) belongs to a family of RNA-binding proteins involved in localization, stability, and translational regulation of target RNAs. IGF2BP3 is used as a diagnostic and prognostic marker in several malignancies. Although the prognosis of pediatric B-cell acute lymphoblastic leukemia (B-ALL) has improved, a subgroup of patients exhibits high-risk features and suffer from disease recurrence. We sought to identify additional biomarkers to improve diagnostics, and we assessed expression of IGF2BP3 in a population-based pediatric cohort of B-ALL using a tissue microarray platform. The majority of pediatric B-ALL cases were positive for IGF2BP3 immunohistochemistry and were associated with an increased proliferative phenotype and activated STAT5 signaling pathway. Two large gene expression data sets were probed for the expression of IGF2BP3—the highest levels were seen among the B-cell lymphomas of a germinal center origin and well-established (KMT2A-rearranged and ETV6-RUNX1) and novel subtypes of B-ALL (e.g., NUTM1 and ETV6-RUNX1-like). A high mRNA for IGF2BP3 was associated with a proliferative “metagene” signature and a high expression of CDK6 in B-ALL. A low expression portended inferior survival in a high-risk cohort of pediatric B-ALL. Overall, our results show that IGF2BP3 shows subtype-specificity in expression and provides prognostic utility in high-risk B-ALL.

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Wang, Sihyung, Youngmi Jung, Jeongeun Hyun, Matthew Friedersdorf, Seh-Hoon Oh, Jieun Kim, Richard T. Premont, Jack D. Keene i Anna Mae Diehl. "RNA Binding Proteins Control Transdifferentiation of Hepatic Stellate Cells into Myofibroblasts". Cellular Physiology and Biochemistry 48, nr 3 (2018): 1215–29. http://dx.doi.org/10.1159/000491987.

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Background/Aims: Myofibroblasts (MF) derived from quiescent nonfibrogenic hepatic stellate cells (HSC) are the major sources of fibrous matrix in cirrhosis. Because many factors interact to regulate expansion and regression of MF-HSC populations, efforts to prevent cirrhosis by targeting any one factor have had limited success, motivating research to identify mechanisms that integrate these diverse inputs. As key components of RNA regulons, RNA binding proteins (RBPs) may fulfill this function by orchestrating changes in the expression of multiple genes that must be coordinately regulated to affect the complex phenotypic modifications required for HSC transdifferentiation. Methods: We profiled the transcriptomes of quiescent and MF-HSC to identify RBPs that were differentially-expressed during HSC transdifferentiation, manipulated the expression of the most significantly induced RBP, insulin like growth factor 2 binding protein 3 (Igf2bp3), and evaluated transcriptomic and phenotypic effects. Results: Depleting Igf2bp3 changed the expression of thousands of HSC genes, including multiple targets of TGF-β signaling, and caused HSCs to reacquire a less proliferative, less myofibroblastic phenotype. RNA immunoprecipitation assays demonstrated that some of these effects were mediated by direct physical interactions between Igf2bp3 and mRNAs that control proliferative activity and mesenchymal traits. Inhibiting TGF-β receptor-1 signaling revealed a microRNA-dependent mechanism that induces Igf2bp3. Conclusions: The aggregate results indicate that HSC transdifferentiation is ultimately dictated by Igf2bp3-dependent RNA regulons and thus, can be controlled simply by manipulating Igf2bp3.

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Klingbeil, Kyle D., Jack Pengfei Tang, Sarah M. Dry, Fritz C. Eilber, Dinesh S. Rao, Brian E. Kadera i Anusha Kalbasi. "Abstract 3490: IGF2BP3 (IMP3) expression is associated with worse survival in well-differentiated/dedifferentiated (WD/DD) liposarcoma". Cancer Research 82, nr 12_Supplement (15.06.2022): 3490. http://dx.doi.org/10.1158/1538-7445.am2022-3490.

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Abstract Background: Liposarcoma (LPS) is an understudied form of soft tissue sarcoma (STS). The well-differentiated (WD) and de-differentiated (DD) subtypes of LPS are associated with indolent and aggressive disease courses, respectively, but this histologic stratification fails to fully capture disease heterogeneity. Molecular approaches may help refine prognostication and inform treatment intensification. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3 or IMP3), is an RNA-binding protein that regulates gene expression by controlling mRNA stability and has been implicated in tumorigenesis and poor prognosis in many cancers. We hypothesized IGF2BP3 would refine the prognostication of LPS beyond its WD/DD histologic status. Methods: We examined the association between IGF2BP3 gene or protein expression and clinical data in four datasets: (1) patients with STS subtypes (n=206) in the cancer genome atlas (TCGA) database, (2) an in-house gene microarray of lipomatous tumors (n=71), LPS cell lines (n=3) and patient-derived xenografts (PDX, n=3), (3) an in-house tissue microarray (TMA) of lipomatous tumors (n=115), LPS cell lines (n=3) and PDXs (n=3) and (4) an in-house TMA of WD/DD LPS (n=71). IGF2BP3 protein expression in TMAs was quantified by immunohistochemistry (IHC). IGF2BP3 gene and protein expression values from identical samples were compared by Pearson correlation (n=43). The Kaplan-Meier method and log-rank test were used to compare survival outcomes. Results: In the TCGA cohort, which does not include WD LPS, IGF2BP3 expression was a poor prognostic factor solely in DD LPS (n=50, median overall survival (mOS): 1.6 vs 5.0 years, p=0.009). Among gene microarray samples, IGF2BP3 expression was highest in DD LPS (n=18) compared to WD LPS (n=29) and lipoma (n=7) by paired t-tests (p=0.03 and 0.002, respectively) and IGF2BP3 expression was associated with worse survival in WD/DD LPS (mOS 7.7 vs 21.5 years, p=0.02). In both TMAs, IGF2BP3 expression (>25% cell positivity/core) portended worse survival in WD/DD LPS (mOS (3): 3.7 vs 13.8 years, p<0.001 and mOS (4): 2.7 vs 14.9 years, p<0.001). IGF2BP3 was not expressed in myxoid LPS (n=21) or lipoma (n=8) samples. Gene and protein expression of IGF2BP3 were positively correlated in WD/DD LPS (r2 = 0.69). IGF2BP3 expression was more strongly associated with survival than LPS differentiation status (mOS: 7.0 (DD) vs 15.2 years (WD), p=0.02). Furthermore, all LPS cell lines and PDXs demonstrated high gene and protein expression of IGF2BP3. Conclusion: IGF2BP3 is highly expressed in a subset of LPS. Across independent datasets, IGF2BP3 is also a biomarker of disease progression and worse survival, and may stratify patients more effectively than histologic differentiation. Mechanistic studies of IGF2BP3 in LPS tumorigenesis and progression using aforementioned LPS cell lines and PDX models are ongoing. Citation Format: Kyle D. Klingbeil, Jack Pengfei Tang, Sarah M. Dry, Fritz C. Eilber, Dinesh S. Rao, Brian E. Kadera, Anusha Kalbasi. IGF2BP3 (IMP3) expression is associated with worse survival in well-differentiated/dedifferentiated (WD/DD) liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3490.

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Suvasini, Ramaswamy, Bhargava Shruti, Balaram Thota, Sridevi Vijay Shinde, Dinorah Friedmann-Morvinski, Zahid Nawaz, Krishnarao Venkatesh Prasanna i in. "Insulin Growth Factor-2 Binding Protein 3 (IGF2BP3) Is a Glioblastoma-specific Marker That Activates Phosphatidylinositol 3-Kinase/Mitogen-activated Protein Kinase (PI3K/MAPK) Pathways by Modulating IGF-2". Journal of Biological Chemistry 286, nr 29 (25.05.2011): 25882–90. http://dx.doi.org/10.1074/jbc.m110.178012.

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Hyun, Jeongeun, Seh-Hoon Oh, Richard T. Premont, Cynthia D. Guy, Carl L. Berg i Anna Mae Diehl. "Dysregulated activation of fetal liver programme in acute liver failure". Gut 68, nr 6 (22.01.2019): 1076–87. http://dx.doi.org/10.1136/gutjnl-2018-317603.

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ObjectiveUncertainty about acute liver failure (ALF) pathogenesis limits therapy. We postulate that ALF results from excessive reactivation of a fetal liver programme that is induced in hepatocytes when acutely injured livers regenerate. To evaluate this hypothesis, we focused on two molecules with known oncofetal properties in the liver, Yes-associated protein-1 (YAP1) and Insulin-like growth factor-2 RNA-binding protein-3 (IGF2BP3).DesignWe compared normal liver with explanted livers of patients with ALF to determine if YAP1 and IGF2BP3 were induced; assessed whether these factors are upregulated when murine livers regenerate; determined if YAP1 and IGF2BP3 cooperate to activate the fetal programme in adult hepatocytes; and identified upstream signals that control these factors and thereby hepatocyte maturity during recovery from liver injury.ResultsLivers of patients with ALF were massively enriched with hepatocytes expressing IGF2BP3, YAP1 and other fetal markers. Less extensive, transient accumulation of similar fetal-like cells that were proliferative and capable of anchorage-independent growth occurred in mouse livers that were regenerating after acute injury. Fetal reprogramming of hepatocytes was YAP1-dependent and involved YAP1-driven reciprocal modulation of let7 microRNAs and IGF2BP3, factors that negatively regulate each other to control fate decisions in fetal cells. Directly manipulating IGF2BP3 expression controlled the fetal-like phenotype regardless of YAP1 activity, proving that IGF2BP3 is the proximal mediator of this YAP1-directed fate.ConclusionAfter acute liver injury, hepatocytes are reprogrammed to fetal-like cells by a YAP1-dependent mechanism that differentially regulates let7 and IGF2BP3, identifying novel therapeutic targets for ALF.

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Huang, Huilin, Hengyou Weng, Mingli Sun, Huizhe Wu, Zhenhua Chen, Savanna Stanford, Xiaolan Deng, Rui Su, Minjie Wei i Jianjun Chen. "The Oncogenic Role of N6-Methyladenosine Reader Protein IGF2BP3 in Acute Myeloid Leukemia". Blood 132, Supplement 1 (29.11.2018): 1334. http://dx.doi.org/10.1182/blood-2018-99-117535.

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Abstract RNA N6-Methyladenosine (m6A) modification is an abundant modification of internal mRNAs in eukaryotes and some viruses, which is dynamically and reversibly fine-tuned during normal and pathological bioprocesses. Recent studies have shown that m6A methyltransferases, METTL3 and METTL14, play important roles in maintaining self-renewal capacity of hematopoietic stem/progenitor cells (HSPCs) and promoting acute myeloid leukemia (AML) development (Barbiori et al., Nature, 2017; Vu et al., Nature Method, 2017; Weng et al. Cell Stem Cell, 2018). The m6A demethylase, FTO, was also shown to promote leukemic cell transformation and leukemogenesis in various type of AML (Li et al., Cancer Cell, 2017). However, little is known about the functions of m6A readers in malignant hematopoiesis. We recently reported that Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is an specific m6A binding protein, which recognize m6A transcripts through the K Homology (KH) domains to stabilize and promote translation of its target mRNAs (Huang et al., Nature Cell Biology, 2018). In analysis of TCGA AML dataset (n=157), we found that a higher expression level of IGF2BP3 is significantly associated with a poor prognosis in AML patients (p<0.001; Median overall survival: IGF2BP3-High vs. IGF2BP3-Low = 11 months vs. 31 months). In addition, we analyzed our in-house microarray profiling of 113 AML patient samples and found that IGF2BP3 is highly expressed in mononuclear cells (MNC) from MLL-rearranged leukemia patients as compared to those from healthy donors (p<0.05) or non-MLL-rearranged leukemic patients (p<0.001). Consistent with the overexpression of IGF2BP3 in human MLL-rearranged AML, MLL-AF9 or MLL-AF10 transformed mouse hematopoietic stem/progenitor cells (HSPCs; herein mouse lineage negative (Lin-) bone marrow cells) showed a >10 fold increase in expression level of Igf2bp3, compare to the non-transformed counterpart HSPCs. Furthermore, in analysis of 562 samples from adult patients with AML (GSE37642), we found that within cytogenetically normal human AML, patients carrying FLT3-ITD mutation showed a significantly higher level of IGF2BP3 expression than those without FLT3-ITD mutation (p<0.01). To investigate the potential oncogenic role of IGF2BP3 in AML, we cotransduced mouse Lin- BM progenitor cells with MLL-AF9 and three individual shRNAs targeting Igf2bp3 or a scrambled control shRNA and performed colony-forming/replating assays. Knockdown of Igf2bp3 significantly (p<0.05) reduced the colony-forming capacity of MLL-AF9-transduced HSPCs to 20-50% of that of the control group. Conversely, forced expression of wild-type IGF2BP3 significantly (p<0.05) promoted colony formation of MLL-AF9-transduced Lin- BM progenitor cells. Such promotion was almost completely impaired when KH3-4 domain of IGF2BP3 was mutated or when Mettl14 was depleted, suggesting that IGF2BP3 exerts its oncogenic function as an m6A reader through an m6A-dependent mechanism. We further used human leukemia cell lines to investigate the function of IGF2BP3 in human AML cells. Silencing of IGF2BP3 by two shRNAs significantly inhibited cell viability and proliferation and induced cell apoptosis (p<0.01) in MonoMac6 AML cell line which harbors the t(9;11) translocation. In Molm13 and MV4-11 AML cells which are heterozygous and homozygous for the FLT3-ITD mutation, respectively, a further decrease of cell viability and increase of apoptotic cells upon IGF2BP3 knockdown was observed compared to MonoMac6 with wild-type FLT3. Mechanically, through cross-linking immunoprecipitation sequencing (CLIP-seq), we showed that IGF2BP3 targets mRNAs in cell cycle, DNA replication and protein synthesis pathways. Taken together, these results demonstrated the oncogenic role of the new m6A reader protein IGF2BP3 in AML. Given the fact that expression of IGF2BP3 correlates with an overall poor prognosis in AML, IGF2BP3 is likely a promising therapeutic target for AML treatment. Disclosures No relevant conflicts of interest to declare.

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Skibiel, C., S. Ren i L. Reid. "Clinicopathologic features of thyroid neoplasm with THADA-IGF2BP3 fusion". American Journal of Clinical Pathology 156, Supplement_1 (1.10.2021): S53—S54. http://dx.doi.org/10.1093/ajcp/aqab191.109.

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Abstract Introduction/Objective Thyroid adenoma-associated (THADA)-IGF2BP3 fusions is related to strong overexpression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) mRNA and protein, increased IGF2 translation and IGF1 receptor signaling via PI3K and MAPK pathways. THADA-IGF2BP3 have been identified as an oncogenic event in thyroid neoplasms, but the clinicopathologic features have not been greatly evaluated. The purpose of this cases review is to describe the clinical and pathologic findings of thyroid nodules with THADA-IGF2BP3 fusion on molecular testing. Methods/Case Report Surgical Pathology 220 cases of total and hemithyroidectomy from January 2018 to December 2019 were reviewed for cytology fine needle aspiration (FNA), molecular testing results and surgical resection pathology. Results (if a Case Study enter NA) Three cases of THADA-IGF2BP3 fusion identified by Thyroseq testing from FNA of thyroid nodules with all diagnosed as atypia of undetermined significance, Bethesda category 3. No other mutations or gene fusions are identified. Successive surgical interventions are performed. Case 1 is a 49-year-old female right hemithyroidectomy with pathologic diagnosis of papillary thyroid carcinoma (PTC) follicular variant with tumor capsular invasion and no lymphvascular invasion. The tumor is 2cm, two lymph nodes evaluated are not involved by tumor and pathological stage is pT1b pN0. Case 2 is a 71-year-old female total thyroidectomy and the pathologic diagnosis is PTC follicular variant with tumor capsular invasion and no lymphvascular invasion. The tumor is 2cm, one lymph node evaluated is not involved by tumor and pathologic stage is pT1b pN0. Case 3 is a 76-year-old male left hemithyroidectomy and pathologic diagnosis is PTC follicular variant with tumor capsular invasion and no lymphvascular invasion. The tumor is 2cm, two lymph nodes evaluated are not involved by tumor and pathologic stage is pT1b pN0. Conclusion THADA-GF2BP3 fusion is uncommon in thyroid neoplasms and only three cases are detected in 220 cases evaluated. The three cases of thyroid nodules are all diagnosed as AUS by FNA, and all are diagnosed as PTC follicular variant with capsular invasion upon resection without lymphvascular invasion or lymph node involvement. THADA-F2BP3 fusion is associated with thyroid carcinoma, with low-risk non-aggressive behavior, conservative surgery appears necessary and lobectomy is likely adequate.

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Zhao, Wei, Dan Lu i Jun Zhang. "Insulin growth factor-2 binding protein 3 (IGF2BP3) to promote lung tumorigenesis viaregulation of p53 stability." Journal of Clinical Oncology 34, nr 15_suppl (20.05.2016): e23013-e23013. http://dx.doi.org/10.1200/jco.2016.34.15_suppl.e23013.

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Fan, Jin, Mengqi Zhuang, Wei Fan i Ming Hou. "RNA N6-methyladenosine reader IGF2BP3 promotes acute myeloid leukemia progression by controlling stabilization of EPOR mRNA". PeerJ 11 (30.08.2023): e15706. http://dx.doi.org/10.7717/peerj.15706.

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Background N6-methyladenosine (m6A) methylation epigenetically regulates normal hematopoiesis and plays a role in the pathogenesis of acute myeloid leukemia (AML). However, its potential value for prognosis remains elusive. Methods Analysis of the datasets downloaded from The Cancer Genome Atlas and Genotype Tissue Expression databases revealed that the expression level of 20 regulators related to m6A RNA methylation differ between patients with AML and normal individuals. A prognostic risk model with three genes (YTHDF3, IGF2BP3, and HNRNPA2B1) was developed using univariate Cox regression and the least absolute shrinkage and selection operator Cox regression methods. Results This established signature demonstrated good predictive efficacy with an area under the curve of 0.892 and 0.731 in the training cohort and the validation cohort, respectively. Patients with AML and an increased level of Insulin growth factor 2 mRNA binding protein 3 (IGF2BP3) expression exhibited a poor prognosis. IGF2BP3 knockdown significantly induced G0/G1 phase arrest and inhibited cell proliferation, apoptosis, and/or differentiation. Further, the JAK/STAT pathway may be involved in the regulation of EPOR expression by IGF2BP3-mediated m6A RNA methylation. Conclusion These findings indicate that IGF2BP3 plays a carcinogenic role in AML, implying that it can predict patient survival and could be an effective strategy for AML therapy.

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Huang, Shan, Zheng Wu, Yunyun Cheng, Wenzhen Wei i Linlin Hao. "Insulin-like growth factor 2 mRNA binding protein 2 promotes aerobic glycolysis and cell proliferation in pancreatic ductal adenocarcinoma via stabilizing GLUT1 mRNA". Acta Biochimica et Biophysica Sinica 51, nr 7 (15.05.2019): 743–52. http://dx.doi.org/10.1093/abbs/gmz048.

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Abstract Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) is a member of the IGF2BP protein family consisting of IGF2BP1~3 with the capacity of binding to many transcripts and regulating RNA stability, localization, and translation. In this study, we discovered that expression of IGF2BP2 was upregulated and led to a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). IGF2BP2 protein was gradually elevated from normal pancreas, pancreatic intraepithelial neoplasia to PDAC in an LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx1-Cre mouse model. Furthermore, we demonstrated that IGF2BP2 promoted aerobic glycolysis and PDAC cell proliferation through directly binding to and stabilizing GLUT1 mRNA. In summary, our study unveiled an important role of IGF2BP2 in PDAC development by modulating aerobic glycolysis and as a potential therapeutic target for PDAC treatment.

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Zhao, Wei, Dan Lu, Liang Liu, Juan Cai, Yu Zhou, Ying Yang, Yu Zhang i Jun Zhang. "Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) promotes lung tumorigenesis via attenuating p53 stability". Oncotarget 8, nr 55 (27.09.2017): 93672–87. http://dx.doi.org/10.18632/oncotarget.21280.

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Shen, Xiaoxu, Yuanhang Wei, Guishuang You, Wei Liu, Felix Kwame Amevor, Yao Zhang, Haorong He i in. "Circular PPP1R13B RNA Promotes Chicken Skeletal Muscle Satellite Cell Proliferation and Differentiation via Targeting miR-9-5p". Animals 11, nr 8 (13.08.2021): 2396. http://dx.doi.org/10.3390/ani11082396.

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Skeletal muscle plays important roles in animal locomotion, metabolism, and meat production in farm animals. Current studies showed that non-coding RNAs, especially the circular RNA (circRNA) play an indispensable role in skeletal muscle development. Our previous study revealed that several differentially expressed circRNAs among fast muscle growing broilers (FMGB) and slow muscle growing layers (SMGL) may regulate muscle development in the chicken. In this study, a novel differentially expressed circPPP1R13B was identified. Molecular mechanism analysis indicated that circPPP1R13B targets miR-9-5p and negatively regulates the expression of miR-9-5p, which was previously reported to be an inhibitor of skeletal muscle development. In addition, circPPP1R13B positively regulated the expression of miR-9-5p target gene insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) and further activated the downstream insulin like growth factors (IGF)/phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway. The results also showed that the knockdown of circPPP1R13B inhibits chicken skeletal muscle satellite cells (SMSCs) proliferation and differentiation, and the overexpression of circPPP1R13B promotes the proliferation and differentiation of chicken SMSCs. Furthermore, the overexpression of circPPP1R13B could block the inhibitory effect of miR-9-5p on chicken SMSC proliferation and differentiation. In summary, our results suggested that circPPP1R13B promotes chicken SMSC proliferation and differentiation by targeting miR-9-5p and activating IGF/PI3K/AKT signaling pathway.

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Elagib, Kamaleldin E., Chih-Huan Lu, Goar Mosoyan, Ewelina Zasadzińska, Daniel R. Foltz, Peter Balogh, Els Verhoeyen i in. "An IGF2BP3-Cdk9 Pathway Governs the Human Fetal-Adult Megakaryocyte Transition". Blood 128, nr 22 (2.12.2016): 886. http://dx.doi.org/10.1182/blood.v128.22.886.886.

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Abstract Hematopoietic transitions that accompany fetal development, for example erythroid globin chain switching, play important roles in normal physiology and disease development. In the megakaryocyte lineage, human fetal progenitors show impaired execution of the morphogenesis program of enlargement, polyploidization, and proplatelet formation. Although these defects decline with gestational stage, they remain sufficiently severe at birth to predispose newborns to thrombocytopenia. These defects also contribute to inferior platelet recovery after cord blood stem cell transplantation and to inefficient platelet production by megakaryocytes (Mk) derived from pluripotent stem cells. In this study, comparison of neonatal versus adult human progenitors identified a blockade in the specialized positive transcription elongation factor b (P-TEFb) activation mechanism known to drive adult Mk morphogenesis. A central feature of this pathway is known to involve sustained high amplitude activation of the P-TEFb kinase (Cdk9/cyclin T1). This cascade is initiated by downregulation of core components of the repressive complex of P-TEFb: the 7SK snRNP consisting of the 7SK small nuclear RNA (7SK) and its stabilizing factors MePCE and LARP7. The resulting high amplitude activation of P-TEFb drives multiple features of Mk differentiation: induction of cytoskeletal morphogenetic factors (ACTN1, FLNA, MKL1, HIC5), silencing of erythroid genes, promotion of histone H2B K120 monoubiquitiniation (H2BUb1), and phosphorylation of Spt5 at T806 (pSpt5 T806). Critical, rate-limiting steps triggering this pathway comprise MePCE proteolysis by calpain 2 and downregulation of LARP7, both resulting in destabilization of 7SK. In comparison to Mk derived from adult peripheral blood stem cells (adult Mk), Mk derived from umbilical cord blood stem cells (neonatal Mk) showed evidence of decreased P-TEFb activation with decreases in: 1) the expression of the cytoskeletal morphogenetic factors, 2) global H2BUb1, and 3) pSpt5 T806. In addition, neonatal Mk retained expression of the erythroid marker glycophorin A (GPA). Surprisingly, neonatal Mk failed to downregulate 7SK despite the downregulation of its stabilizers MePCE and LARP7, suggesting the existence of alternative 7SK stabilizing factor/s unique to neonatal Mk. Our screening identified the oncofetal RNA-binding protein IGF2BP3 to be expressed in neonatal but not adult Mk, and ectopic expression of IGF2BP3 in adult Mk conferred neonatal phenotypic features including reduction in size, increased proliferation and leaky erythroid antigen expression. Immunoprecipitation and glycerol gradient studies indicated the participation of IGF2BP3 in the 7SK snRNP complex. Mining of endogenous IGF2BP3 iCLIP data indicated that 7SK is one of the top direct targets of IGF2BP3 and further mapped binding to the 7SK fourth hairpin, a critical stability determinant. In loss of function studies, the knockdown of IGF2BP3 in neonatal Mk resulted in destabilization of 7SK and upregulation of the Mk morphogenetic cytoskeletal factors, as well as increased levels of H2BUb1, pSpt5 T806, and hyperphosphorylated RNA Pol II. Phenotypically, the knockdown of IGF2BP3 in neonatal Mk elicited adult features including increased size, enhanced polyploidization, reduced proliferation and silencing of erythroid antigen expression. Collectively, these findings suggest that the block in P-TEFb activation in neonatal Mk results from ontogentic stage-specific expression of IGF2BP3 which prevents the 7SK destabilization normally associated with adult megakaryocytic P-TEFb activation. We also identified a pharmacologic approach to inhibit IGF2BP3 expression, through inhibition of bromodomain and extra- terminal (BET) proteins, which reproducibly promoted adult features in neonatal Mk including enlargement, inhibition of erythroid antigen expression, upregulation of morphogenetic cytoskeletal factors, and increased platelet formation in vitro. Enforced expression of IGF2BP3 in neonatal Mk significantly blunted the effects of BET inhibitors indicating the specificity of their action in downregulating IGF2BP3. These results identify IGF2BP3 as a human ontogenic masterswitch that restricts megakaryocyte development through modulating a lineage-specific P-TEFb activation mechanism, revealing new strategies toward enhancing platelet production. Disclosures No relevant conflicts of interest to declare.

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Lochhead, Paul, Yu Imamura, Teppei Morikawa, Aya Kuchiba, Mai Yamauchi, Xiaoyun Liao, Zhi Rong Qian i in. "Insulin-like growth factor 2 messenger RNA binding protein 3 (IGF2BP3) is a marker of unfavourable prognosis in colorectal cancer". European Journal of Cancer 48, nr 18 (grudzień 2012): 3405–13. http://dx.doi.org/10.1016/j.ejca.2012.06.021.

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Elagib, Kamaleldin E., Chih-Huan Lu, Ewelina Zasadzińska, Daniel R. Foltz, Peter Balogh i Adam N. Goldfarb. "The Distinctive Morphogenesis of Infantile Megakaryopoiesis Is Associated with Altered P-TEFb Regulation By the Oncofetal Factor IGF2BP3". Blood 124, nr 21 (6.12.2014): 2911. http://dx.doi.org/10.1182/blood.v124.21.2911.2911.

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Abstract Infantile (fetal/neonatal) megakaryocytes (Mk) differ from "adult" Mk in several important aspects. They are smaller, more proliferative, less polyploid and show leaky expression of erythroid genes. Their distinctive properties contribute to multiple disease states including neonatal thrombocytopenia, poor platelet recovery post umbilical cord blood (CB) transplantation, and acute Mk leukemias (AMkL). Their leukemic propensity is highlighted by the capacity of the AMkL oncoprotein GATA1s to transform infantile but not adult Mk. Despite their altered morphogenesis, infantile megakaryocytes retain most features of the adult differentiation and signaling program. Their principal signaling perturbation has been characterized as excessive responsiveness to thrombopoietin (Tpo) particularly with regard to the mTOR pathway. Thus Tpo agonists used to treat adult thrombocytopenia may not offer appropriate therapy for neonatal thrombocytopenia. We previously identified a signaling pathway that drives megakaryocyte morphogenesis and is disrupted by the GATA1s oncoprotein in AMkL (Elagib et al., Dev. Cell, 2013). A central feature of this pathway is the irreversible activation of the P-TEFb kinase (Cdk9/Cyclin T). This cascade is initiated by downregulation of core components of the repressive 7SK snRNP complex (MePCE, LARP7, 7SK snRNA). The resulting constitutive P-TEFb activation drives multiple features of Mk differentiation: induction of cytoskeletal morpho-genetic factors, silencing of erythroid genes, and promotion of histone H2B K120 monoubiquitiniation (H2BUb1). A critical, rate-limiting step triggering this pathway comprises MePCE proteolysis by calpain 2. GATA1s disrupts this pathway by preventing induction of calpain 2 by wild type GATA1. We now report that infantile Mk display intrinsic defects in the Mk P-TEFb activation pathway. In repeated experiments, human CB Mk failed to upregulate P-TEFb-dependent cytoskeletal factors, exhibited global deficiency in H2BUb1, and incompletely silenced erythroid antigen expression. Their defective P-TEFb activation resulted from an inability to downregulate 7SK snRNA, despite downregulation of the key 7SK stabilizers MePCE and LARP7. The inexplicable stabilization of 7SK in CB Mk argues for the existence of an alternative, infantile 7SK snRNP complex refractory to activation by calpain. Accordingly, screening studies identified candidate 7SK binding factors preferentially expressed in CB as opposed to adult progenitors. Among these factors, the RNA binding protein IGF2BP3 showed high abundance in CB Mk but complete absence from adult peripheral blood-derived (PB) Mk. Furthermore, immunoprecipitation studies consistently showed interaction of endogenous IGF2BP3 and HEXIM1 in K562 cells. HEXIM1 is the 7SK snRNP component that mediates repression of P-TEFb. Immunoprecipitation of epitope-tagged IGF2BP3 from HEK293 cells consistently identified an association with endogenous 7SK snRNA. In addition, enforced expression of IGF2BP3 in HEK293 cells, to levels seen in CB Mk, shifted the fractionation pattern of HEXIM1 on glycerol gradient sedimentation. Notably, a similar difference in HEXIM1 fractionation was seen when comparing CB and adult Mk by glycerol gradient sedimentation. Thus, IGF2BP3 represents a fetal/neonatal factor that reconfigures the composition and/or conformation of the 7SK snRNP, potentially altering regulation of P-TEFb. Contribution of IGF2BP3 to the infantile Mk phenotype was supported by experiments in which shRNA-mediated knockdown in CB Mk consistently enhanced enlargement, polyploidization, growth arrest, and erythroid silencing. Conversely, enforced expression of IGF2BP3 in adult Mk inhibited their enlargement, polyploidization, and growth arrest. Our results thus implicate IGF2BP3 as a key contributor to the infantile Mk phenotype, interfering with morphogenesis by stabilizing 7SK and thwarting irreversible P-TEFb activation. In light of our prior published results on the inhibitory effects of GATA1s in Mk morphogenesis (Elagib et al., Dev. Cell, 2013), our current findings highlight P-TEFb regulation as a convergence point for oncogenic stimuli during megakaryopoiesis. Disclosures No relevant conflicts of interest to declare.

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Christiansen, Jan, Astrid M. Kolte, Thomas v. O. Hansen i Finn C. Nielsen. "IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes". Journal of Molecular Endocrinology 43, nr 5 (8.05.2009): 187–95. http://dx.doi.org/10.1677/jme-09-0016.

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Recent genome-wide association (GWA) studies of type 2 diabetes (T2D) have implicated IGF2 mRNA-binding protein 2 (IMP2/IGF2BP2) as one of the several factors in the etiology of late onset diabetes. IMP2 belongs to a family of oncofetal mRNA-binding proteins implicated in RNA localization, stability, and translation that are essential for normal embryonic growth and development. This review provides a background to the IMP protein family with an emphasis on human IMP2, followed by a closer look at the GWA studies to evaluate the significance, if any, of the proposed correlation between IMP2 and T2D.

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Tuo, Hu, Baozhen Yao, Bing He, Shiqian Yu, Danni Li, Wenjing Li i Lin Jin. "Silence of Insulin-Like Growth Factor 2 mRNA-Binding Protein 1 Prevents Vascular Smooth Muscle Cells Proliferation via Nuclear Factor of Activated T Cells Isoform-3/Ca2+/Calmodulin Pathway". Journal of Biomaterials and Tissue Engineering 11, nr 4 (1.04.2021): 704–10. http://dx.doi.org/10.1166/jbt.2021.2747.

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Increased proliferation of vascular smooth muscle cells (VSMCs) contributes to the pathogenesis of atherosclerosis (AS), and the insulin like growth factor 2 (IGF2) is involved in AS through effects on VSMCs growth and migration. The IGF2 mRNA-binding protein 1(IGF2BP1) is a secreted protein that can bind to IGF2 and regulate its localization, however, whether IGF2BP1 could regulate VSMCs proliferation remains to be elucidated. This study aimed to investigate the role of IGF2BP1 in VSMCs proliferation and uncover the potential mechanism. Primary human aortic VSMCs that transfected with or without shRNA-IGF2BP1 were stimulated by platelet-derived growth factor-BB (PDGF-BB), and then cell proliferation, intracellular Ca2+ level, cell apoptosis and the expression of IGF2BP1, calmodulin (CaM) and cell cycle-related proteins were detected. RNA pull down assay was used to determine the interaction between IGF2BP1 and nuclear factor of activated T cells isoform-3 (NFATc3). We found that PDGF-BB promoted cell proliferation and enhanced IGF2BP1 protein expression in a concentration-dependent manner. The 10 μg/L PDGF-BB significantly increased intracellular Ca2+ level, NFATc3, CaM and calcineurin A protein expression, TUNEL-positive cells, and the expression of cell cycle-related proteins cyclin D1/E1/B1. However, knockdown of IGF2BP1 significantly blunted all these effects induced by PDGF-BB. In addition, IGF2BP1 could bind to NFATc3 RNA. Collectively, knockdown of IGF2BP1 could inhibit PDGFBB- induced VSMCs proliferation via targeting NFATc3/Ca2+/calmodulin pathway and disturbing the effect of NFATc3/ on cell cycle.

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Bell, Jessica L., Raseswari Turlapati, Tao Liu, Johannes H. Schulte i Stefan Hüttelmaier. "IGF2BP1 Harbors Prognostic Significance by Gene Gain and Diverse Expression in Neuroblastoma". Journal of Clinical Oncology 33, nr 11 (10.04.2015): 1285–93. http://dx.doi.org/10.1200/jco.2014.55.9880.

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Purpose Chromosomal 17q21-ter gain in neuroblastoma is both a common and prognostically significant event. The insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) gene is located near the proximal edge of this region. Here, its prognostic value is evaluated in neuroblastoma. Methods The mRNA expression of IGF2BP family members was first evaluated by microarray data sets. In addition, in a separate cohort of 69 tumors, IGF2BP1 gene copy number, mRNA, and protein abundance were determined and compared with clinical parameters. Results In two independent microarray data sets, 77% to 100% of tumors had substantial IGF2BP1 mRNA levels measured. High IGF2BP1 transcript abundance was significantly associated with stage 4 tumors (P < .001) and decreased patient survival (P < .001). IGF2BP1 was also associated with MYCN gene amplification and MYCN mRNA abundance. In the 69 neuroblastoma samples, IGF2BP1 DNA copy number (increased in 84% of tumors), mRNA, and protein abundance were significantly higher in stage 4 compared with stage 1 tumors. Importantly, IGF2BP1 protein levels were associated with lower overall patient survival (P = .012) and positively correlated with MYCN mRNA, even when excluding MYCN-amplified tumors. Moreover, IGF2BP1 clearly affected MYCN expression and neuroblastoma cell survival in vitro. Conclusion In neuroblastoma, IGF2BP1 was expressed in the majority of neuroblastoma specimens analyzed and was associated with lower overall patient survival and MYCN abundance. These data demonstrate that IGF2BP1 is a potential oncogene and an independent negative prognostic factor in neuroblastoma.

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Falih, Zubaida, Bayadir Ali Wannas Khodair, Noaman Ibadi Mohammed i Tahseen Kadhem Mohammed. "Insulin-like Growth Factor-2 Binding Protein-2 Gene Polymorphisms in Iraqi Patients with Type 2 Diabetes Mellitus". Open Access Macedonian Journal of Medical Sciences 10, A (21.05.2022): 1178–83. http://dx.doi.org/10.3889/oamjms.2022.9754.

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Background: Diabetes mellitus type2 (T2DM) represent a hyperglycemia causing metabolic disease which exists in the peripheral tissues due to incomplete pancreatic insulin secretion or insulin resistance. IGF2BP2 is a protein that is involved in embryogenesis and pancreatic development. Genetic association researches had suggested that the single nucleotide polymorphisms (SNP) spanning IGF2BP2 gene are associated with the progression as well as development of the T2DM. Aim: This study aims to evaluate the association of IGF2BP2 gene polymorphisms (rs4402960 & rs1470579) with T2DM in a sample of Iraqi individuals. Methods: A case-control study has been conducted on 800 participants, they were divided to two equal groups, which are a healthy control group (400) and type 2 diabetic patients (400). Fast blood sugar (FBS), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and HbA1c] measured suitable for both participant groups. IGF2BP2 gene has been genotyped for polymorphisms; rs4402960 and rs1470579 by using the PCR-RFLP technique. Results: There is significant changes in the biochemical parameters in patients group when compared to the control group.The SNP rs4402960 show minor allele frequency of T allele considerably different between the two participating groups (p 0.0013) with 33.6 % in T2DM group. Homo-variant TT shows a significant p <0.0001) odd ratio (4.5) as codominant type. Similarly, dominant and recessive models exert significant (0.02 & <0.0001 respectively) adjusted odd ratio (1.45 & 4.14 respectively). The rs1470579 SNP show a significant (0.024) risk (1.28) of C allele in the patients group than in A allele. The CC genotype in codominant and recessive models show significant (0.03) odd ratio differences (2.03 & 1.96 respectively. The rs1470579 SNP exerts significant differences as codominant model in biochemical features of BMI, FBG, Tgs, VLDL-C, insulin and HOMA-IR. The study power of rs4402960 is 69.5% and rs1470579 is 34.1%. Conclusion: This study confirmed the association of rs4402960 as codominant, dominant and recessive with T2DM significantly. However, rs1470579 is associate as recessive model with T2DM in Iraqi population.

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Hack, Theresa, Stefanie Bertram, Guntram Büsche, Helmut Hanenberg, Ludger Klein-Hitpass, Nils Von Neuhoff, Dirk Reinhardt, Markus Schneider i Mareike Rasche. "Induction of a Leukemic Bone Marrow Niche Mediated By TGFB1 of Leukemic Blasts in Pediatric Acute Mekaryoblastic Leukemia: Results of an in Vitro and In Vivo Analysis". Blood 134, Supplement_1 (13.11.2019): 3734. http://dx.doi.org/10.1182/blood-2019-126536.

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Background: An increasing knowledge about the bone marrow niche demonstrates the high complexity of leukemogenesis. Mesenchymal stromal cells (MSC) are important members of the bone marrow niche and source of fibrosis. Further, the microenvironment seems to be regulated by megakaryocytes and platelets via cytokines, such as transforming growth factor beta 1 (TGFB1). Despite extensive research, the pathogenesis of the bone marrow niche in childhood leukemia and the therapeutic potential is still unclear. We focus on acute childhood megakaryoblastic leukemia (AMKL) as a disease model and include patients with (ML-DS) and without Down syndrome. Based on similar clinical progressions - myelofibrosis occurs as a side-effect of both leukemia subtypes; these two diseases suit to characterize the leukemic bone marrow niche. Methods: We performed a comprehensive characterisation of MSC from ML-DS (n=9), AMKL patients (n=5) and healthy donors (HD; n=6) via e.g. differentiation assays (adipogenic, osteogenic), gene expression profiles and western blot analysis. In addition, we established an in vivo model with humanized ossicles, representing a human bone marrow microenvironment (as described by Chen et al. 2012; Reinisch et al. 2015): We injected MSC mixed with pooled human umbilical vein endothelial cells (HUVEC) and Matrigel subcutaneously into NOD scid gamma (NSG) mice. After 8 weeks, the engrafted ossicles were injected with megakaryoblastic cells (CMK cell line); injected ossicles (n=16); uninjected ossicle (n=27), MSC from ML-DS (n=19 ossicles), AML M1 (n=15 ossicles) and HD (n=9 ossicles). After 4 more weeks, histopathology evaluation of fibrosis in the ossicles was performed in accordance with the European Consensus on Grading Bone Marrow criteria from an independent pathologist. Results: The detailed characterisation of MSC with ML-DS and AMKL demonstrated a high similarity to MSC of HD: morphology, osteogenic differentiation potential, colony forming unit-fibroblast assay, proliferation and gene expression profiles. However, two differences emerged in our analysis: MSC showed a decreased adipogenic differentiation potential in ML-DS and AMKL compared to HD (ML-DS vs. HD=0.26-fold, p<0.05; AMKL vs. HD=0.50-fold). Gene expression profiling identified an upregulation of IGF2BP3, an oncofetal RNA binding protein, in MSC of ML-DS compared to HD confirmed by qRT-PCR (2.6-fold, p<0.05). IGF2BP3 is known to be highly expressed in many cancers and seems to be associated with proliferation. The increased level of IGF2BP3 (protein: IF2B3) was confirmed at protein-level detected by western blot analysis (ML-DS vs HD: 37.3-fold, p<0.05 and AMKL-MSC vs HD: 13.1-fold, p<0.05). TGFB1 - known to be secreted by leukemic megakaryoblasts - induced a fibrotic state in MSC regardless of their origin indicated by decreased adipogenic differentiation potential (treated vs. untreated: ML-DS 0.22-fold; AMKL 0.08-fold; HD 0.06-fold, p<0.05) and increased expression of collagen genes (qRT-PCR; COL1A1: ML-DS=1.63-fold, AMKL=1.80-fold (p<0.01), HD=1.66-fold (p<0.05); COL3A1: ML-DS=1.31-fold, AMKL=1.52-fold (p<0.05), HD=1.24-fold). The humanized bone marrow niche in our mouse model demonstrated a development of myelofibrosis after injection of the megakaryoblastic cell line (CMK): Grade 1 or 2 in 81% of the ossicles. The induction was independent of the MSC entity (HD/ML-DS). Of note, a monocytic subpopulation, which engrafted unexpectedly in ossicle from HD-MSC (n=3 ossicle), did not induce fibrotic fibers. Conclusion: Our data impressively illustrate the mutual influence between MSC and leukemic blasts that leads to a fibrotic microenvironment. This correlation has been observed in vitro but also in a unique mouse model. The interaction of MSC and leukemic blasts seems to be the key factor for the development of the leukemic niche in AMKL mediated inter alia by the TGFB pathway. However, we could identify several disease specific characteristics of MSC. Our model offers a unique opportunity to fundamentally examine of the leukemic niche in order to subsequently evaluate the potential therapeutic use in further studies. Disclosures Reinhardt: Novartis: Other: Participation in Advisory Boards; CSL Behring: Research Funding; Jazz: Other: Participation in Advisory Boards, Research Funding; Roche: Research Funding.

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Mancarella, Caterina, i Katia Scotlandi. "40 YEARS OF IGF1: IGF system in sarcomas: a crucial pathway with many unknowns to exploit for therapy". Journal of Molecular Endocrinology 61, nr 1 (lipiec 2018): T45—T60. http://dx.doi.org/10.1530/jme-17-0250.

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The insulin-like growth factor (IGF) system has gained substantial interest due to its involvement in regulating cell proliferation, differentiation and survival during anoikis and after conventional and targeted therapies. However, results from clinical trials have been largely disappointing, with only a few but notable exceptions, such as trials targeting sarcomas, especially Ewing sarcoma. This review highlights key studies focusing on IGF signaling in sarcomas, specifically studies underscoring the properties that make this system an attractive therapeutic target and identifies new relationships that may be exploited. This review discusses the potential roles of IGF2 mRNA-binding proteins (IGF2BPs), discoidin domain receptors (DDRs) and metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) in regulating the IGF system. Deeper investigation of these novel regulators of the IGF system may help us to further elucidate the spatial and temporal control of the IGF axis, as understanding the control of this axis is essential for future clinical studies.

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Elagib, Kamaleldin E., Ashton Brock, Goar Mosoyan, Cara Clementelli, Lorrie L. Delehanty, Alexandra Pacheco-Benichou, Corinne Fruit i in. "Harnessing a Novel Dyrk1a-Ablim2-MKL1 Regulatory Module in Megakaryocyte Morphogenesis to Enable Scalable Platelet "Pharming"". Blood 134, Supplement_1 (13.11.2019): 3250. http://dx.doi.org/10.1182/blood-2019-129049.

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Growing clinical demands for platelet transfusions combined with supply limitations have created shortages which are trending toward a global crisis. Major efforts have been taken to address key issues of platelet sources, storage, and utilization. Recent progress in ex vivo culture-based production of megakaryocytes (Mk) and platelets, "pharming," has highlighted the potential for novel, donor-independent sources amenable to antigenic editing and cryo-stockpiling. Such cultures can be easily initiated from umbilical cord blood (CB) progenitors, induced pluripotent stem cells (iPSC), or directly re-programmed somatic cells. The major roadblock associated with these Mk sources consists of their fetal ontogenic status, which is beneficial for expansion but severely limits platelet production. The ability to elicit in pre-expanded Mk an adult program of morphogenesis (polyploidization, enlargement, and proplatelet formation) would enable circumvention of this scalability barrier. A master regulator of adult Mk morphogenesis consists of the transcriptional coactivator MKL1 which undergoes nuclear translocation in response to RhoA-mediated actin polymerization, stimulated by thrombopoietin and environmental mechano-sensing. Nuclear MKL1 associates with the transcription factor SRF1 to upregulate cytoskeletal remodeling factors, including filamin A and Hic-5, that act as morphogenesis effectors. Our previous studies identified in infantile CB Mk a failure in MKL1 upregulation resulting from repression by the oncofetal RNA-binding factor IGF2BP3. Pharmacologic suppression of IGF2BP3 with BET inhibitors rescued MKL1 expression and improved platelet production but caused cycle arrest preventing polyploidization. As an alternative approach to abrogate the fetal blockade in Mk morphogenesis, we sought to promote MKL1 activity by targeting a kinase, Dyrk1a, which had been shown to restrain MKL1 from nuclear translocation. Treatment of infantile CB Mk with a variety of Dyrk1-selective inhibitors including harmine and EHT 1610 strongly enhanced polyploidization (p = 0.015 and 0.009 respectively), enlargement (p < 0.005) , and in vitro platelet release (2 fold each, p = 0.001 and 0.007 respectively), attaining levels seen with adult Mk. When xenotransplanted into NSG mice, harmine-treated CB Mk demonstrated enhanced capability for in vivo platelet release (about 5 fold, p = 0.016). CB stem cells expanded with the AHR antagonist SR1 and an iPSC-Mk cell line also responded to Dyrk1 inhibition with robustly increased morphogenesis. Several findings implicated MKL1 in this response: 1) induction of nuclear translocation by the inhibitors, 2) induction of target genes (filamin A and Hic-5) by the inhibitors, and 3) loss of response to inhibitors in Mkl1-ko murine progenitors. Supporting Dyrk1a as a relevant target, mice with Mk-specific loss of one Dyrk1a allele (Dyrk1aflox/wt;Pf4-Cre) displayed increases in platelet counts (p = 0.037) and marrow Mk polyploidization (p = 0.02). In addition, retroviral expression in human progenitors of a dominant negative Dyrk1a mutant K188R promoted Mk enlargement (p = 0.014). shRNA knockdowns could not be obtained due to toxicity of > ~60% loss of Dyrk1a. To determine mechanisms for Dyrk1a control of morphogenesis, we analyzed the actin cytoskeleton, a key regulator of MKL1. Dyrk1 inhibition in all types of Mk progenitors (adult, infantile, and iPSC) induced assembly of cortical filamentous actin (F-actin), as detected by Alexa594-phalloidin staining. Prior studies showed cytoskeletal binding by Dyrk1a and direct phosphorylation of F-actin regulators N-WASP and Ablim1. A survey of human marrow expression patterns for candidate Dyrk1a substrates (The Human Protein Atlas) identified Ablim2, as showing a Mk-specific, cortical staining pattern. Dyrk1 inhibition increased Ablim2 levels ~5-fold in CB Mk (p < 0.005), and immunofluorescence displayed a cortical distribution similar to F-actin. Lentiviral shRNA knockdown of Ablim2 abrogated all effects of Dyrk1 inhibition, blocking: F-actin formation, MKL1 nuclear translocation, activation of the MKL1 targets, and Mk morphogenesis. These findings thus delineate a novel Dyrk1a-Ablim2-MKL1 regulatory module in Mk morphogenesis that can be manipulated to address the problem of scaling ex vivo production and might also serve as a future in vivo therapeutic target for thrombocytopenia. Disclosures Eto: Megakaryon Co. Ltd.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Tangprasittipap, Amornrat, Pavita Kaewprommal, Orapan Sripichai, Nuankanya Sathirapongsasuti, Chonthicha Satirapod, Philip J. Shaw, Jittima Piriyapongsa i Suradej Hongeng. "Comparison of gene expression profiles between human erythroid cells derived from fetal liver and adult peripheral blood". PeerJ 6 (31.08.2018): e5527. http://dx.doi.org/10.7717/peerj.5527.

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BackgroundA key event in human development is the establishment of erythropoietic progenitors in the bone marrow, which is accompanied by a fetal-to-adult switch in hemoglobin expression. Understanding of this event could lead to medical application, notably treatment of sickle cell disease andβ-thalassemia. The changes in gene expression of erythropoietic progenitor cells as they migrate from the fetal liver and colonize the bone marrow are still rather poorly understood, as primary fetal liver (FL) tissues are difficult to obtain.MethodsWe obtained human FL tissue and adult peripheral blood (AB) samples from Thai subjects. Primary CD34+cells were culturedin vitroin a fetal bovine serum-based culture medium. After 8 days of culture, erythroid cell populations were isolated by flow cytometry. Gene expression in the FL- and AB-derived cells was studied by Affymetrix microarray and reverse-transcription quantitative PCR. The microarray data were combined with that from a previous study of human FL and AB erythroid development, and meta-analysis was performed on the combined dataset.ResultsFL erythroid cells showed enhanced proliferation and elevated fetal hemoglobin relative to AB cells. A total of 1,391 fetal up-regulated and 329 adult up-regulated genes were identified from microarray data generated in this study. Five hundred ninety-nine fetal up-regulated and 284 adult up-regulated genes with reproducible patterns between this and a previous study were identified by meta-analysis of the combined dataset, which constitute a core set of genes differentially expressed between FL and AB erythroid cells. In addition to these core genes, 826 and 48 novel genes were identified only from data generated in this study to be FL up- and AB up-regulated, respectively. Thein vivorelevance for some of these novel genes was demonstrated by pathway analysis, which showed novel genes functioning in pathways known to be important in proliferation and erythropoiesis, including the mitogen-activated protein kinase (MAPK) and the phosphatidyl inositol 3 kinase (PI3K)-Akt pathways.DiscussionThe genes with upregulated expression in FL cells, which include many novel genes identified from data generated in this study, suggest that cellular proliferation pathways are more active in the fetal stage. Erythroid progenitor cells may thus undergo a reprogramming during ontogenesis in which proliferation is modulated by changes in expression of key regulators, primarily MYC, and others including insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), neuropilin and tolloid-like 2 (NETO2), branched chain amino acid transaminase 1 (BCAT1), tenascin XB (TNXB) and proto-oncogene, AP-1 transcription factor subunit (JUND). This reprogramming may thus be necessary for acquisition of the adult identity and switching of hemoglobin expression.

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Ballard, F. J., M. Ross, F. M. Upton i G. L. Francis. "Specific binding of insulin-like growth factors 1 and 2 to the type 1 and type 2 receptors respectively". Biochemical Journal 249, nr 3 (1.02.1988): 721–26. http://dx.doi.org/10.1042/bj2490721.

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1. Competitive binding and receptor cross-linking experiments have been used to examine the receptor-ligand interactions between three bovine insulin-like growth factors (IGF) and monolayer cultures of myoblasts and fibroblasts. 2. Labelled IGF-2 bound predominantly to the type 2 receptor with negligible label cross-linked to the type 1 receptor, notwithstanding the ability of IGF-2 to compete effectively for the binding of IGF-1 to the type 1 receptor. Approx. 100-fold higher concentrations of IGF-1 or the N-terminal truncated (des-Gly-Pro-Glu) IGF-1 (-3N:IGF-1) were required to produce competition equivalent to IGF-2. 3. All IGF peptides, but especially IGF-1, enhanced the binding of labelled IGF-2 to the type 2 receptor of lung fibroblasts. This unusual effect was probably a consequence of the displacement of labelled IGF-2 otherwise bound to a medium protein, a conclusion supported by the demonstration of a 38 kDa membrane protein cross-linked to labelled IGF-2. 4. Both IGF-1 and -3N:IGF-1 bound only to the type 1 IGF receptor in L6 myoblasts, rat vascular smooth-muscle cells and human lung fibroblasts. The peptides competed for labelled IGF-1 binding with potencies in the order -3N:IGF-1 greater than IGF-1 greater than IGF-2 much greater than insulin. Since the IGF peptides were equipotent in skin fibroblasts, it was proposed that the apparently higher affinity of -3N:IGF-1 for receptors in the other cell types was instead a consequence of a low affinity of this peptide for the competing 38 kDa binding protein.

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de Vasconcellos, Jaira F., Y. Terry Lee, Colleen Byrnes, Benjamin A. Clarke, Pauline C. Xu, Antoinette Rabel, Richard L. Proia i Jeffery L. Miller. "IGF2BP1 Protein Binding of Erythroblast Transcription Factor mRNA: A Cytoplasm-Localized Mechanism for Globin Gene Regulation". Blood 128, nr 22 (2.12.2016): 1009. http://dx.doi.org/10.1182/blood.v128.22.1009.1009.

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Abstract Pharmacologic and genetic regulation of fetal hemoglobin (HbF) remains a major goal for treatment of the beta-thalassemias and sickle cell disease. Recently, the let-7 microRNA heterochronic pathway of RNA-binding factors was shown to be developmentally correlated with HbF expression in humans. Experimental manipulation of the pathway components (LIN28, let-7, and the IGF2 binding proteins) demonstrated moderate increases in fetal hemoglobin (around 15-35% HbF) with the exception of IGF2BP1, which caused a nearly complete reversal in gamma- and beta-globin gene expression resulting in HbF levels of 60-70% among cultured adult human erythrocytes. To further explore IGF2BP1 effects on HbF and erythropoiesis, lentiviral transduction of CD34(+) cells was performed with let-7 resistant expression of IGF2BP1 driven by the human SPTA1 gene (IGF2BP1-OE). Donor-matched control transductions were studied for comparison. For protein localization studies, confocal imaging of sorted cells was utilized. IGF2BP1-OE caused IGF2BP1 protein expression throughout the cytoplasm and localized to small granules. Granules were unevenly distributed and more abundantly observed in the perinuclear regions. Nuclear detection of IGF2BP1 protein remained at background control levels. We thus hypothesized that IGF2BP1 protein in these cytoplasmic granules may regulate globin gene expression by binding RNAs that encode epigenetic modifiers of the beta-globin locus. To test this hypothesis, RNA-immunoprecipitation (RIP) was performed using a RIP-certified anti-IGF2BP1 antibody. Next generation sequencing and qRT-PCR were used to determine the mRNA species bound by IGF2BP1. RIP-enrichment of BCL11A mRNA was identified (4.6 ± 1.2 fold compared to input sample), as well as mRNA encoding other modifiers of globin gene expression including KLF1 and ZBTB7A. Further analyses of BCL11A showed no significant changes in BCL11A mRNA levels among IGF2BP1-OE cells (control: 6.5.E+03 ± 3.8.E+03, IGF2BP1-OE: 4.1.E+03 ± 1.2.E+02, p=0.403). However, BCL11A protein detection was reduced to background levels by Western analysis compared to transduction control cell lysates. These studies suggest that RNA-binding and cytoplasmic compartmentalization provide IGF2BP1 with a mechanism for increasing fetal hemoglobin via post-transcriptional regulation of globin gene transcription factors. Disclosures No relevant conflicts of interest to declare.

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Ouyang, Jun, Junqing Li, Dongwei Li, Jianlong Jiang, Tengfei Hao, Yujian Xia, Xiaofang Lu, Changhua Zhang i Yulong He. "IGF2BP2 Promotes Epithelial to Mesenchymal Transition and Metastasis through Stabilizing HMGA1 mRNA in Gastric Cancer". Cancers 14, nr 21 (31.10.2022): 5381. http://dx.doi.org/10.3390/cancers14215381.

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As an RNA-binding protein, insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is involved in enhancing the progression of a few malignant tumors by recognizing N6-methyladenosine on targeted RNA. However, the specific effects of IGF2BP2 on gastric cancer (GC) and the underlying mechanisms remain unclear. In this study, the expression level of IGF2BP2 was evaluated by analyzing data from a public database and performing immunohistochemical staining with GC specimens. The effect of IGF2BP2 on GC cell metastasis was investigated by Transwell assays and animal studies. RNA immunoprecipitation (RIP) was performed to identify potential mRNA bound to IGF2BP2. The levels of these identified RNAs were measured by RT-PCR, while corresponding proteins were quantified via Western blot. It was revealed that IGF2BP2 expression in GC tissues was significantly upregulated, and its overexpression was significantly associated with worse survival in GC patients. The aberrant expression of IGF2BP2 was demonstrated to promote the invasion and metastasis of GC cells by both in vivo and in vitro experiments. In subsequent experiments, it was then verified that by directly interacting with HMGA1 mRNA, IGF2BP2 augmented its stability and thus increased its expression. The knocking down of IGF2BP2 could significantly decrease the migration and invasion of GC cells, which could be reversed by increasing HMGA1 expression. Additionally, both in vitro and in vivo epithelial–mesenchymal transition (EMT) of GC cells were enhanced by IGF2BP2/HMGA1 axis. In conclusion, it was proven in our study that the IGF2BP2/HMGA1/EMT axis contributed to GC metastasis, suggesting its potential as a novel predictive and therapeutic biomarker for GC.

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Chen, Hung-Ming, Chun-Chi Lin, Wei-Shone Chen, Jeng-Kai Jiang, Shung-Haur Yang, Shih-Ching Chang, Ching-Liang Ho i in. "Insulin-Like Growth Factor 2 mRNA-Binding Protein 1 (IGF2BP1) Is a Prognostic Biomarker and Associated with Chemotherapy Responsiveness in Colorectal Cancer". International Journal of Molecular Sciences 22, nr 13 (28.06.2021): 6940. http://dx.doi.org/10.3390/ijms22136940.

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Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an RNA-binding protein and serves as a post-transcriptional fine-tuner regulating the expression of mRNA targets. However, the clinicopathological roles of IGF2BP1 in colorectal cancer (CRC) remains limited. Thus, we aimed to elucidate the clinical significance and biomarker potentials of IGF2BP1 in CRC. A total of 266 specimens from two sets of CRC patients were collected. IGF2BP1 expression was studied by immunohistochemical (IHC) staining. The Kaplan-Meier survival plot and a log-rank test were used for survival analysis. The Cox proportional hazards model was applied to determine the survival impact of IGF2BP1. Public datasets sets from The Cancer Genome Atlas (TCGA) and Human Cancer Metastasis Database (HCMDB), receiver operating characteristic (ROC) plotter, and two CRC cell lines, HCT-116 and DLD-1, were used for validating our findings. We showed that IGF2BP1 was overexpressed in tumor specimens compared to 13 paired normal parts by examining the immunoreactivity of IGF2BP1 (p = 0.045). The increased expression of IGF2BP1 in primary tumor parts was observed regardless of metastatic status (p < 0.001) in HCMDB analysis. IGF2BP1 expression was significantly associated with young age (59.6% vs. 46.7%, p-value = 0.043) and advanced stage (61.3% vs. 40.0%, p-value = 0.001). After controlling for confounding factors, IGF2BP1 remained an independent prognostic factor (HR = 1.705, p-value = 0.005). TCGA datasets analysis indicated that high IGF2BP1 expression showed a lower 5-year survival rate (58% vs. 65%) in CRC patients. The increased expression of IGF2BP1 in chemotherapy non-responder rectal cancer patients was observed using a ROC plotter. Overexpression of IGF2BP1 promoted the colony-forming capacity and 5-fluorouracil and etoposide resistance in CRC cells. Here, IGF2BP1 was an independent poor prognostic marker in CRC patients and contributed to aggressive phenotypes in CRC cell lines.

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Neely, E. Kirk, Stephen D. Smith i Ron G. Rosenfeld. "Human leukemic T and B lymphoblasts produce insulin-like growth factor binding proteins 2 and 4". Acta Endocrinologica 124, nr 6 (czerwiec 1991): 707–14. http://dx.doi.org/10.1530/acta.0.1240707.

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Abstract. The production of insulin-like growth factors and insulin-like growth factor binding proteins by twelve human leukemic lymphoblast cell lines was evaluated by radioimmunoassay, affinity cross-linking, ligand blot, and immunoprecipitation of conditioned media. In all cell lines, detectable IGF-I and IGF-II levels were <0.1 μg/l and <0.3 μg/l, respectively. IGF binding proteins were identified in 6/12 of the lymphoblast cell lines studied. A pair of IGF binding proteins at 31 and 33 kD, immunoprecipitated with an antibody recognizing IGF binding protein 2 but not by an IGF binding protein 3 antibody, was produced by both T and B cells. A 24 kD IGF binding protein, presumably IGF binding protein 4, since it was not recognized by the antibodies for IGF binding proteins 1, 2, and 3, was produced by B cell precursor cells and faintly by one T cell line. These IGF binding proteins were not altered by deglycosylation. Neither IGF binding protein 1 nor IGF binding protein 3 was identified in any of the conditioned media. We speculate that local production of IGF binding proteins 2 and 4 regulates access of the IGFs to lymphoblasts and to hematopoietic precursors in general.

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Glaß, Markus, Patrick Michl i Stefan Hüttelmaier. "RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma". International Journal of Molecular Sciences 21, nr 11 (11.06.2020): 4190. http://dx.doi.org/10.3390/ijms21114190.

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Pancreatic ductal adenocarcinomas (PDAC) belong to the most frequent and most deadly malignancies in the western world. Mutations in KRAS and TP53 along with some other frequent polymorphisms occur almost universally and are likely to be responsible for tumor initiation. However, these mutations cannot explain the heterogeneity in therapeutic responses observed in PDAC patients, which limits efficiency of current therapeutic strategies. Instead, recent classifications of PDAC tumor samples are based on transcriptomics data and thus include information about epigenetic, transcriptomic, and post-transcriptomic deregulations. RNA binding proteins (RBPs) are important post-transcriptional regulators involved in every aspect of the RNA life cycle and thus considerably influence the transcriptome. In this study, we systematically investigated deregulated expression, prognostic value, and essentiality reported for RBPs in PDAC or PDAC cancer models using publicly available data. We identified 44 RBPs with suggested oncogenic potential. These include various proteins, e.g., IGF2 mRNA binding proteins (IGF2BPs), with reported tumor-promoting roles. We further characterized these RBPs and found common patterns regarding their expression, interaction, and regulation by microRNAs. These analyses suggest four prime candidate oncogenic RBPs with partially validated target potential: APOBEC1, IGF2BP1 and 3, and OASL.

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Simon, Yvette, Sonja M. Kessler, Rainer M. Bohle, Johannes Haybaeck i Alexandra K. Kiemer. "The insulin-like growth factor 2 (IGF2) mRNA-binding protein p62/IGF2BP2-2 as a promoter of NAFLD and HCC?" Gut 63, nr 5 (30.10.2013): 861–63. http://dx.doi.org/10.1136/gutjnl-2013-305736.

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Sánchez-Sendra, Beatriz, Silvia Pérez-Debén, José F. González-Muñoz, Amelia Murgui i Carlos Monteagudo. "Prognostic Value of IGF2 mRNA-Binding Protein 3 (IGF2BP3) Intratumoral Expression in Melanoma Patients at the Time of Diagnosis: Comparative Analysis of RT-qPCR Versus Immunohistochemistry". Cancers 14, nr 9 (7.05.2022): 2319. http://dx.doi.org/10.3390/cancers14092319.

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Screening for prognostic biomarkers is crucial for clinical melanoma management. Insulin-like growth factor-II mRNA-binding protein 3 (IGF2BP3) has emerged as a potential melanoma diagnostic and prognostic biomarker. It is commonly tested by immunohistochemistry (IHC). Our study retrospectively examines IGF2BP3 mRNA and protein expression in primary melanomas, their correlation with clinicopathologic factors, clinical outcome, and selected miRNAs expression, and their efficiency in predicting melanoma progression and survival. RT-qPCR and IHC on IGF2BP3 expression were performed in 61 cryopreserved and 63 formalin-fixed paraffin-embedded primary melanomas, respectively, and correlated to clinicopathologic factors, distant metastasis-free survival (DMFS), and melanoma -specific survival (MSS). The correlation between RT-qPCR and IHC was significant but moderate. IGF2BP3 mRNA showed a stronger association with clinicopathologic factors (Breslow thickness, ulceration, mitosis rate, growth phase, development of metastasis, and melanoma-specific survival) than its protein counterpart. Interestingly, higher IGF2BP3 mRNA expression was detected in primary melanomas that further metastasized to distant sites and was an independent prognostic factor for the risk of unfavorable DMFS and MSS. RT-qPCR outperformed IHC in sensitivity and in predicting worse clinical outcomes. Therefore, RT-qPCR may successfully be implemented for routine IGF2BP3 assessing for the selection of melanoma patients with a higher risk of developing distant metastasis and dying of melanoma.

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Singh, Vikash, Chethana P. Gowda, Vishal Singh, Ashwinkumar S. Ganapathy, Dipti M. Karamchandani, Melanie A. Eshelman, Gregory S. Yochum, Prashant Nighot i Vladimir S. Spiegelman. "The mRNA-binding protein IGF2BP1 maintains intestinal barrier function by up-regulating occludin expression". Journal of Biological Chemistry 295, nr 25 (8.05.2020): 8602–12. http://dx.doi.org/10.1074/jbc.ac120.013646.

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Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an mRNA-binding protein that has an oncofetal pattern of expression. It is also expressed in intestinal tissue, suggesting that it has a possible role in intestinal homeostasis. To investigate this possibility, here we generated Villin CreERT2:Igf2bp1flox/flox mice, which enabled induction of an IGF2BP1 knockout specifically in intestinal epithelial cells (IECs) of adult mice. Using gut barrier and epithelial permeability assays and several biochemical approaches, we found that IGF2BP1 ablation in the adult intestinal epithelium causes mild active colitis and mild-to-moderate active enteritis. Moreover, the IGF2BP1 deletion aggravated dextran sodium sulfate–induced colitis. We also found that IGF2BP1 removal compromises barrier function of the intestinal epithelium, resulting from altered protein expression at tight junctions. Mechanistically, IGF2BP1 interacted with the mRNA of the tight-junction protein occludin (Ocln), stabilizing Ocln mRNA and inducing expression of occludin in IECs. Furthermore, ectopic occludin expression in IGF2BP1-knockdown cells restored barrier function. We conclude that IGF2BP1-dependent regulation of occludin expression is an important mechanism in intestinal barrier function maintenance and in the prevention of colitis.

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45

Ross, M., G. L. Francis, L. Szabo, J. C. Wallace i F. J. Ballard. "Insulin-like growth factor (IGF)-binding proteins inhibit the biological activities of IGF-1 and IGF-2 but not des-(1-3)-IGF-1". Biochemical Journal 258, nr 1 (15.02.1989): 267–72. http://dx.doi.org/10.1042/bj2580267.

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(1) Many cell types secrete insulin-like growth factor (IGF)-binding proteins that can be expected to sequester free IGF and modify the biological activities of the growth factors. (2) A binding protein purified from bovine kidney (MDBK) cells potently inhibited the ability of IGF-2 to stimulate DNA synthesis or protein accumulation as well as to reduce rates of protein breakdown in chick embryo fibroblasts. The binding protein did not influence the biological activities of des-(1-3)-IGF-1, while effects on IGF-1 were intermediate. Since the chick embryo fibroblasts contain only the type 1 IGF receptor, the MDBK-cell binding protein must have reduced the accessibility of IGF-2 and IGF-1 to that receptor. Binding to the type 2 receptor on L6 myoblasts was also inhibited. (3) Inhibiting effects on both protein breakdown responsiveness to IGF and IGF binding to cell receptors were also observed with human amniotic fluid binding protein, although here IGF-1 and IGF-2 were equipotent. These results contrast with stimulatory responses on different IGF-1 actions of the same binding protein reported previously [Elgin, Busby & Clemmons (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 3254-3258]. (4) The biological potencies of IGF-1, IGF-2 and des-(1-3)-IGF-1 correlate inversely with their binding to proteins released into the medium by cells, so that the enhanced potency of des-(1-3)-IGF-1 is a consequence of it not binding to purified binding proteins or those released by cultured cells.

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46

Lund, Jacob, Mads T. Søndergaard, Cheryl A. Conover i Michael T. Overgaard. "Heparin-binding mechanism of the IGF2/IGF-binding protein 2 complex". Journal of Molecular Endocrinology 52, nr 3 (6.03.2014): 345–55. http://dx.doi.org/10.1530/jme-13-0184.

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IGF1 and IGF2 are potent stimulators of diverse cellular activities such as differentiation and mitosis. Six IGF-binding proteins (IGFBP1–IGFBP6) are primary regulators of IGF half-life and receptor availability. Generally, the binding of IGFBPs inhibits IGF receptor activation. However, it has been shown that IGFBP2 in complex with IGF2 (IGF2/IGFBP2) stimulates osteoblast function in vitro and increases skeletal mass in vivo. IGF2 binding to IGFBP2 greatly increases the affinity for 2- or 3-carbon O-sulfated glycosaminoglycans (GAGs), e.g. heparin and heparan sulfate, which is hypothesized to preferentially and specifically target the IGF2/IGFBP2 complex to the bone matrix. In order to obtain a more detailed understanding of the interactions between the IGF2/IGFBP2 complex and GAGs, we investigated heparin-binding properties of IGFBP2 and the IGF2/IGFBP2 complex in a quantitative manner. For this study, we mutated key positively charged residues within the two heparin-binding domains (HBDs) in IGFBP2 and in one potential HBD in IGF2. Using heparin affinity chromatography, we demonstrate that the two IGFBP2 HBDs contribute differentially to GAG binding in free IGFBP2 and the IGF2/IGFBP2 protein complex. Moreover, we identify a significant contribution from the HBD in IGF2 to the increased IGF2/IGFBP2 heparin affinity. Using molecular modeling, we present a novel model for the IGF2/IGFBP2 interaction with heparin where all three proposed HBDs constitute a positively charged and surface-exposed area that would serve to promote the increased heparin affinity of the complex compared with free intact IGFBP2.

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47

Glaß, Markus, i Stefan Hüttelmaier. "IGF2BP1—An Oncofetal RNA-Binding Protein Fuels Tumor Virus Propagation". Viruses 15, nr 7 (24.06.2023): 1431. http://dx.doi.org/10.3390/v15071431.

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The oncofetal RNA-binding protein IGF2BP1 has been reported to be a driver of tumor progression in a multitude of cancer entities. Its main function is the stabilization of target transcripts by shielding these from miRNA-mediated degradation. However, there is growing evidence that several virus species recruit IGF2BP1 to promote their propagation. In particular, tumor-promoting viruses, such as hepatitis B/C and human papillomaviruses, benefit from IGF2BP1. Moreover, recent evidence suggests that non-oncogenic viruses, such as SARS-CoV-2, also take advantage of IGF2BP1. The only virus inhibited by IGF2BP1 reported to date is HIV-1. This review summarizes the current knowledge about the interactions between IGF2BP1 and different virus species. It further recapitulates several findings by presenting analyses from publicly available high-throughput datasets.

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48

Braulke, T. "Type-2 IGF Receptor: A Multi-Ligand Binding Protein". Hormone and Metabolic Research 31, nr 02/03 (styczeń 1999): 242–46. http://dx.doi.org/10.1055/s-2007-978725.

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49

Ballard, F. J., L. C. Read, G. L. Francis, C. J. Bagley i J. C. Wallace. "Binding properties and biological potencies of insulin-like growth factors in L6 myoblasts". Biochemical Journal 233, nr 1 (1.01.1986): 223–30. http://dx.doi.org/10.1042/bj2330223.

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Protein synthesis in rat L6 myoblasts is stimulated and protein breakdown inhibited in a co-ordinate manner by insulin-like growth factors (IGF) or insulin. For both processes, bovine IGF-1 was somewhat more potent than human IGF-1, which was effective at a tenth the concentration of insulin, rat IGF-2 or human IGF-2. A similar order of potency is noted when DNA synthesis or protein accumulation is monitored over a 24 h period, but between 20- and 50-fold higher concentrations of each growth factor are required than those needed to produce effects in the 4 h protein-synthesis or -breakdown measurements. Binding experiments with labelled human or bovine IGF-1 as ligand demonstrated competition at concentrations of IGF-2, especially human IGF-2, lower than that of either IGF-1 preparation. This pattern was much more pronounced when the radioligand was either human IGF-2 or rat IGF-2. Insulin competed 10-15% for the binding of labelled IGF-1, but not at all with labelled IGF-2. Ligand-receptor cross-linking experiments showed that labelled bovine IGF-1 bound approximately equally to the type 1 IGF receptor (Mr 130000 after reduction) and to the type 2 IGF receptor (Mr 270000 after reduction), and that unlabelled IGF-1 competed equally with radioligand binding to both receptors. On the other hand, rat IGF-2 competed more effectively for binding to the type-2 receptor, and insulin competed only for binding to the type-1 receptor. Further cross-linking experiments with rat IGF-2 as radioligand demonstrated binding only to the type-2 receptor and to proteins with Mr values after reduction of 230000 and 200000. This binding was prevented by high rat IGF-2 concentrations, less effectively by bovine IGF-1 and not at all by insulin. The apparently conflicting biological potencies and receptor binding of the different growth factors can be explained if all the biological actions are mediated via the type-1 IGF receptor, rather than through the abundant type-2 receptor.

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Forbes, B., F. J. Ballard i J. C. Wallace. "An insulin-like growth factor-binding protein purified from medium conditioned by a human lung fibroblast cell line (He[39]L) has a novel N-terminal sequence". Journal of Endocrinology 126, nr 3 (wrzesień 1990): 497–506. http://dx.doi.org/10.1677/joe.0.1260497.

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ABSTRACT We have identified a novel insulin-like growth factor (IGF)-binding protein secreted into the culture medium of a human lung fibroblast cell line (He[39]L). This binding protein was purified by S-Sepharose cation exchange chromatography, IGF affinity chromatography and reverse-phase high-performance liquid chromatography. Analysis of the He[39]L-binding protein on silver-stained polyacrylamide gels and by ligand blotting showed that it had a molecular weight of 32 kDa under non-reducing conditions. In charcoal competition binding assays, IGF-II competed at lower concentrations than IGF-I for binding to the He[39]L-binding protein and the more potent form of IGF-I (des-(1–3)-IGF-I) was not bound. This is a similar IGF binding pattern to that of the bovine IGF-binding protein-2 (bIGFBP-2). However, immunoblotting with an antibody to bIGFBP-2 demonstrated that the He[39]L-binding protein is not immunochemically related to bIGFBP-2. It is a glycosylated protein, having N-acetyl-glucosaminyl sugars detected by wheatgerm agglutinin affinity chromatography. Of the first 15 N-terminal amino acids of the He[39]L-binding protein, 13 are identical to the 15 amino acid sequence of a recently sequenced cerebrospinal fluid-binding protein. However, the total He[39]L-binding protein sequence (25 amino acids) showed no homology to other previously sequenced binding proteins (IGFBP-1, IGFBP-2 and IGFBP-3). We conclude that the He[39]L-binding protein is a novel binding protein. Journal of Endocrinology (1990) 126, 497–506

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