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1
Kondo, Yukio, Eric Wieder, Sijie Lu, and Jeffrey Molldrem. "High Avidity Cyclin E1-Derived Peptide-Specific CTL Kill Lymphoid Leukemia Cells and Cross-Recognize a Homologous Cyclin E2-Derived Peptide." Blood 104, no. 11 (November 16, 2004): 4498. http://dx.doi.org/10.1182/blood.v104.11.4498.4498.
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Abstract Using a similar strategy that successfully identified PR1 as a leukemia-associated antigen (LAA), we identified two homologous HLA-A2-restricted peptides from cyclin E1 (CCNE1) and cyclin E2 (CCNE2) that could be used to elicit peptide-specific CTL from healthy donors in vitro. Two homologous nonameric peptides from CCNE1 (CCNE1144–152) and CCNE2 (CCNE2144–152), which differ by a single amino acid at position 7, have equal binding affinity for HLA-A2 and each elicited peptide-specific CTL with equal efficiency, as measured by specific lysis of T2 cells pulsed with either peptide (CCNE1 59.7% vs CCNE2 72.6% specific lysis, respectively, at E: T 10:1). TCR-Vβ spectratype analysis showed CCNE1-CTL clones to be derived from 3 Vβ families, while CCNE2-CTL clones were derived from a single Vβ family. The CCNE1-CTL and the CCNE2-CTL bound to each of the CCNE1/A2 and CCNE2/A2 tetramers, but staining intensity was greater for the CCNE1-CTL, suggesting greater TCR avidity of the CCNE1-CTL for both peptides. Because each clone cross-recognized the other homologous peptide, we hypothesized that each clone would efficiently kill leukemia that over-expressed either or both CCNE1 and CCNE2 proteins. FACsorted high avidity CTL showed higher specific lysis of peptide-pulsed T2 than did low avidity CTL (38.8% vs 31.9% specific lysis, respectively, at E: T 10:1, p = 0.02). The fluorescence decay of tetramer dissociation (ln (peptide/HLA-A2 tetramer)) over time was linear for each clone, suggesting that avidity was proportional to TCR affinity and tetramer dissociation t1/2 was determined based on first order kinetics. CCNE1-CTL had higher affinity for CCNE1144–152/HLA-A2 (CCNE1/A2, t1/2=84.5min; CCNE2/A2, t1/2=25.3min) and preferentially killed CCNE1144–152-pulsed T2 cells (CCNE1, 56.9% vs CCNE2, 38%, respectively, at E: T 10:1, p = 0.004). Interestingly, CCNE2-CTL also had higher TCR affinity for CCNE1144–152/HLA-A2 (CCNE1/A2, t1/2=29.5min; CCNE2/A2, t1/2=10.7min), but showed only slightly higher specific lysis of CCNE1144–152-pulsed T2 cells (CCNE1 = 49.3% vs CCNE2 = 44.2% specific lysis, respectively, at E: T 10:1, p = 0.33). Each clone specifically lysed HLA-A2+ T-ALL leukemia cells in proportion to both CCNE1 and CCNE2 protein overexpression assessed by Western blot (CCNE1-CTL, R2=0.89; CCNE2-CTL, R2=0.88). In contrast, healthy HLA-A2+ BM cells, which do not overexpress CCNE1 or CCNE2, and control HLA-A2− CML cells that overexpress both proteins, were not lysed. Both the high and low affinity clones showed equal lysis of T-ALL cells that expressed large amounts of each protein (specific lysis = 24.3% by CCNE1-CTL, vs lysis = 23.8% by CCNE2-CTL, at E: T 10:1). However, high affinity CCNE1-CTL killed T-ALL cells significantly better than low affinity CCNE2-CTL (16.8% vs 6.6% lysis, respectively, at E: T 10:1, p =0.02) when the T-ALL expressed a 2.5-fold lower amount of both CCNE1 and CCNE2 proteins. We conclude that the CCNE1 and CCNE2 homologous self-peptides are lymphoid leukemia-associated antigens. Furthermore, while the higher TCR affinity of CCNE1-CTL suggests that the CCNE1 peptide is the more dominant epitope, ultimate target susceptibility is enhanced due to degeneracy of the resulting CTL clones against homologous peptide epitopes.
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Sonntag, Roland, Nives Giebeler, Yulia A. Nevzorova, Jörg-Martin Bangen, Dirk Fahrenkamp, Daniela Lambertz, Ute Haas, et al. "Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma." Proceedings of the National Academy of Sciences 115, no. 37 (August 27, 2018): 9282–87. http://dx.doi.org/10.1073/pnas.1807155115.
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E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of cyclin-dependent kinase 2 (Cdk2) and thought to control the transition of quiescent cells into the cell cycle. Initial findings indicated that CcnE1 and CcnE2 have largely overlapping functions for cancer development in several tumor entities including hepatocellular carcinoma (HCC). In the present study, we dissected the differential contributions of CcnE1, CcnE2, and Cdk2 for initiation and progression of HCC in mice and patients. To this end, we tested the HCC susceptibility in mice with constitutive deficiency for CcnE1 or CcnE2 as well as in mice lacking Cdk2 in hepatocytes. Genetic inactivation of CcnE1 largely prevented development of liver cancer in mice in two established HCC models, while ablation of CcnE2 had no effect on hepatocarcinogenesis. Importantly, CcnE1-driven HCC initiation was dependent on Cdk2. However, isolated primary hepatoma cells typically acquired independence on CcnE1 and Cdk2 with increasing progression in vitro, which was associated with a gene signature involving secondary induction of CcnE2 and up-regulation of cell cycle and DNA repair pathways. Importantly, a similar expression profile was also found in HCC patients with elevated CcnE2 expression and poor survival. In general, overall survival in HCC patients was synergistically affected by expression of CcnE1 and CcnE2, but not through Cdk2. Our study suggests that HCC initiation specifically depends on CcnE1 and Cdk2, while HCC progression requires expression of any E-cyclin, but no Cdk2.
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Ishiyama, Ken, Yukio Kondo, Eric Wieder, Sijie Lu, and Jeffrey Molldrem. "High Avidity Cyclin E-Derived Peptide-Specific CTL Contribute to Induction of Remission after Stem Cell Transplantation without Associated Graft-Versus-Host Disease." Blood 106, no. 11 (November 16, 2005): 1424. http://dx.doi.org/10.1182/blood.v106.11.1424.1424.
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Abstract Cyclin E1 (CCNE1) and cyclin E2 (CCNE2) are cell cycle genes that are overexpressed in AML, ALL, and CML, and in solid tumors such as breast cancer, lung cancer, and gastric cancer. We reported that two homologous nonameric peptides from CCNE1 (CCNE1144-152, ILLDWLMEV) and CCNE2 (CCNE2144-152, ILLDWLLEV), which differ by a single amino acid at position 7, have equal binding affinity for HLA-A2 and that CCNE1- and CCNE2- specific CTL elicited from healthy donors kill ALL and CML cells that overexpress CCNE1 and CCNE2. Interestingly, CCNE1/A2 and CCNE2/A2 tetramers bind to both T-cell receptors (TCR), but the longer tetramer dissociation t1/2 of CCNE1/A2 compared with CCNE2/A2 tetramer suggests CCNE1 is the more dominant epitope. To determine the clinical significance of CTL immunity to these self-epitopes, we studied peripheral blood mononuclear cells from 18 patients before and after allogeneic stem cell transplantation (SCT) using CCNE1/A2 and CCNE2/A2 tetramers. An increase in the absolute number of circulating CCNE1- or CCNE2-CTL after SCT was considered evidence of an immune response (IR). Of the18 patients, there were 10 with CML and 8 with ALL, and all were HLA-A2+ and had sufficient blood samples cryopreserved from various time points before SCT and 3–12 months after SCT for analysis. Ten patients, including all 8 ALL patients, were in complete remission (CR) prior to SCT and 5 patients achieved CR after SCT. An IR to CCNE1 was found in 12 of 18 (67%) patients and an IR to CCNE2 was found in 14 of 18 (78%) patients. All 12 patients who had an IR to CCNE1 also had an IR to CCNE2, reflecting possible cross-recognition of both peptides by the same CTL clones. By Chi-square analysis, IR to either CCNE1 or CCNE2 did not correlate with diagnosis (CML vs. ALL), source of the graft (matched related donors vs. mismatched donors), or disease status prior to SCT (remission vs. no remission). Six patients developed acute graft-versus-host disease (aGVHD) and 12 developed chronic graft-versus-host disease (cGVHD). IR to either CCNE1 or CCNE2 occurred more frequently in patients without aGVHD than in the patients with aGVHD (92% vs. 50%, p<0.05), although no significant difference in the IR frequency was observed amongst those who developed cGVHD versus those that did not. Of 8 CML patients who were not in CR prior to SCT, IR to either CCNE1 or CCNE2 occurred more frequently in patients that achieved CR compared to those that did not achieve CR after SCT (100% vs. 33%, respectively; p<0.04). These results provide clinical evidence that both CCNE1 and CCNE2 peptides are novel leukemia-associated antigens, and they justify future clinical trials to determine whether CTL immunity can be enhanced against these antigens in patients with ALL and CML.
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He, Hong, Ken Ishiyama, Gheath Alatrash, Yukio Kondo, Sijie Lu, and Jeffrey J. Molldrem. "T-Cell Immunity to Two HLA-A2-Restricted Self-Determinants of Cyclin E May Contribute to Remission After Stem Cell Transplantation." Blood 114, no. 22 (November 20, 2009): 686. http://dx.doi.org/10.1182/blood.v114.22.686.686.
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Abstract Abstract 686 Cyclin E1 (CCNE1) and cyclin E2 (CCNE2) are tightly regulated cell cycle genes in normal cells but are over-expressed and constitutively active in breast cancer and in the majority of hematological malignances. To validate CCNE as a potential target antigen for T-cells in leukemia, we first confirmed aberrant CCNE1 and CCNE2 protein in PBMC from 26 (93%) of 28 patients (CML = 16; AML = 7; ALL =2; NHL = 3) by Western Blot compared to 4 (33%) of 12 healthy controls (p < 0.0005). Next, we screened the sequences of CCNE1 and CCNE2 for HLA-A*0201 binding motifs and identified a pair of homologous nonameric peptides with highest predicted binding to HLA-A*0201 using an NCBI algorithm. The peptides, denoted CCNE1M (144ILLDWLMEV152) and CCNE2L (144ILLDWLLEV152), differed at P7 (M or L), and both differed from mouse sequence at P1 (V). Synthetic mouse and human peptides were used to confirm high affinity HLA-A2 binding on T2 cells by FACS analysis and peptide-pulsed T2 were used to elicit peptide-specific CTLs from healthy HLA-A2+ PBMC in vitro. CCNE1M-CTL lines specifically lysed both CCNE1M-loaded and CCNE2L-loaded T2 cells, while no CTL could be elicited with mouse peptide. Similarly, CCNE2L-stimulated CTL lines killed CCNE1M-loaded and CCNE2L-loaded T2 cells but not non-loaded T2 cells. Using CCNE1M and CCNE2L HLA-A2 tetramers, we found that either tetramer could bind equally to either the CCNE1M- or CCE2L-derived CTL lines, suggesting that both peptides could be cross-recognized by CTL lines elicited with either peptide. To further study the cross-recognition and potential immune dominance of both peptides and to determine their potential anti-leukemia activity, CCNE1M- and CCNE2L-CTL clones were derived by limiting dilution assay. Two peptide-specific CTL clones from each of the lines showed 25% and 26% specific lysis, respectively, of leukemia cells at E:T 10:1. Neither CCNE-specific CTLs showed lysis of BM cells that were obtained from the same patient during remission, nor HLA-A2+ BM cells from a healthy donor. Next, we compared the T-cell antigen receptor (TCR) avidity of these CCNE1M- and the CCNE2L-CTL clones by measuring tetramer dissociation half-times (t1/2) at 25°C using CCNE1M/HLA-A2 and CCNE2L/HLA-A2 (and control pp65/HLA-A2) tetramers analyzed by flow cytometry. The decay of normalized (to time = 0) tetramer-bound fluorescence versus time was linear for each clone with either tetramer (R2 = 0.85 to 0.91), showing that tetramer binding avidity could be used to proportionally determine TCR affinity. Furthermore, first order kinetics could be used to determine the t1/2 of each of the clones. The t1/2 of CCNE1M/HLA-A2 tetramer was 85 min and 25 min, respectively, while the t1/2of CCNE1L/HLA-A2 was 30 min and 11 min, respectively, for the CCNE1M-CTL and the CCNE2L-CTL. This suggests that while both peptides were cross recognized by unique T-cell clones (with unique TCR, determined by TCR-Vβ sequence comparisons), CCNE1M appeared to be immunodominant. To determine whether immune response (IR) to either peptide occurred in leukemia patients, we studied PBMC from 18 patients (10 CML; 8 ALL) before and 3–6 mo after SCT with CCNE1M/HLA-A2- and CCNE2L/HLA-A2-tetramer assay. The mean number of CCNE1M-CTL and CCNE2L-CTL cells increased after SCT (p< 0.002 in CCNE1M-CTL and CCNE2L-CTL) compared to no change in mean number of pp65-CTL before/after SCT. IR (defined as ≥ 20% increase of specific CTL after SCT) to either CCNE1M or CCNE2L did not correlate with type of leukemia, donor-recipient HLA disparity (matched or mismatched), or disease status prior to SCT by Fisher's exact test. However, in 8 CML patients not in remission prior to SCT, IR to either CCNE1 or CCNE2 occurred more frequently in patients who achieved CR compared to those that did not achieve CR after SCT (100% vs. 33%, respectively; p < 0.04). These findings were confirmed in an additional 25 AML patients with active disease at SCT. To study whether the peptide-specific CTL were functional, we measured IFN-γ and TNF-αa production after peptide stimulation by Luminex bead assay and by intracellular cytokine flow cytometry (CFC). The assays showed production of IFN-γ and TNF-αa cytokines by T-cells after stimulation with CCNE1M or CCNE2Lpeptides. Taken together, these results show that CCNE1M and CCNE2Lself-peptides from constitutively active cell cycle proteins are novel leukemia-associated antigens that could be studied in immunotherapy strategies. Disclosures: No relevant conflicts of interest to declare.
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Martín-Garcia, David, Alba Navarro, Rafael Valdés-Mas, Guillem Clot, Jesús Gutiérrez-Abril, Miriam Prieto, Inmaculada Ribera-Cortada, et al. "CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1− mantle cell lymphoma." Blood 133, no. 9 (February 28, 2019): 940–51. http://dx.doi.org/10.1182/blood-2018-07-862151.
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Abstract Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1− MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1−/D2− MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1−/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1− MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1− MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1− MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1−/D2−/D3− MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1− MCL.
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Wu, Lizheng, Kuan Yang, Yajie Gui, and Xiaojing Wang. "Nicotine-upregulated miR-30a arrests cell cycle in G1 phase by directly targeting CCNE2 in human periodontal ligament cells." Biochemistry and Cell Biology 98, no. 3 (June 2020): 354–61. http://dx.doi.org/10.1139/bcb-2019-0156.
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The consumption of nicotine via smoking tobacco has been reported to stimulate the occurrence and progression of periodontitis. Many studies have demonstrated that nicotine prevents the regeneration of periodontal tissues primarily by inhibiting the proliferation of human periodontal ligament (PDL) cells. However, the mechanisms underlying this process are still unclear. Therefore, we investigated whether nicotine-upregulated miR-30a inhibited the proliferation of human PDL cells by downregulating cyclin E2 (CCNE2), in vitro. Quantitative real-time PCR analysis revealed that nicotine upregulated the expression of miR-30a in human PDL cells. In addition, nicotine inhibited the proliferation of human PDL cells by inducing cell cycle arrest. To support this hypothesis, we showed that nicotine downregulated the expression of CCNE2 in human PDL cells, whereas inhibition of miR-30a restored CCNE2 expression that had been downregulated by nicotine. Furthermore, using luciferase reporter assays, we found that miR-30a directly interacts with the CCNE2 3′UTR. In conclusion, these findings indicate that nicotine-upregulated miR-30a inhibits the proliferation of human PDL cells by downregulating the expression of CCNE2.
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Tao, Kaiyi, JinShi Liu, JinXiao Liang, XiaoFang Xu, LiWei Xu, and WeiMin Mao. "Vascular endothelial cell-derived exosomal miR-30a-5p inhibits lung adenocarcinoma malignant progression by targeting CCNE2." Carcinogenesis 42, no. 8 (June 15, 2021): 1056–67. http://dx.doi.org/10.1093/carcin/bgab051.
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Abstract This study tried to explore the molecular mechanism underlying progression of lung adenocarcinoma (LUAD) and discuss the extracellular communication between cancer cells and vascular endothelial cells. Roughly, differential analysis was carried out to note that miR-30a-5p was lowly expressed in LUAD, whereas CCNE2 was highly expressed. Cell functional experiments demonstrated that overexpressed miR-30a-5p led to suppressed cell abilities in proliferation, migration and invasion. Dual-luciferase reporter gene assay and RNA immunoprecipitation verified the binding of miR-30a-5p and CCNE2, as well as decreased mRNA and protein expression of CCNE2 with miR-30a-5p overexpression. Simultaneous up-regulation of miR-30a-5p and CCNE2 reversed the promotion of CCNE2 on malignant behaviors of LUAD cells. In vivo mice experiments exhibited that high miR-30a-5p expression hindered tumor growth. Additionally, miR-30a-5p was localized on the Extracellular Vesicles microRNA (EVmiRNA) database. MiR-30a-5p was abundant in exosomes derived from vascular endothelial cells. To validate that miR-30a-5p could be delivered to LUAD cells via exosomes and then make an effect, exosomes from vascular endothelial cells were first extracted and identified by transmission electron microscopy and detection of exosomal marker proteins (Alix, CD63, TSG101). Sequentially, the extracted exosomes were labeled with DIO to note that exosomes could be internalized by cancer cells. Further experiments indicated that miR-30a-5p was increased in cancer cells co-cultured with exosomes, which in turn suppressed cell malignant behaviors and made cell cycle arrest. In all, our findings clarified that exosomes derived from vascular endothelial cells delivered miR-30a-5p to LUAD cells to affect tumor malignant progression via the miR-30a-5p/CCNE2 axis.
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Diab, Sami, Matei P. Socoteanu, Carlos A. Encarnacion, Cynthia R. C. Osborne, Carolyn B. Hendricks, Kristi McIntyre, Vibha Taneja Thomas, et al. "High-risk breast cancer genes at 8q22-24 and their role in over 5,000 patients evaluated with the 70-gene risk of recurrence assay." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3569. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3569.
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3569 Background: Previous studies have shown that CCNE2 expression is higher in patients’ cancers resistant to CDK4/6 inhibitors. Increased expression of CCNE2, MTDH, or TSPYL5, genes contained within the 70-gene risk of distant recurrence signature (70GS), has also been implicated in breast oncogenesis, poor prognosis, and chemoresistance. These genes are located on chromosome region 8q22.1, one of the most recurrently amplified regions out of all 70GS genes in breast tumors (Fatima et al. 2017). MYC, located on 8q24, is overexpressed in 40% of all breast cancers (BC). Here we examined the expression of CCNE2, MTDH, and TSPYL5 in relation to 70GS risk and the 80-gene molecular subtype signature (80GS), and their correlation with MYC expression in early stage BC patients. Methods: CCNE2, MTDH, TSPYL5, and MYC mRNA expression was measured in 5022 BC samples sent to Agendia (Irvine, CA) for 70GS and 80GS testing, which included FFPE microarray full-transcriptome data. 70GS was used to stratify patients into Ultra Low Risk (UL), Low Risk (LR), High Risk (HR), and Ultra High Risk (UH). Both 70GS and 80GS were used to classify patient samples into Luminal A, Luminal B, HER2, or Basal type. Wilcoxon rank sum test was used to assess expression differences. Results: The expression of CCNE2, MTDH, and TSPYL5 significantly correlated with each other and was higher in HR patients compared to LR patients (p < 0.001) and higher in UH patients compared to HR patients (p < 0.001). Expression of these genes was highest in Basal type tumors, 83% of which were UH, followed by Luminal B type tumors, and lowest in Luminal A type tumors. CCNE2 and MYC expression was elevated in LR compared to UL patients (p < 0.001 and p = 0.0043). There was no difference in MYC expression between HR vs. LR or UH vs. HR. Lastly, there was no association between the expression of 8q22.1 genes and MYC in any 70GS subgroup. Conclusions: Within the 70GS, CCNE2, MTDH, and TSPYL5 have similar expression patterns and when overexpressed may identify an UH cohort of BC. This observation, in addition to their physical proximity at 8q22.1 suggests a possible amplicon in this region. The highest expression of CCNE2, MTDH, and TSPYL5 associated with UH patients and is concordant with previous studies that support the role of these genes in BC metastasis. Furthermore, this analysis suggests MYC may not stratify patients based on metastatic potential. These data may be clinically relevant for stratifying patients in ongoing clinical trials evaluating response and resistance to targeted therapies in early stage BC.
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Lee, Christine, Kristine J. Fernandez, Sarah Alexandrou, C. Marcelo Sergio, Niantao Deng, Samuel Rogers, Andrew Burgess, and C. Elizabeth Caldon. "Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer." Cancers 12, no. 8 (August 13, 2020): 2268. http://dx.doi.org/10.3390/cancers12082268.
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Genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but few drivers have been identified for this process. Due to their physiological roles in the genome reduplication of normal cells, we hypothesised that the oncogenes cyclins E1 and E2 may be drivers of genome doubling in cancer. We show that both cyclin E1 (CCNE1) and cyclin E2 (CCNE2) mRNA are significantly associated with high genome ploidy in breast cancers. By live cell imaging and flow cytometry, we show that cyclin E2 overexpression promotes aberrant mitosis without causing mitotic slippage, and it increases ploidy with negative feedback on the replication licensing protein, Cdt1. We demonstrate that cyclin E2 localises with core preRC (pre-replication complex) proteins (MCM2, MCM7) on the chromatin of cancer cells. Low CCNE2 is associated with improved overall survival in breast cancers, and we demonstrate that low cyclin E2 protects from excess genome rereplication. This occurs regardless of p53 status, consistent with the association of high cyclin E2 with genome doubling in both p53 null/mutant and p53 wildtype cancers. In contrast, while cyclin E1 can localise to the preRC, its downregulation does not prevent rereplication, and overexpression promotes polyploidy via mitotic slippage. Thus, in breast cancer, cyclin E2 has a strong association with genome doubling, and likely contributes to highly proliferative and genomically unstable breast cancers.
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Kikuchi, Kei, and Daisuke Kaida. "CCNE1 and E2F1 Partially Suppress G1 Phase Arrest Caused by Spliceostatin A Treatment." International Journal of Molecular Sciences 22, no. 21 (October 27, 2021): 11623. http://dx.doi.org/10.3390/ijms222111623.
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The potent splicing inhibitor spliceostatin A (SSA) inhibits cell cycle progression at the G1 and G2/M phases. We previously reported that upregulation of the p27 cyclin-dependent kinase inhibitor encoded by CDKN1B and its C-terminal truncated form, namely p27*, which is translated from CDKN1B pre-mRNA, is one of the causes of G1 phase arrest caused by SSA treatment. However, the detailed molecular mechanism underlying G1 phase arrest caused by SSA treatment remains to be elucidated. In this study, we found that SSA treatment caused the downregulation of cell cycle regulators, including CCNE1, CCNE2, and E2F1, at both the mRNA and protein levels. We also found that transcription elongation of the genes was deficient in SSA-treated cells. The overexpression of CCNE1 and E2F1 in combination with CDKN1B knockout partially suppressed G1 phase arrest caused by SSA treatment. These results suggest that the downregulation of CCNE1 and E2F1 contribute to the G1 phase arrest induced by SSA treatment, although they do not exclude the involvement of other factors in SSA-induced G1 phase arrest.
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Irving-Rodgers, H. F., S. T. Lee, N. Hatzirodos, K. Hummitzsch, T. R. Sullivan, and R. J. Rodgers. "143. DIFFERENCES IN GENE EXPRESSION BETWEEN APICAL AND BASAL CELLS OF THE MEMBRANA GRANULOSA." Reproduction, Fertility and Development 22, no. 9 (2010): 61. http://dx.doi.org/10.1071/srb10abs143.
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Granulosa cells constitute the ovarian follicular epithelium which at the beginning of folliculogenesis forms a single layer of flattened cells. As the follicle matures the cells acquire a cuboidal morphology, proliferate and differentiate into the cumulus cells surrounding the oocyte, and the mural granulosa cells forming the inner layer of the follicle (the membrana granulosa). Mural granulosa cells may further differ in their functionality depending on whether they are situated apically or basally within the stratified membrana granulosa. Late in folliculogenesis granulosa cells develop the ability to produce oestradiol, and also a specialised extracellular matrix (focimatrix) which is more abundant between apical cells. In order to investigate possible differences between granulosa cells, the expression of genes for oestradiol synthesis (CYP11A1, CYP19A1), focimatrix components (LAMB2, COL4A1, HSPG2), FSH and LH receptors, and cell cycle genes (CCND2, CCNE1, CCNE2, CDKN1B, CDKN2D) were examined in apical and basal granulosa cells from large healthy bovine follicles [n = 18, 14.3 ± 0.3 mm (mean + SEM)] using quantitative RT-PCR. Apical granulosa cells were collected by flushing the follicle with balanced salt solution. The remaining cells were detached from the follicular basal lamina by gently scraping; these are the basal granulosa cells. This collection method resulted in equivalent cell yields of apical and basal cells. Expression for all genes was significantly higher in basal cells in comparison to apical cells (P < 0.05), except for the cycle genes CCND2 and CDKN2D, which did not differ between cell populations. These results suggest that functional heterogeneity exists within the membrana granulosa. How differences between apical and basal cells are established is unknown but may be due to the proximity of the basal cells to the follicular basal lamina. The relevance of this aspect of follicle maturation to the endocrine function of granulosa cells has yet to be determined.
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Deng, Yu, He Huang, Jiangcheng Shi, and Hongyan Jin. "Identification of Candidate Genes in Breast Cancer Induced by Estrogen Plus Progestogens Using Bioinformatic Analysis." International Journal of Molecular Sciences 23, no. 19 (October 6, 2022): 11892. http://dx.doi.org/10.3390/ijms231911892.
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Menopausal hormone therapy (MHT) was widely used to treat menopause-related symptoms in menopausal women. However, MHT therapies were controversial with the increased risk of breast cancer because of different estrogen and progestogen combinations, and the molecular basis behind this phenomenon is currently not understood. To address this issue, we identified differentially expressed genes (DEGs) between the estrogen plus progestogens treatment (EPT) and estrogen treatment (ET) using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data. As a result, a total of 96 upregulated DEGs were first identified. Seven DEGs related to the cell cycle (CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3) were validated by RT-qPCR. Specifically, these seven DEGs were increased in EPT compared to ET (p < 0.05) and had higher expression levels in breast cancer than adjacent normal tissues (p < 0.05). Next, we found that estrogen receptor (ER)-positive breast cancer patients with a higher CNNE2 expression have a shorter overall survival time (p < 0.05), while this effect was not observed in the other six DEGs (p > 0.05). Interestingly, the molecular docking results showed that CCNE2 might bind to 17β-estradiol (−6.791 kcal/mol), progesterone (−6.847 kcal/mol), and medroxyprogesterone acetate (−6.314 kcal/mol) with a relatively strong binding affinity, respectively. Importantly, CNNE2 protein level could be upregulated with EPT and attenuated by estrogen receptor antagonist, acolbifene and had interactions with cancer driver genes (AKT1 and KRAS) and high mutation frequency gene (TP53 and PTEN) in breast cancer patients. In conclusion, the current study showed that CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3 might contribute to EPT-related tumorigenesis in breast cancer, with CCNE2 might be a sensitive risk indicator of breast cancer risk in women using MHT.
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Xu, Xuting, Limin Xu, Huilian Huang, Jing Li, Shunli Dong, Lili Jin, Zhihong Ma, and Liqin Li. "Identification of Hub Genes as Biomarkers Correlated with the Proliferation and Prognosis in Lung Cancer: A Weighted Gene Co-Expression Network Analysis." BioMed Research International 2020 (June 11, 2020): 1–11. http://dx.doi.org/10.1155/2020/3416807.
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Lung cancer is one of the most malignant tumors in the world. Early diagnosis and treatment of lung cancer are vitally important to reduce the mortality of lung cancer patients. In the present study, we attempt to identify the candidate biomarkers for lung cancer by weighted gene co-expression network analysis (WGCNA). Gene expression profile of GSE30219 was downloaded from the gene expression omnibus (GEO) database. The differentially expressed genes (DEGs) were analyzed by the limma package, and the co-expression modules of genes were built by WGCNA. UALCAN was used to analyze the relative expression of normal group and tumor subgroups based on tumor individual cancer stages. Survival analysis for the hub genes was performed by Kaplan–Meier plotter analysis with the TCGA database. A total of 2176 genes (745 upregulated and 1431 downregulated genes) were obtained from the GSE30219 database. Seven gene co-expression modules were conducted by WGCNA and the blue module might be inferred as the most crucial module in the pathogenesis of lung cancer. In the pathway enrichment analysis of KEGG, the candidate genes were enriched in the “DNA replication,” “Cell cycle,” and “P53 signaling pathway” pathways. Among these, the cell cycle pathway was the most significant pathway in the blue module with four hub genes CCNB1, CCNE2, MCM7, and PCNA which were selected in our study. Kaplan–Meier plotter analysis indicated that the high expressions of four hub genes were correlated with a worse overall survival (OS) and advanced tumors. qRT-PCR showed that mRNA expression levels of MCM7 (p=0.038) and CCNE2 (0.003) were significantly higher in patients with the TNM stage. In summary, the high expression of the MCM7 and CCNE2 were significantly related with advanced tumors and worse OS in lung cancer. Thus, the MCM7 and CCNE2 genes can be good indicators for cellular proliferation and prognosis in lung cancer.
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Feng, Weiliang, Chen Wang, Chenlu Liang, Hongjian Yang, Daobao Chen, Xingfei Yu, Wenyan Zhao, et al. "The Dysregulated Expression of KCNQ1OT1 and Its Interaction with Downstream Factors miR-145/CCNE2 in Breast Cancer Cells." Cellular Physiology and Biochemistry 49, no. 2 (2018): 432–46. http://dx.doi.org/10.1159/000492978.
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Background/Aims: Next-generation sequencing (NGS) has revealed abundant long noncoding RNAs (lncRNAs) that have been characterized as critical components of cancer biology in humans. The present study aims to investigate the role of the lncRNA KCNQ1OT1 in breast cancer (BRCA) as well as the underlying molecular mechanisms and functions of KCNQ1OT1 involved in the progression of BRCA. Methods: The Cancer Genome Atlas (TCGA) and StarBase v2.0 were used to obtain the required gene data. Dual luciferase reporter gene assays were conducted to verify the relevant intermolecular target relationships. QRT-PCR and Western blot were performed to measure the expression levels of different molecules. Cell proliferation was detected by using the MTT and colony formation assays, while cell migration and invasion were examined by transwell assay. Variations in cell apoptosis and cell cycle were determined through flow cytometry. A tumor xenograft model was applied to assess tumor growth in vivo. Results: KCNQ1OT1 was found to be remarkably highly expressed in BRCA tissues and cells. KCNQ1OT1 modulated CCNE2 through sponging miR-145 in BRCA. KCNQ1OT1 promoted tumor growth in vivo by regulating miR-145/CCNE2. Conclusion: The KCNQ1OT1/miR-145/CCNE2 axis plays a critical regulatory role in BRCA, potentially giving rise to BRCA tumorigenesis and progression. These findings provide valuable evidence for improving the diagnosis and treatment of BRCA in the future.
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Zhou, Jian, Wei-Qiang Ju, Xiao-Peng Yuan, Xiao-Feng Zhu, Dong-Ping Wang, and Xiao-Shun He. "miR-26a regulates mouse hepatocyte proliferation via directly targeting the 3' untranslated region of CCND2 and CCNE2." Hepatobiliary & Pancreatic Diseases International 15, no. 1 (February 2016): 065–72. http://dx.doi.org/10.1016/s1499-3872(15)60383-6.
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Welsch, Eva, Eva Schuster, Michael Krainer, Maximilian Marhold, Rupert Bartsch, Michael B. Fischer, Michael Hermann, et al. "Comparison of RNA Marker Panels for Circulating Tumor Cells and Evaluation of Their Prognostic Relevance in Breast Cancer." Cancers 15, no. 4 (February 16, 2023): 1271. http://dx.doi.org/10.3390/cancers15041271.
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Liquid biopsy is a promising tool for therapy monitoring of cancer patients, but a need for further research in this field exists in order to improve sensitivity, specificity, standardization and minimize costs. In our present study, we evaluated two panels of transcripts related with the presence of circulating tumor cells (CTCs) (Panel 1: CK19, EpCAM, SCGB2A2 and Panel 2: EMP2, SLC6A8, HJURP, MAL2, PPIC and CCNE2) in two cohorts of breast cancer patients (metastatic and early). A blood cell fraction possibly containing CTCs was isolated with density gradient centrifugation, followed by RNA isolation and qPCR using TaqMan® or RT-qPCR using hybridization probes. The positivity rates of the investigated panels were similar, albeit higher in metastatic (69.4% Panel 1, 75.0% Panel 2; total 86.1%) compared to early (18.9% Panel 1, 23.3% Panel 2; total 31.1%) breast cancer patients. CK19, SCGB2A2, EMP2, HJURP, MAL2, and CCNE2 individually correlated with shorter overall survival in the metastatic patient cohort. The findings highlight the additional value of Panel 2 markers, which are in contrast to CK19 and EpCAM not solely linked to an epithelial phenotype.
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Sotiriou, C., M. Paesmans, A. Harris, M. A. Colozza, S. Fox, M. Taylor, A. Sorre, P. Martiat, F. Cardoso, and M. Piccart. "Cyclin E1 (CCNE1) and E2 (CCNE2) as prognostic and predictive markers for endocrine therapy (ET) in early breast cancer." Journal of Clinical Oncology 22, no. 14_suppl (July 15, 2004): 9504. http://dx.doi.org/10.1200/jco.2004.22.90140.9504.
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Sotiriou, C., M. Paesmans, A. Harris, M. A. Colozza, S. Fox, M. Taylor, A. Sorre, P. Martiat, F. Cardoso, and M. Piccart. "Cyclin E1 (CCNE1) and E2 (CCNE2) as prognostic and predictive markers for endocrine therapy (ET) in early breast cancer." Journal of Clinical Oncology 22, no. 14_suppl (July 15, 2004): 9504. http://dx.doi.org/10.1200/jco.2004.22.14_suppl.9504.
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Pegoraro, Silvia, Gloria Ros, Yari Ciani, Riccardo Sgarra, Silvano Piazza, and Guidalberto Manfioletti. "A novel HMGA1-CCNE2-YAP axis regulates breast cancer aggressiveness." Oncotarget 6, no. 22 (May 22, 2015): 19087–101. http://dx.doi.org/10.18632/oncotarget.4236.
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Gao, Li, Rong-quan He, Hua-yu Wu, Tong-tong Zhang, Hai-wei Liang, Zhi-hua Ye, Zu-yun Li, et al. "Expression Signature and Role of miR-30d-5p in Non-Small Cell Lung Cancer: a Comprehensive Study Based on in Silico Analysis of Public Databases and in Vitro Experiments." Cellular Physiology and Biochemistry 50, no. 5 (2018): 1964–87. http://dx.doi.org/10.1159/000494875.
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Background/Aims: The purpose of this study was to probe the clinico-pathological significance and the underlying mechanism of miR-30d-5p expression in non-small cell lung cancer (NSCLC). Methods: We initially examined the level of miR-30d-5p expression in NSCLC and non-cancer tissues using RT-qPCR. Then, a series of validation analyses including a meta-analysis of data from microarray chips in Gene Expression Omnibus (GEO), data mining of the cancer genome atlas (TCGA) and an integrated meta-analysis incorporating GEO microarray chips, TCGA data, in-house RT-qPCR and literature studies were performed to examine the clinico-pathological value of miR-30d-5p expression in NSCLC. In vitro experiments were further conducted to investigate the impact of miR-30d-5p on NSCLC cell growth. The molecular mechanism by which miR-30d-5p regulates the pathogenesis of NSCLC was probed through a bioinformatics analysis of its target genes. Moreover, dual luciferase reporter assay was conducted to verify the targeting regulatory relationship between miR-30d-5p and CCNE2. Results: Based on results from RT-qPCR, GEO meta-analysis, TCGA data mining and the integrated meta-analysis incorporating GEO microarray chips, TCGA data, in-house RT-qPCR and literature studies, miR-30d-5p expression was decreased in NSCLC tissues, and patients with NSCLC who presented with lower miR-30d-5p expression tended to display an advanced clinical progression. Significant pathways including the Mucin type O-glycan biosynthesis pathway, cell cycle pathway and cysteine and methionine metabolism pathway (all P< 0.05) revealed potential roles of the target genes of miR-30d-5p in the oncogenesis of NSCLC. Results from in vitro experiments indicated that miR-30d-5p could attenuate proliferation and viability of NSCLC cells. Among the 12 identified hub genes, nine genes including E2F3, CCNE2, SKP2, CDK6, TFDP1, LDHA, GOT2, DNMT3B and ST6GALNAC1 were validated by Pearson’s correlation test and the human protein atlas (HPA) database as targets of miR-30d-5p with higher probability. Specifically, dual luciferase reporter assay confirmed that CCNE2 was directly targeted by miR-30d-5p. Conclusion: In summary, miR-30d-5p expression is decreased in NSCLC, and it might play the role as tumor suppressor in NSCLC by regulating target genes.
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Zeillinger, R., E. Obermayr, A. Fink-Retter, G. Heinze, A. Reinthaller, R. Horvat, and D. C. Castillo-Tong. "Molecular markers for circulating tumor cells in breast cancer." Journal of Clinical Oncology 29, no. 27_suppl (September 20, 2011): 223. http://dx.doi.org/10.1200/jco.2011.29.27_suppl.223.
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223 Background: Recently, we identified a six gene panel (CCNE2, DKFZp762E1312, EMP2, MAL2, PPIC, and SLC6A8) for the RT-qPCR based detection of circulating tumor cells (CTC) in breast cancer patients. The aim of the present study was to evaluate the gene panel in further blood samples. Methods: Blood samples were taken from breast cancer patients with metastatic disease (MBC, N=10) or with no evidence of disease (NED, N=30). Putative CTC were enriched by Oncoquick density gradient centrifugation. Total RNA was isolated with RNeasy Micro Kit (QIAgen). Template cDNA was generated with M-MLV Reverse Transcriptase, RNase H Minus (Promega) and random nonamers as primers. RT-qPCR was performed in duplicate reactions using TaqMan Assays (Applied Biosystems) with default thermal cycling parameters. Raw data were analyzed with the AB7900 Sequence Detection Software version 2.2.2 using automatic baseline correction and manual cycle threshold setting. Gene expression was normalized to GAPDH expression. A threshold value TX for each gene X was set at two standard deviations above the mean dCtX value in the healthy control group. A patient was defined as CTC-positive, if at least one gene marker was over-expressed compared to the defined threshold. Results: The gene panel consisting of CCNE2, DKFZp762E1312, EMP2, MAL2, PPIC, and SLC6A8 identified 4/11 MBC but only 5/27 NED patients as CTC positive (p=0.163). By adding known CTC markers (SCGB2A2, TFF1, FXYD3, AGR2, S100A18, and EPCAM) to the panel, 7/11 MBC but only 6/27 NED patients were CTC positive (p=0.018). The presence of CTC in NED patients correlated with pN staging (p=0.026). Only one out of the six CTC positive NED patients relapsed within the observation period (median 35 months, range 25-39 months from blood sampling). We observed no correlation of CTC positivity and recurrence in NED patients. Conclusions: The sensitivity of the RT-qPCR based CTC detection in breast cancer patients may be enhanced by adding known CTC markers (SCGB2A2, TFF1, FXYD3, AGR2, S100A18, and EPCAM) to the six gene panel (CCNE2, DKFZp762E1312, EMP2, MAL2, PPIC, and SLC6A8). Longer follow-up times are needed to evaluate the predictive value of the gene markers on survival.
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Shao, Li, Ri-Cheng Chian, Yixin Xu, Zhengjie Yan, Yihui Zhang, Chao Gao, Li Gao, Jiayin Liu, and Yugui Cui. "Genomic expression profiles in cumulus cells derived from germinal vesicle and MII mouse oocytes." Reproduction, Fertility and Development 28, no. 11 (2016): 1798. http://dx.doi.org/10.1071/rd15077.
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Cumulus cells (CCs) are distinct from other granulosa cells and the mutual communication between CCs and oocytes is essential for the establishment of oocyte competence. In the present study we assessed genomic expression profiles in mouse CCs before and after oocyte maturation in vitro. Microarray analysis revealed significant changes in gene expression in CCs between the germinal vesicle (GV) and metaphase II (MII) stages, with 2615 upregulated and 2808 downregulated genes. Genes related to epidermal growth factor, extracellular matrix (Ptgs2, Ereg, Tnfaip6 and Efemp1), mitochondrial metabolism (Fdx1 and Aifm2), gap junctions and the cell cycle (Gja1, Gja4, Ccnd2, Ccna2 and Ccnb2) were highlighted as being differentially expressed between the two development stages. Real-time polymerase chain reaction confirmed the validity and reproducibility of the results for the selected differentially expressed genes. Similar expression patterns were identified by western blot analysis for some functional proteins, including EFEMP1, FDX1, GJA1 and CCND2, followed by immunofluorescence localisation. These genes may be potential biomarkers for oocyte developmental competence following fertilisation and will be investigated further in future studies.
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Mizuno, Keiko, Kengo Tanigawa, Shunsuke Misono, Takayuki Suetsugu, Hiroki Sanada, Akifumi Uchida, Minami Kawano, et al. "Regulation of Oncogenic Targets by Tumor-Suppressive miR-150-3p in Lung Squamous Cell Carcinoma." Biomedicines 9, no. 12 (December 11, 2021): 1883. http://dx.doi.org/10.3390/biomedicines9121883.
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Several recent studies have shown that both strands of certain miRNAs derived from miRNA duplexes are involved in cancer pathogenesis. Our own recent studies revealed that both strands of the miR-150 duplex act as tumor-suppressive miRNAs in lung adenocarcinoma (LUAD) through the targeting of several oncogenes. The aim of the study here was to further investigate the tumor-suppressive roles of miR-150-3p (the passenger strand) in lung squamous cell carcinoma (LUSQ) and its control of cancer-promoting genes in LUSQ cells. The downregulation of miR-150-3p in LUSQ tissues was confirmed by data in The Cancer Genome Atlas (TCGA). The ectopic expression of miR-150-3p attenuated cancer cell aggressive features, e.g., cell cycle arrest, migration and invasive abilities. Our target search strategy successfully identified a total of 49 putative targets that were listed as subjects of miR-150-3p regulation in LUSQ cells. Interestingly, among these targets, 17 genes were categorized as related to the “cell cycle” based on Gene Ontology (GO) classification, namely CENPA, CIT, CCNE1, CCNE2, TIMELESS, BUB1, MCM4, HELLS, SKA3, CDCA2, FANCD2, NUF2, E2F2, SUV39H2, CASC5, ZWILCH and CKAP2). Moreover, we show that the expression of HELLS (helicase, lymphoid specific) is directly controlled by miR-150-3p, and its expression promotes the malignant phenotype of LUSQ cells.
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Liu, Cui-Zhen, Wan-Ping Guo, Jin-Bo Peng, Gang Chen, Peng Lin, Xiao-Li Huang, Xiao-Fan Liu, et al. "Clinical significance of CCNE2 protein and mRNA expression in thyroid cancer tissues." Advances in Medical Sciences 65, no. 2 (September 2020): 442–56. http://dx.doi.org/10.1016/j.advms.2020.09.001.
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Wu, Deqin, Jing He, Wei Zhang, Kai Wang, Shidai Jin, Jun Li, and Wen Gao. "CARM1 promotes non-small cell lung cancer progression through upregulating CCNE2 expression." Aging 12, no. 11 (June 2, 2020): 10578–93. http://dx.doi.org/10.18632/aging.103280.
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Kabir, Mohammad Faujul, Johari Mohd Ali, and Onn Haji Hashim. "Microarray gene expression profiling in colorectal (HCT116) and hepatocellular (HepG2) carcinoma cell lines treated withMelicope ptelefolialeaf extract reveals transcriptome profiles exhibiting anticancer activity." PeerJ 6 (July 18, 2018): e5203. http://dx.doi.org/10.7717/peerj.5203.
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BackgroundWe have previously reported anticancer activities ofMelicope ptelefolia(MP) leaf extracts on four different cancer cell lines. However, the underlying mechanisms of actions have yet to be deciphered. In the present study, the anticancer activity of MP hexane extract (MP-HX) on colorectal (HCT116) and hepatocellular carcinoma (HepG2) cell lines was characterized through microarray gene expression profiling.MethodsHCT116 and HepG2 cells were treated with MP-HX for 24 hr. Total RNA was extracted from the cells and used for transcriptome profiling using Applied Biosystem GeneChip™ Human Gene 2.0 ST Array. Gene expression data was analysed using an Applied Biosystems Expression Console and Transcriptome Analysis Console software. Pathway enrichment analyses was performed using Ingenuity Pathway Analysis (IPA) software. The microarray data was validated by profiling the expression of 17 genes through quantitative reverse transcription PCR (RT-qPCR).ResultsMP-HX induced differential expression of 1,290 and 1,325 genes in HCT116 and HepG2 cells, respectively (microarray data fold change, MA_FC ≥ ±2.0). The direction of gene expression change for the 17 genes assayed through RT-qPCR agree with the microarray data. In both cell lines, MP-HX modulated the expression of many genes in directions that support antiproliferative activity. IPA software analyses revealed MP-HX modulated canonical pathways, networks and biological processes that are associated with cell cycle, DNA replication, cellular growth and cell proliferation. In both cell lines, upregulation of genes which promote apoptosis, cell cycle arrest and growth inhibition were observed, while genes that are typically overexpressed in diverse human cancers or those that promoted cell cycle progression, DNA replication and cellular proliferation were downregulated. Some of the genes upregulated by MP-HX include pro-apoptotic genes (DDIT3, BBC3, JUN), cell cycle arresting (CDKN1A, CDKN2B), growth arrest/repair (TP53, GADD45A) and metastasis suppression (NDRG1). MP-HX downregulated the expression of genes that could promote anti-apoptotic effect, cell cycle progression, tumor development and progression, which include BIRC5, CCNA2, CCNB1, CCNB2, CCNE2, CDK1/2/6, GINS2, HELLS, MCM2/10 PLK1, RRM2 and SKP2. It is interesting to note that all six top-ranked genes proposed to be cancer-associated (PLK1, MCM2, MCM3, MCM7, MCM10 and SKP2) were downregulated by MP-HX in both cell lines.DiscussionThe present study showed that the anticancer activities of MP-HX are exerted through its actions on genes regulating apoptosis, cell proliferation, DNA replication and cell cycle progression. These findings further project the potential use of MP as a nutraceutical agent for cancer therapeutics.
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Yu, Ai Qing, Zhi Xiao Wang, Wu Wu, Ke Yu Chen, Shi Rong Yan, and Ze Bin Mao. "Circular RNA CircCCNB1 sponges micro RNA-449a to inhibit cellular senescence by targeting CCNE2." Aging 11, no. 22 (November 25, 2019): 10220–41. http://dx.doi.org/10.18632/aging.102449.
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Minegishi, Naoko, Hideo Harigae, and Masayuki Yamamoto. "Bidirectional Control of Transcription Factor GATA2 and Cyclin/Cdks in Hematopoietic Cells." Blood 112, no. 11 (November 16, 2008): 1382. http://dx.doi.org/10.1182/blood.v112.11.1382.1382.
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Abstract GATA2 is a transcription factor indispensable for development and maintenance of hematopoietic stem cells. Hematopoietic stem cells in G0 phase express GATA2 (Suzuki N, PNAS 103: 2202 2006), but proliferating hematopoietic progenitor cells, as well as proliferating cells in several other tissues, also express this factor. Gata2 knockout experiments indicate that GATA2 regulates cell proliferation; however, precise mechanisms have not been elucidated. Previously, we found oscillatory expressions of GATA2 during the cell cycle. In G1/S and G2/M phases, Cdk4 and Cdk2, forming complexes with several cyclins, phosphorylate GATA2 and induce GATA2 degradation (Koga S, Blood109: 4200, 2007). In this study, we demonstrate the bidirectional control between GATA2 and Cyclin/Cdk systems. To identify GATA2 target genes regulating cell proliferation, we searched for conserved GATA factor-binding sequences in evolutionarily conserved regions (ECRs, http://ecrbrowser.dcode.org), and found conserved GATA sequences in ECRs in intron 3 and intron 4 of the CyclinD2 (Ccnd2) gene, and in intron 3 and 3′UTR of the CyclinE1 (Ccne1) gene. In ChIP experiments using synchronized Ba/F3 and P815 cells, GATA2 binding to these regions was high in late G1 phase, and then rapidly declined in early S phase. One hour treatment using a Cdk1/2 inhibitor, roscovitine, cancelled this regression in early S phase, implicating Cdk2 as a negative regulator of GATA2 binding to target genes. Significant GATA2 binding to Ccnd2 and Ccne1 genes was also detected in embryonic day 13.5 fetal liver cells. Exogenous GATA2 expression augmented transcriptional activity of these binding regions in luciferase assay. Induction of GATA2 siRNA repressed Ccnd2 and Ccne1 mRNA expression. Furthermore, Ccnd2 and Ccne1 mRNA expression, as well as Gata2 mRNA expression, was significantly reduced in placental and aortic regions of embryonic day 10.0 conceptihar boring insertions of green fluorescent protein cDNA at translation start sites of bothGata2 alleles (Minegishi N, Blood102: 896, 2003). These results indicate that Ccnd2 andCcne1 genes are direct targets of GATA2. GATA2 binds to Ccnd2 and Ccne1 genes and activates their transcription in the G1 phase of proliferating cells. In G1/S transition, Cdk2activity, probably enhanced by CyclinE1 expression, attenuate GATA2 binding to Ccnd2and Ccne1 genes. In this fashion, bidirectional control of GATA2 and G1 cyclins may contribute to the transient expression of CyclinD2 and CyclinE1 in G1 phase, and to the acceleration of S-phase entry. In addition, it appears plausible that lack of Cdk activities causes differences in GATA2 functions in hematopoietic stem cells in G0 phase.
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Büchel, Janine, Maria Bartosova, Gwendolyn Eich, Timo Wittenberger, Ludger Klein-Hitpass, Sonja Steppan, Thilo Hackert, Franz Schaefer, Jutta Passlick-Deetjen, and Claus P. Schmitt. "Interference of Peritoneal Dialysis Fluids with Cell Cycle Mechanisms." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 35, no. 3 (May 2015): 259–74. http://dx.doi.org/10.3747/pdi.2013.00010.
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Introduction Peritoneal dialysis fluids (PDF) differ with respect to osmotic and buffer compound, and pH and glucose degradation products (GDP) content. The impact on peritoneal membrane integrity is still insufficiently described. We assessed global genomic effects of PDF in primary human peritoneal mesothelial cells (PMC) by whole genome analyses, quantitative real-time polymerase chain reaction (RT-PCR) and functional measurements. Methods PMC isolated from omentum of non-uremic patients were incubated with conventional single chamber PDF (CPDF), lactate- (LPDF), bicarbonate- (BPDF) and bicarbonate/lactate-buffered double-chamber PDF (BLPDF), icodextrin (IPDF) and amino acid PDF (APDF), diluted 1:1 with medium. Affymetrix GeneChip U133Plus2.0 (Affymetrix, CA, USA) and quantitative RT-PCR were applied; cell viability was assessed by proliferation assays. Results The number of differentially expressed genes compared to medium was 464 with APDF, 208 with CPDF, 169 with IPDF, 71 with LPDF, 45 with BPDF and 42 with BLPDF. Out of these genes 74%, 73%, 79%, 72%, 47% and 57% were downregulated. Gene Ontology (GO) term annotations mainly revealed associations with cell cycle ( p = 10 −35), cell division, mitosis, and DNA replication. One hundred and eighteen out of 249 probe sets detecting genes involved in cell cycle/division were suppressed, with APDF-treated PMC being affected the most regarding absolute number and degree, followed by CPDF and IPDF. Bicarbonate-containing PDF and BLPDF-treated PMC were affected the least. Quantitative RT-PCR measurements confirmed microarray findings for key cell cycle genes (CDK1/CCNB1/CCNE2/AURKA/KIF11/ KIF14). Suppression was lowest for BPDF and BLPDF, they upregulated CCNE2 and SMC4. All PDF upregulated 3 out of 4 assessed cell cycle repressors (p53/BAX/p21). Cell viability scores confirmed gene expression results, being 79% of medium for LPDF, 101% for BLPDF, 51% for CPDF and 23% for IPDF. Amino acid-containing PDF (84%) incubated cells were as viable as BPDF (86%). Conclusion In conclusion, PD solutions substantially differ with regard to their gene regulating profile and impact on vital functions of PMC, i.e. on cells known to be essential for peritoneal membrane homeostasis.
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Gorjala, P., J. G. Cairncross, and R. K. Gary. "p53-dependent up-regulation of CDKN1A and down-regulation of CCNE2 in response to beryllium." Cell Proliferation 49, no. 6 (September 9, 2016): 698–709. http://dx.doi.org/10.1111/cpr.12291.
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Gao, Peng, Huan Wang, Jiarui Yu, Jie Zhang, Zhao Yang, Meiyue Liu, Yi Niu, et al. "miR-3607-3p suppresses non-small cell lung cancer (NSCLC) by targeting TGFBR1 and CCNE2." PLOS Genetics 14, no. 12 (December 17, 2018): e1007790. http://dx.doi.org/10.1371/journal.pgen.1007790.
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Li, Chuan, Zhi Peng, You Zhou, Yongyue Su, Pengfei Bu, Xuhan Meng, Bo Li, and Yongqing Xu. "Comprehensive analysis of pathological changes in hip joint capsule of patients with developmental dysplasia of the hip." Bone & Joint Research 10, no. 9 (September 1, 2021): 558–70. http://dx.doi.org/10.1302/2046-3758.109.bjr-2020-0421.r2.
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Aims Developmental dysplasia of the hip (DDH) is a complex musculoskeletal disease that occurs mostly in children. This study aimed to investigate the molecular changes in the hip joint capsule of patients with DDH. Methods High-throughput sequencing was used to identify genes that were differentially expressed in hip joint capsules between healthy controls and DDH patients. Biological assays including cell cycle, viability, apoptosis, immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were performed to determine the roles of the differentially expressed genes in DDH pathology. Results More than 1,000 genes were differentially expressed in hip joint capsules between healthy controls and DDH. Both gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that extracellular matrix (ECM) modifications, muscle system processes, and cell proliferation were markedly influenced by the differentially expressed genes. Expression of Collagen Type I Alpha 1 Chain (COL1A1), COL3A1, matrix metalloproteinase-1 (MMP1), MMP3, MMP9, and MMP13 was downregulated in DDH, with the loss of collagen fibres in the joint capsule. Expression of transforming growth factor beta 1 (TGF-β1) was downregulated, while that of TGF-β2, Mothers against decapentaplegic homolog 3 (SMAD3), and WNT11 were upregulated in DDH, and alpha smooth muscle actin (αSMA), a key myofibroblast marker, showed marginal increase. In vitro studies showed that fibroblast proliferation was suppressed in DDH, which was associated with cell cycle arrest in G0/G1 and G2/M phases. Cell cycle regulators including Cyclin B1 (CCNB1), Cyclin E2 (CCNE2), Cyclin A2 (CCNA2), Cyclin-dependent kinase 1 (CDK1), E2F1, cell division cycle 6 (CDC6), and CDC7 were downregulated in DDH. Conclusion DDH is associated with the loss of collagen fibres and fibroblasts, which may cause loose joint capsule formation. However, the degree of differentiation of fibroblasts to myofibroblasts needs further study. Cite this article: Bone Joint Res 2021;10(9):558–570.
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Zhuang, Liping, Zongguo Yang, and Zhiqiang Meng. "Upregulation of BUB1B, CCNB1, CDC7, CDC20, and MCM3 in Tumor Tissues Predicted Worse Overall Survival and Disease-Free Survival in Hepatocellular Carcinoma Patients." BioMed Research International 2018 (September 30, 2018): 1–8. http://dx.doi.org/10.1155/2018/7897346.
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Objective. To evaluate the association between upregulated differentially expressed genes (DEGs) and the outcomes of patients with hepatocellular carcinoma (HCC). Methods. Using Gene Expression Omnibus (GEO) datasets including GSE45436, GSE55092, GSE60502, GSE84402, and GSE17548, we detected upregulated DEGs in tumors. KEGG, GO, and Reactome enrichment analysis of the DEGs was conducted to clarify their function. The impact of the upregulated DEGs on patients’ survival was analyzed based on TCGA profile. Results. 161 shared upregulated DEGs were identified among GSE45436, GSE55092, GSE60502, and GSE84402 profiles. Cell cycle was the shared pathway/biological process in the gene sets investigation among databases of KEGG, GO, and Reactome. After being validated in GSE17548, 13 genes including BUB1B, CCNA2, CCNB1, CCNE2, CDC20, CDC6, CDC7, CDK1, CDK4, CDKN2A, CHEK1, MAD2L1, and MCM3 in cell cycle pathway were shared in the three databases for enrichment. The expression of BUB1B, CCNB1, CDC7, CDC20, and MCM3 was upregulated in HCC tissues when compared with adjacent normal tissues in 6.67%, 7.5%, 8.06%, 5.56%, and 9.72% of HCC patients, respectively. Overexpression of BUB1B, CCNB1, CDC7, CDC20, and MCM3 in HCC tissues accounted for poorer overall survival (OS) and disease-free survival (DFS) in HCC patients (all log rank P < 0.05). BUB1B, CCNB1, CDC7, CDC20, and MCM3 were all overexpressed in HCC patients with neoplasm histologic grade G3-4 compared to those with G1-2 (all P < 0.05). BUB1B, CCNB1, and CDC20 were significantly upregulated in HCC patients with vascular invasion (all P < 0.05). Additionally, levels of BUB1B, CCNB1, CDC7, and CDC20 were significantly higher in HCC patients deceased, recurred, or progressed (all P < 0.05). Conclusion. Correlated with advanced histologic grade and/or vascular invasion, upregulation of BUB1B, CCNB1, CDC7, CDC20, and MCM3 in HCC tissues predicted worse OS and DFS in HCC patients. These genes could be novel therapeutic targets for HCC treatment.
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Lei, Brian, and Anjana Saxena. "Abstract C049: Investigating cancer racial disparities through TCGA transcriptomic and proteomic database." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): C049. http://dx.doi.org/10.1158/1538-7755.disp22-c049.
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Abstract In the United States, epidemiological studies have highlighted a disparity in cancer incidence and outcome rates between racial groups. This disparity is attributed to numerous factors, including gene polymorphisms, differences in lifestyle and environmental exposures, and socioeconomic factors. Although an abundance of tumor molecular data exists, the effect of race on gene expression signatures often remains unexplored. In this project, we investigated racial molecular differences in tumors of 10 carcinoma types. We used publicly available data from The Cancer Genome Atlas (TCGA) in conjunction with online analysis tools to identify patterns of differential gene expression in tumors obtained from 4,112 White, Black/African American, and Asian patients. We identified race-dependent expression of numerous genes whose mRNA transcript levels were significantly correlated with patient survival outcomes. A small subset of these genes was differentially expressed in multiple carcinomas, including genes involved in cell cycle progression such as CCNB1, CCNE1, CCNE2, and FOXM1. This suggests that cell cycle dysregulation is a major culprit in the health disparity. In contrast, genes such as transcriptional factor ETS1 and apoptotic gene BAK1 were differentially expressed and clinically significant only in specific cancer types. In numerous cancer types we also observed race-dependent regulation of cancer-relevant biological pathways, especially DNA repair mechanisms. This large-scale pan-cancer study refines our understanding of the molecular basis for the cancer racial health disparity and can help inform the use of novel biomarkers in clinical settings as well as the future development of precision therapies. Citation Format: Brian Lei, Anjana Saxena. Investigating cancer racial disparities through TCGA transcriptomic and proteomic database [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C049.
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Entin, Igor, Shmuel Yaccoby, Wen Zhining, John Shaughnessy, Bart Barlogie, and Joshua Epstein. "Myeloma Cell Interaction with Osteoclasts and Mesenchymal Stem Cells Reveals Genes Associated with Post Relapse Survival." Blood 116, no. 21 (November 19, 2010): 2957. http://dx.doi.org/10.1182/blood.v116.21.2957.2957.
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Abstract Abstract 2957 Myeloma is intimately associated with osteolytic bone disease, resulting from myeloma cells' interactions with osteoclasts and osteoblasts and their progenitors, and is dependent on the changes it induces in bone metabolism for progression. Myeloma cell dependence on the bone marrow microenvironment is also evident experimentally, where interaction of primary myeloma plasma cells (MMPC) with osteoclasts (OC) and with mesenchymal stem cells (MSC) support the survival of primary myeloma cells. To understand the molecular mechanisms associated with the survival of MMPC, we used Acuity 4 software to analyze Affymetrix U133 Plus2 chip data and identify changes in gene expression in induced MMPC freshly isolated from 8 patients by interaction with OC and from 8 additional patients with MSC. Expression by MMPC of 675 genes was changed following interaction with OC; 552 genes were upregulated and 123 down regulated. Expression of 296 genes was changed in MSC co cultures (161 upregulated, 135 down regulated). Comparison of the genes whose expression was similarly changed in both co culture systems identified 72 probesets, representing 58 genes, that were commonly changed; 33 were upregulated and 25 down regulated. Ingenuity Pathway Analysis assigned 54 of the 58 genes to 4 distinguished networks of interrelated genes with high probability scores. We next tested the hypothesis that the expression of genes whose expression was commonly changed in the co culture systems has clinical significance. To accomplish this, we used gene expression data available on 127 relapsed patients who had been uniformly treated on our Total Therapy 2 protocol, and for whom gene expression (GEP) data at first relapse (RL) were available. 71 of these patients also had pre treatment (BL) GEP data; for these 71 patients we calculated change in expression of the 72 probesets as the ratio of RL/BL expression signal. We identified 7 genes whose expression changes were significantly (p≤0.05) associated with survival after relapse: These genes were, in order of significance: CCNE2, PECAM1, KLHL21, ICAM1, PLAU, ANPEP, and DUSP1, with p-values ranging from 0.017 to 0.05. Up regulation of PECAM1, ANPEP, DUSP1, and down regulation of CCNE2, KLHL21, ICAM1, and PLAU were associated with longer survival. We further determined whether expression level of these 72 probesets at relapse, defined by signal intensity, correlated with post relapse survival of the 127 patients; 18 genes were significantly (p<0.05)associated with survival: of these, the top 6 genes, sorted in order of p-values of the univariate test were CCNE2 (p<1e-7, HR, defined as ratio of hazard for a twofold increased in signal) =1.83), PECAM1 (p=2e-7, HR=0.64), FOSB (p=2.3e-6, HR=0.76), HMOX1 (p=8.2e-5; HR=0.72), CISH (p<0.0002, HR=0.76), and JUN (p=0.0008, HR=0.78). Eleven other genes associated with survival had p values ranging from <0.002 to 0.047. Although not the purpose of this work, we also tested the ability of the 72 probesets to predict survival with each probeset dichotomized at the median. Using the BRB Array tool, we found that 17 genes predict post relapse survival with at p=0.01 based on log-rank tests in 100 permutations. The percent variability explained by the first 2 principal components = 42.5. Using co culture of myeloma cells with osteoclasts and MSC we identified MMPC genes whose expression is associated with the survival of patients after relapse. These genes define potential targets for improving the survival of relapsed myeloma patients. Disclosures: No relevant conflicts of interest to declare.
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Yang, Jie, Zhen Dong, Aishu Ren, Gang Fu, Kui Zhang, Changhong Li, Xiangwei Wang, and Hongjuan Cui. "Antibiotic tigecycline inhibits cell proliferation, migration and invasion via down‐regulating CCNE2 in pancreatic ductal adenocarcinoma." Journal of Cellular and Molecular Medicine 24, no. 7 (March 6, 2020): 4245–60. http://dx.doi.org/10.1111/jcmm.15086.
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Gong, Ke, Huiling Zhou, Haidan Liu, Ting Xie, Yong Luo, Hui Guo, Jinlan Chen, Zhiping Tan, Yifeng Yang, and Li Xie. "Identification and Integrate Analysis of Key Biomarkers for Diagnosis and Prognosis of Non-Small Cell Lung Cancer Based on Bioinformatics Analysis." Technology in Cancer Research & Treatment 20 (January 2021): 153303382110602. http://dx.doi.org/10.1177/15330338211060202.
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Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer affecting humans. However, appropriate biomarkers for diagnosis and prognosis have not yet been established. Here, we evaluated the gene expression profiles of patients with NSCLC to identify novel biomarkers. Methods: Three datasets were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes were analyzed. Venn diagram software was applied to screen differentially expressed genes, and gene ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. Cytoscape was used to analyze protein-protein interactions (PPI) and Kaplan–Meier Plotter was used to evaluate the survival rates. Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA), and The Human Protein Atlas (THPA) were used to analyze protein expression. Quantitative real-time polymerase (qPCR) chain reaction was used to verify gene expression. Results: We identified 595 differentially expressed genes shared by the three datasets. The PPI network of these differentially expressed genes had 202 nodes and 743 edges. Survival analysis identified 10 hub genes with the highest connectivity, 9 of which ( CDC20, CCNB2, BUB1, CCNB1, CCNA2, KIF11, TOP2A, NDC80, and ASPM) were related to poor overall survival in patients with NSCLC. In cell experiments, CCNB1, CCNB2, CCNA2, and TOP2A expression levels were upregulated, and among different types of NSCLC, these four genes showed highest expression in large cell lung cancer. The highest prognostic value was detected for patients who had successfully undergone surgery and for those who had not received chemotherapy. Notably, CCNB1 and CCNA2 showed good prognostic value for patients who had not received radiotherapy. Conclusion: CCNB1, CCNB2, CCNA2, and TOP2A expression levels were upregulated in patients with NSCLC. These genes may be meaningful diagnostic biomarkers and could facilitate the development of targeted therapies.
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Li, Dongfeng, Zaixu Pan, Kun Zhang, Minli Yu, Debing Yu, Yinglin Lu, Jiantao Wang, Jin Zhang, Kangning Zhang, and Wenxing Du. "Identification of the Differentially Expressed Genes of Muscle Growth and Intramuscular Fat Metabolism in the Development Stage of Yellow Broilers." Genes 11, no. 3 (February 26, 2020): 244. http://dx.doi.org/10.3390/genes11030244.
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High-quality chicken meat is an important source of animal protein for humans. Gene expression profiles in breast muscle tissue were determined, aiming to explore the common regulatory genes relevant to muscle and intramuscular fat (IMF) during the developmental stage in chickens. Results show that breast muscle weight (BMW), breast meat percentage (BMP, %), and IMF (%) continuously increased with development. A total of 256 common differentially expressed genes (DEGs) during the developmental stage were screened. Among them, some genes related to muscle fiber hypertrophy were upregulated (e.g., CSRP3, LMOD2, MUSTN1, MYBPC1), but others (e.g., ACTC1, MYL1, MYL4) were downregulated from Week 3 to Week 18. During this period, expression of some DEGs related to the cells cycle (e.g., CCNB3, CCNE2, CDC20, MCM2) changed in a way that genetically suggests possible inhibitory regulation on cells number. In addition, DEGs associated with energy metabolism (e.g., ACOT9, CETP, LPIN1, DGAT2, RBP7, FBP1, PHKA1) were found to regulate IMF deposition. Our data identified and provide new insights into the common regulatory genes related to muscle growth, cell proliferation, and energy metabolism at the developmental stage in chickens.
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Ke, Shandong, and Xiaofen Zhou. "LncRNA MVIH knockdown inhibits the malignancy progression through downregulating miR-505 mediated HMGB1 and CCNE2 in acute myeloid leukemia." Translational Cancer Research 8, no. 7 (November 2019): 2526–34. http://dx.doi.org/10.21037/tcr.2019.10.12.
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Chen, Di, Weijie Guo, Zhaoping Qiu, Qifeng Wang, Yan Li, Linhui Liang, Li Liu, Shenglin Huang, Yingjun Zhao, and Xianghuo He. "MicroRNA-30d-5p inhibits tumour cell proliferation and motility by directly targeting CCNE2 in non-small cell lung cancer." Cancer Letters 362, no. 2 (July 2015): 208–17. http://dx.doi.org/10.1016/j.canlet.2015.03.041.
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Ishiyama, Ken, Yukio Kondo, Eric Wieder, Sijie Lu, and Jeffrey Molldrem. "Aberrantly expressed neutrophil elastase (ELA2) in the nucleus and cytoplasm of acute lymphocytic leukemia (ALL) cells cleaves cyclin E (CCNE) into low-molecular-weight forms (LMWFs) yielding novel HLA-A2 restricted determinants (50.28)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S95—S96. http://dx.doi.org/10.4049/jimmunol.178.supp.50.28.
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Abstract We reported that CCNE-specific CTL elicited from healthy donors (HDs) kill ALL and CML cells, which aberrantly express CCNE. Further, 5 LMWFs of CCNE1 are present only in malignant cells and constitutively active to promote cell division. In addition, we showed ELA2-specific CTL also kill AML and CML, and ELA2 is normally expressed only in myeloid cells. To determine whether ELA2 might be aberrantly expressed in ALL and whether ELA2 cleaves CCNE to LMWF’s, we first found CCNE of LMWF to be overexpressed by western blot of cell lysates from ALL, but not from ALL in remission or HD B-cells. ELA2 added to ALL lysates increased LMWF’s and was inhibited by the ELA2 inhibitor elafin. Subcellular fractionation and co-immunoprecipitation showed ELA2 to be aberrantly associated with CCNE in nucleus, cytoplasm, and membrane-bound organelles in ALL, but not normal bone marrow cells. Because determinants recognized by CCNE-CTL are also found in the LMWFs and lysis of leukemia correlates with target protein overexpression, we studied the effect of induced CCNE expression on target susceptibility to cytolysis. While normal PBMC were not killed, PHA or α-CD3/28 stimulated PBMC were killed by CCNE-CTL, although non-specifically. We conclude that in ALL, aberrant expression of the myeloid protein ELA2 results in mistrafficking of ELA2 to cytoplasm and nucleus, thus mediating CCNE cleavage to LMWF’s and increasing susceptibility to CCNE-CTL killing. This shows novel tumor antigen interaction that may cooperatively reverse CTL tolerance.
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Bae, Jung Yoon, Jun Kanamune, Dong-Wook Han, Kazuaki Matsumura, and Suong-Hyu Hyon. "Reversible Regulation of Cell Cycle-Related Genes by Epigallocatechin Gallate for Hibernation of Neonatal Human Tarsal Fibroblasts." Cell Transplantation 18, no. 4 (April 2009): 459–69. http://dx.doi.org/10.3727/096368909788809776.
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We investigated the hibernation effect of epigallocatechin-3- O-gallate (EGCG) on neonatal human tarsal fibroblasts (nHTFs) by analyzing the expression of cell cycle-related genes. EGCG application to culture media moderately inhibited the growth of nHTFs, and the removal of EGCG from culture media led to complete recovery of cell growth. EGCG resulted in a slight decrease in the cell population of the S and G2/M phases of cell cycle with concomitant increase in that of the G0/G1 phase, but this cell cycle profile was restored to the initial level after EGCG removal. The expression of cyclin D1 (CCND1), CCNE2, CCN-dependent kinase 6 (CDK6), and CDK2 was restored, whereas that of CCNA, CCNB1, and CDK1 was irreversibly attenuated. The expression of a substantial number of genes analyzed by cDNA microarray was affected by EGCG application, and these affected expression levels were restored to the normal levels after EGCG removal. We also found the incorporation of FITC-EGCG into the cytosol of nHTFs and its further nuclear translocation, which might lead to the regulation of the exogenous signals directed to genes for cellular responses including proliferation and cell cycle progression. These results suggest that EGCG temporarily affects not only genes related to the cell cycle but also various other cellular functions.
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Shi, Hao, Gao-Feng Liang, Yang Li, Jing-Hua Li, Ai-Hua Jing, Wen-Po Feng, Guang-Da Li, Jing-Xia Du, and Shu-Ying Feng. "Preparation and Evaluation of Upconversion Nanoparticles Based miRNA Delivery Carrier in Colon Cancer Mice Model." Journal of Biomedical Nanotechnology 15, no. 11 (November 1, 2019): 2240–50. http://dx.doi.org/10.1166/jbn.2019.2840.
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Therapeutic efficacy of solid tumor is often severely hampered by poor penetration of therapeutics into diseased tissues and lack of tumor targeting. In this study, the functionalized upconversion nanoparticles (UCNP)-based delivery vector targeting cancer cells was developed. Firstly, NaYF4:Yb/Tm (UCNP) was prepared with the solvothermal method for the uniform nanoparticle size and brilliant lattice structure. The SiO2 coated UCNP was demonstrated a high upconversion emission and good monodispersity, which was coupled with polyetherimide (PEI) and miR-145 vector. Then, it was further functionalized via hyaluronic acid (HA) (UCNP/PEI/HA Nanocomplex, UCNPs) coating for the targeted delivery and improved biocompatibility. The UCNPs/miR-145 displays an excellent biocompatibility, a high level of cellular uptake and miR-145 expression, which results in a significant cell cycle arrest in G1, and induces CCND1, CDK6 and CCNE2 proteins downregulation. In vivo, the HA-coated UCNPs were enriched at the tumor site by targeting and retention effects, which resulted in a significant inhibition of tumor growth. Histological experiments demonstrated that UCNPs did not show significant toxicity in mice colon cancer model. Taken together, a UCNPs-based delivery platform was successfully constructed and used for miRNA target delivery, which provided a new method and idea for bioengineering and nanotechnology-based tumor therapy.
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Wang, Ji-fang, Zhuo-na Xi, Hong-jian Su, Zhen Bao, and Ya-hong Qiao. "SP1-induced overexpression of LINC00520 facilitates non-small cell lung cancer progression through miR-577/CCNE2 pathway and predicts poor prognosis." Human Cell 34, no. 3 (March 11, 2021): 952–64. http://dx.doi.org/10.1007/s13577-021-00518-y.
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Lin, Ruoyang, Xianfan Lin, Jinming Wu, Tanzhou Chen, and Zhiming Huang. "Inhibitory Effects of Rabdosia rubescens in Esophageal Squamous Cell Carcinoma: Network Pharmacology and Experimental Validation." Evidence-Based Complementary and Alternative Medicine 2022 (November 10, 2022): 1–16. http://dx.doi.org/10.1155/2022/2696347.
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Esophageal squamous cell carcinoma (ESCC) is one of the most frequently occurring diseases in the world. Rabdosia rubescens (RR) has been demonstrated to be effective against ESCC; however, the mechanism is unknown. The primary gene modules related to the clinical characteristics of ESCC were initially investigated in this research using weighted gene co-expression network analysis (WCGNA) and differential expression gene (DEG) analysis. We employed network pharmacology to study the hub genes linked with RR therapy on ESCC. A molecular docking simulation was achieved to identify the binding activity of central genes to RR compounds. Lastly, a chain of experimentations was used to verify the inhibitory effect of RR water extract on the ESCC cell line in vitro. The outcomes revealed that CCNA2, TOP2A, AURKA, CCNB2, CDK2, CHEK1, and other potential central targets were therapeutic targets for RR treatment of ESCC. In addition, these targets are over-represented in several cancer-related pathways, including the cell cycle signaling pathway and the p53 signaling pathway. The predicted targets displayed good bonding activity with the RR bioactive chemical according to a molecular docking simulation. In vitro experiments revealed that RR water extracts could inhibit ESCC cells, induce cell cycle arrest, inhibit cell proliferation, increase P53 expression, and decrease CCNA2, TOP2A, AURKA, CCNB2, CDK2, and CHEK1. In conclusion, our study reveals the molecular mechanism of RR therapy for ESCC, providing great potential for identifying effective compounds and biomarkers for ESCC therapy.
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Yang, Bo, Junying Zhang, Yaling Yin, and Yuanyuan Zhang. "Network-Based Inference Framework for Identifying Cancer Genes from Gene Expression Data." BioMed Research International 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/401649.
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Great efforts have been devoted to alleviate uncertainty of detected cancer genes as accurate identification of oncogenes is of tremendous significance and helps unravel the biological behavior of tumors. In this paper, we present a differential network-based framework to detect biologically meaningful cancer-related genes. Firstly, a gene regulatory network construction algorithm is proposed, in which a boosting regression based on likelihood score and informative prior is employed for improving accuracy of identification. Secondly, with the algorithm, two gene regulatory networks are constructed from case and control samples independently. Thirdly, by subtracting the two networks, a differential-network model is obtained and then used to rank differentially expressed hub genes for identification of cancer biomarkers. Compared with two existing gene-based methods (t-test and lasso), the method has a significant improvement in accuracy both on synthetic datasets and two real breast cancer datasets. Furthermore, identified six genes (TSPYL5, CD55, CCNE2, DCK, BBC3,andMUC1) susceptible to breast cancer were verified through the literature mining, GO analysis, and pathway functional enrichment analysis. Among these oncogenes,TSPYL5andCCNE2have been already known as prognostic biomarkers in breast cancer,CD55has been suspected of playing an important role in breast cancer prognosis from literature evidence, and other three genes are newly discovered breast cancer biomarkers. More generally, the differential-network schema can be extended to other complex diseases for detection of disease associated-genes.
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Borradaile, Nica M., and J. Geoffrey Pickering. "Polyploidy impairs human aortic endothelial cell function and is prevented by nicotinamide phosphoribosyltransferase." American Journal of Physiology-Cell Physiology 298, no. 1 (January 2010): C66—C74. http://dx.doi.org/10.1152/ajpcell.00357.2009.
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Polyploid endothelial cells are found in aged and atherosclerotic arteries. However, whether increased chromosome content has an impact on endothelial cell function is unknown. We show here that human aortic endothelial cells become tetraploid as they approach replicative senescence. Furthermore, accumulation of tetraploid endothelial cells was accelerated during growth in high glucose. Interestingly, induction of polyploidy was completely prevented by modest overexpression of the NAD+ regenerating enzyme, nicotinamide phosphoribosyltransferase (Nampt). To determine the impact of polyploidy on endothelial cell function, independent of replicative senescence, we induced tetraploidy using the spindle poison, nocodazole. Global gene expression analyses of tetraploid endothelial cells revealed a dysfunctional phenotype characterized by a cell cycle arrest profile (decreased CCNE2/A2, RBL1, BUB1B; increased CDKN1A) and increased expression of genes involved in inflammation ( IL32, TNFRSF21/10C, PTGS1) and extracellular matrix remodeling ( COL5A1, FN1, MMP10/14). The protection from polyploidy conferred by Nampt was not associated with enhanced poly(ADP-ribose) polymerase-1 or sirtuin (SIRT) 2 activity, but with increased SIRT1 activity, which reduced cellular reactive oxygen species and the associated oxidative stress stimulus for the induction of polyploidy. We conclude that human aortic endothelial cells are prone to chromosome duplication that, in and of itself, can induce characteristics of endothelial dysfunction. Moreover, the emergence of polyploid endothelial cells during replicative aging and glucose overload can be prevented by optimizing the Nampt-SIRT1 axis.
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Zeng, Lu, Xiude Fan, Xiaoyun Wang, Huan Deng, Kun Zhang, Xiaoge Zhang, Shan He, Na Li, Qunying Han, and Zhengwen Liu. "Bioinformatics Analysis based on Multiple Databases Identifies Hub Genes Associated with Hepatocellular Carcinoma." Current Genomics 20, no. 5 (December 3, 2019): 349–61. http://dx.doi.org/10.2174/1389202920666191011092410.
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Background: Hepatocellular carcinoma (HCC) is the most common liver cancer and the mechanisms of hepatocarcinogenesis remain elusive. Objective: This study aims to mine hub genes associated with HCC using multiple databases. Methods: Data sets GSE45267, GSE60502, GSE74656 were downloaded from GEO database. Differentially expressed genes (DEGs) between HCC and control in each set were identified by limma software. The GO term and KEGG pathway enrichment of the DEGs aggregated in the datasets (aggregated DEGs) were analyzed using DAVID and KOBAS 3.0 databases. Protein-protein interaction (PPI) network of the aggregated DEGs was constructed using STRING database. GSEA software was used to verify the biological process. Association between hub genes and HCC prognosis was analyzed using patients’ information from TCGA database by survminer R package. Results: From GSE45267, GSE60502 and GSE74656, 7583, 2349, and 553 DEGs were identified respectively. A total of 221 aggregated DEGs, which were mainly enriched in 109 GO terms and 29 KEGG pathways, were identified. Cell cycle phase, mitotic cell cycle, cell division, nuclear division and mitosis were the most significant GO terms. Metabolic pathways, cell cycle, chemical carcinogenesis, retinol metabolism and fatty acid degradation were the main KEGG pathways. Nine hub genes (TOP2A, NDC80, CDK1, CCNB1, KIF11, BUB1, CCNB2, CCNA2 and TTK) were selected by PPI network and all of them were associated with prognosis of HCC patients. Conclusion: TOP2A, NDC80, CDK1, CCNB1, KIF11, BUB1, CCNB2, CCNA2 and TTK were hub genes in HCC, which may be potential biomarkers of HCC and targets of HCC therapy.
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Lin, Chiao-Yun, Ren-Chin Wu, Chen-Yang Huang, Chyong-Huey Lai, An-Shine Chao, Hsin-Pai Li, Chia-Lung Tsai, Elizabeth Joo-Wen Kuek, Cheng-Lung Hsu, and Angel Chao. "A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches." Cancers 13, no. 23 (November 26, 2021): 5962. http://dx.doi.org/10.3390/cancers13235962.
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Conventional treatment of dedifferentiated endometrial carcinoma (DEC)–an uncommon and highly aggressive uterine malignancy–is beset by high failure rates. A line of research that holds promise to overcome these limitations is tailored treatments targeted on specific molecular alterations. However, suitable preclinical platforms to allow a reliable implementation of this approach are still lacking. Here, we developed a patient-derived xenograft (PDX) model for preclinical testing of investigational drugs informed by molecular data. The model–termed PDX-mLung was established in mice implanted with lung metastatic lesions obtained from a patient with DEC. Histologic and whole-exome genetic analyses revealed a high degree of identity between PDX-mLung and the patient’s parental lesions (both primary DEC and lung metastases). Interestingly, molecular analyses revealed that PDX-mLung harbored druggable alterations including a FGFR2 mutation and CCNE2 amplification. Targeted combined treatment with the FGFR inhibitor lenvatinib and the cell cycle inhibitor palbociclib was found to exert synergistic therapeutic effects against in vivo tumor growth. Based on the results of RNA sequencing, lenvatinib and palbociclib were found to exert anti-tumor effects by interfering interferon signaling and activating hormonal pathways, respectively. Collectively, these data provide proof-of-concept evidence on the value of PDX models for preclinical testing of molecularly informed drug therapy in difficult-to-treat human malignancies. Further clinical research is needed to examine more rigorously the potential usefulness of the lenvatinib and palbociclib combination in patients with DEC.
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Haydé, Vergara-Castañeda, Guevara-González Ramón, Guevara-Olvera Lorenzo, Oomah B. Dave, Reynoso-Camacho Rosalía, Wiersma Paul, and Loarca-Piña Guadalupe. "Non-digestible fraction of beans (Phaseolus vulgarisL.) modulates signalling pathway genes at an early stage of colon cancer in Sprague–Dawley rats." British Journal of Nutrition 108, S1 (August 23, 2012): S145—S154. http://dx.doi.org/10.1017/s0007114512000785.
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Colorectal cancer is one of the most common causes of morbidity and mortality in Western countries, the second cause of cancer mortality in the USA and a major public health problem in Mexico. A diet rich in legumes is directly related to the prevention of colon cancer, showing an inverse relationship with the development of colorectal adenomas in human subjects. The present study shows the results of molecular changes involved in theTp53pathway at an early stage in the distal colon tissue of azoxymethane (AOM)-induced colon cancer in rats evaluated by PCR array after exposure to diets containing the non-digestible fraction (NDF) of cooked bean (cultivar Bayo Madero). Significant differences were detected in seventy-two genes of theTp53-mediated signalling pathway involved in apoptosis, cell-cycle regulation and arrest, inhibition of proliferation and inflammation, and DNA repair.Tp53,Gadd45a,Cdkn1aandBaxwere highly expressed (9·3-, 18·3-, 5·5- and 3·5-fold, respectively) in the NDF+AOM group, whereasCdc25c,Ccne2,E2f1andBcl2were significantly suppressed ( − 9·2-, − 2·6-, − 18·4- and − 3·5-fold, respectively), among other genes, compared with the AOM group, suggesting that chemoprevention of aberrant crypt foci results from a combination of cell-cycle arrest in G1/S and G2/M phases and cell death by apoptotic induction. We demonstrate that the NDF from common bean modulates gene expression profiles in the colon tissue of AOM-induced rats, contributing to the chemoprotective effect of common bean on early-stage colon cancer.