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Sun, Chenyu, John Pocholo W. Tuason, Chandur Bhan, Arpana Paudel, Marwan K. Ahmed, Na Hyun Kim, Humaed Mohammed Abdul, et al. "Association of ITGA 11 and ITGAV upregulation with outcomes in gastric cancer." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): 332. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.332.
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332 Background: Gastric cancer (GC) is a common cancer worldwide. The integrin α (ITGA) family members play essential roles in various cancers and variants of ITGA are involved in metastatic process in gastric cancer. Thus, this study was conducted to explore the roles of ITGA family members in stomach adenocarcinoma (STAD). Methods: RNA-sequencing FPKM data and corresponding clinical information of 375 STAD tumor tissues and 32 normal tissues were retrieved from The Cancer Genome Atlas (TCGA). The ‘limma’ package was used to compare the expression differences between the normal and cancer tissues using Wilcoxon rank-sum test. Analysis of overall survival (OS) was conducted by Kaplan–Meier (K–M) method via ‘survminer’ package. Univariate Cox hazard regression analysis was applied to seven clinicopathological variables from T stage, N stage, M stage, pathologic stage, histologic grade, gender, age, and expression level of selected ITGA family members, by using ‘survival’ package. Furthermore, a nomogram was also visualized by the R ‘rms’ package and ‘survival’ package to predict the 1-, 3-, and 5-year OS and individual predictors. Results: The expression of ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA11, and ITGAV were upregulated in STAD tissues compared with normal tissues (P<0.05), whereas ITGA7, ITGA8, and ITGA9 were downregulated in tumor tissues (P<0.05). In addition, no statistically significant difference was found for TGA1 and ITGA10 between tumor and normal tissues ((P>0.05). Further survival analysis found that higher expression of ITGA 11 (HR=1.46, 95%CI 1.05-2.03, P<0.026) and ITGAV (HR=1.92, 95%CI 1.37-2.70, P<0.001) were associate with worse OS. Univariate Cox hazard regression analysis showed that T3, T4, N1, N3, M1, pathologic stage III and IV, age>65, and high expression level of ITGA11 and ITGAV were associated with worse OS (all P < 0.05). The nomogram based on six clinicopathological variables (T stage, N stage, M stage, pathologic stage, age, and expression levels of ITGA11 and ITGAV) and 1-, 3-, 5-year OS probabilities were developed. The concordance index (C-index) of the nomograms was 0.673(0.647-0.700), indicating that the potential predicting role and sufficient discrimination ability of the nomogram as C-index was more than 0.5. The calibration curves of 1-, 3-, and 5-year indicated the consistency of our results and the predictive values, indicating satisfactory performance for this nomogram. However, 1-, 3-, 5-year AUCs of ITGA11- and ITGAV-based nomogram were 0.687, 0.691, and 0.687, showing a relatively acceptable accuracy as they were great than 0.5. Conclusions: ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA11, and ITGAV are upregulated, while ITGA7, ITGA8, and ITGA9 are down regulated in STAD tumor samples. High expression levels of ITGA11 and ITGAV are associated with worse OS. The ITGA11- and ITGAV-based monogram developed by this study might be useful in predicting the OS outcome for STAD patients.
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Park, Hye Jin, Ji Eun Park, Hyun Lee, Seong Jae Kim, Jung Im Yun, Minseok Kim, Kyu Hyun Park, and Seung Tae Lee. "Integrins functioning in uterine endometrial stromal and epithelial cells in estrus." Reproduction 153, no. 3 (March 2017): 351–60. http://dx.doi.org/10.1530/rep-16-0516.
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Here, as a basic study in the construction of a non-cellular niche that supports artificial organization of three-dimensional endometrial tissue, we defined the types of integrin heterodimers that are expressed transcriptionally, translationally and functionally in endometrial stromal (ES) and endometrial epithelial (EE) cells isolated from the mouse uterus in estrus. Gene and protein expression of integrin subunits were analyzed at the transcriptional and translational level by real-time PCR and fluorescent immunoassay, respectively. Moreover, the functionality of integrin heterodimers was confirmed by attachment and antibody inhibition assays. Itga2, Itga5, Itga6, Itga9, Itgav, Itgb1, Itgb3 and Itgb5 in ES cells, and Itga2, Itga5, Itga6, Itga7, Itga9, Itgav, Itgb1, Itgb3, Itgb4, Itgb5 and Itga6 and in EE cells showed significantly higher transcriptional levels than the other integrin subunits. Furthermore, translational expression of the total integrin α and β subunit genes that showed increased transcription was determined in ES and EE cells. ES cells showed significantly increased adhesion to collagen I, fibronectin and vitronectin, and functional blocking of integrin α2, α5 or αV significantly inhibited adhesion to these molecules. Moreover, EE cells showed significantly increased adhesion to collagen I, fibronectin, laminin and vitronectin, and functional blocking of integrin α2, α5, α6 or αV significantly inhibited adhesion to these molecules. Accordingly, we confirmed that integrin α2β1, α5β1, αVβ1, αVβ3 and/or αVβ5, and integrin α2β1, α5β1, α6β1 and/or α6β4, αVβ1, αVβ3 and/or αVβ5, actively function on the surface of ES and EE cells from mouse uterus in estrus phase, respectively.
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Chidlow, John H., John D. Glawe, J. Steven Alexander, and Christopher G. Kevil. "VEGF164 differentially regulates neutrophil and T cell adhesion through ItgaL- and ItgaM-dependent mechanisms." American Journal of Physiology-Gastrointestinal and Liver Physiology 299, no. 6 (December 2010): G1361—G1367. http://dx.doi.org/10.1152/ajpgi.00202.2010.
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Leukocyte recruitment to inflamed tissues is the cornerstone of inflammatory responses and the driving force behind the establishment of inflammatory bowel disease, consisting of Crohn's disease and ulcerative colitis. It has been reported that angiogenic cytokines contribute to this inflammatory response that facilitates the chronic nature of disease. We have previously reported (Goebel S, Huang M, Davis WC, Jennings M, Siahaan TJ, Alexander JS, Kevil CG. Am J Physiol Gastrointest Liver Physiol 290: G648–G654, 2006) that vascular endothelial growth factor (VEGF)-A can stimulate neutrophil adhesion to colon microvascular endothelial cells in a β2-integrin (Itgb2)-dependent manner. However, it is not known which of the specific leukocyte integrins are critical for VEGF-A-dependent neutrophil and T cell recruitment. Here we examine the differential importance of either α-integrin (Itga)L or ItgaM in governing neutrophil and T cell adhesion to VEGF-A-activated colonic endothelium. Using an in vitro parallel-plate flow chamber model, we found that genetic deficiency of ItgaM completely blunted neutrophil adhesion to VEGF-A-stimulated endothelium, whereas ItgaL deficiency only partly blocked neutrophil adhesion. Deficiency of ItgaM did significantly decrease neutrophil rolling, whereas deficiency of ItgaL did not. We found that genetic deficiency of either ItgaL or ItgaM did significantly blunt T cell adhesion to VEGF-A-stimulated colon endothelium. We also found that genetic deficiency of these Itgas significantly attenuated T cell rolling behavior. Lastly, we examined whether VEGF-A-mediated leukocyte recruitment occurred through different VEGF receptor (VEGFR) pathways and found that VEGFR2 activation regulates neutrophil recruitment, whereas both VEGFR1 and VEGFR2 modulate T cell recruitment. Together, these data identify differential molecular mechanisms of VEGF-A-mediated leukocyte recruitment.
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Lin, Xiaozeng, Ying Dong, Yan Gu, Fengxiang Wei, Jingyi Peng, Yingying Su, Yanjun Wang, et al. "Taxifolin Inhibits the Growth of Non-Small-Cell Lung Cancer via Downregulating Genes Displaying Novel and Robust Associations with Immune Evasion Factors." Cancers 15, no. 19 (September 30, 2023): 4818. http://dx.doi.org/10.3390/cancers15194818.
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Using an LL2 cell-based syngeneic mouse LC model, taxifolin suppressed allografts along with the appearance of 578 differentially expressed genes (DEGs). These DEGs were associated with enhancement of processes related to the extracellular matrix and lymphocyte chemotaxis as well as the reduction in pathways relevant to cell proliferation. From these DEGs, we formulated 12-gene (TxflSig) and 7-gene (TxflSig1) panels; both predicted response to ICB (immune checkpoint blockade) therapy more effectively in non-small-cell lung cancer (NSCLC) than numerous well-established ICB biomarkers, including PD-L1. In both panels, the mouse counterparts of ITGAL, ITGAX, and TMEM119 genes were downregulated by taxifolin. They were strongly associated with immune suppression in LC, evidenced by their robust correlations with the major immunosuppressive cell types (MDSC, Treg, and macrophage) and multiple immune checkpoints in NSCLC and across multiple human cancer types. ITGAL, ITGAX, and IIT (ITGAL-ITGAX-TMEM119) effectively predicted NSCLC’s response to ICB therapy; IIT stratified the mortality risk of NSCLC. The stromal expressions of ITGAL and ITGAX, together with tumor expression of TMEM119 in NSCLC, were demonstrated. Collectively, we report multiple novel ICB biomarkers—TxflSig, TxflSig1, IIT, ITGAL, and ITGAX—and taxifolin-derived attenuation of immunosuppressive activities in NSCLC, suggesting the inclusion of taxifolin in ICB therapies for NSCLC.
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Takahashi, Toshiaki, Florian Friedmacher, Julia Zimmer, and Prem Puri. "Decreased Expression of Integrin Subunits α3, α6, and α8 in the Branching Airway Mesenchyme of Nitrofen-Induced Hypoplastic Lungs." European Journal of Pediatric Surgery 28, no. 01 (July 12, 2017): 109–14. http://dx.doi.org/10.1055/s-0037-1604022.
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Introduction Pulmonary hypoplasia (PH), characterized by smaller lung size and reduced airway branching, remains a major cause of neonatal mortality in newborns with congenital diaphragmatic hernia (CDH). Integrin-mediated cell–matrix interactions play an essential role in the fetal lung mesenchyme by stimulating branching morphogenesis. Mice lacking integrin subunits α3 (Itga3) and α6 (Itga6) exhibit severe PH. Furthermore, Itga8-knockout mice show defective airway branching, suggesting that Itga3, Itga6, and Itga8 are crucial for fetal lung development. We hypothesized that expression of Itga3, Itga6, and Itga8 is decreased in the branching airway mesenchyme of hypoplastic rat lungs in the nitrofen-induced CDH model. Materials and Methods Time-mated rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D15, D18, and D21, and dissected lungs were divided into control and nitrofen-exposed specimens (n = 12 per time-point and group, respectively). Pulmonary gene expression of Itga3, Itga6, and Itga8 was analyzed by quantitative real-time polymerase chain reaction. Immunofluorescence double-staining for Itga3, Itga6, and Itga8 was combined with the mesenchymal marker Fgf10 to evaluate protein expression and localization in branching airway tissue. Results Relative mRNA expression of Itga3, Itga6, and Itga8 was significantly decreased in lungs of nitrofen-exposed fetuses on D15, D18, and D21 compared with controls. Confocal laser scanning microscopy showed markedly diminished immunofluorescence of Itga3, Itga6, and Itga8 mainly in mesenchymal cells surrounding branching airways of nitrofen-exposed fetuses on D15, D18, and D21 compared with controls. Conclusion Decreased expression of Itga3, Itga6, and Itga8 in the pulmonary mesenchyme may lead to disruptions in airway branching morphogenesis, thus contributing to PH in the nitrofen-induced CDH model.
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Xu, D., T. Li, and R. Mu. "AB0095 EXPRESSION AND PATHOGENIC ROLES OF INTEGRIN FAMILY GENE IN SYSTEMIC SCLEROSIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1076.2–1076. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3646.
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Background:Emerging evidence have shown that some integrin members are associated with inflammation and fibrosis in systemic sclerosis (SSc) patients[1-2]. However, the expression patterns and pathogenic significance of the whole integrin family in SSc are still unclear.Objectives:This study aimed at evaluating the integrin family gene expression in skin lesion from SSc patients and exploring its potential pathogenic mechanism.Methods:We utilized the public datasets of SSc skin tissue from Gene Expression Omnibus (GEO) database to analyze the expression and clinical significance of integrin family genes in SSc. In addition, functional enrichment and pathway analysis were also conducted.Results:Compared with healthy controls, ITGA5, ITGA7, ITGA8, ITGB2, ITGB5, ITGAE and ITGB3BP were abnormally overexpressed in the skin of SSc. Further analysis indicated that ITGA5, ITGA7, ITGA8, ITGB2 and ITGB5 were positively correlated with modified Rodnan skin thickness score (mRSS), while ITGAE and ITGB3BP were negatively correlated with mRSS in SSc. Increased ITGB5 expression was associated with positive of anti-centromere antibody (ACA). Functional enrichment and pathway analysis showed that integrin members had multiple functions in SSc. Among them, ITGA5, ITGB2 and ITGB5 might synergistically promote SSc through affecting extracellular matrix (ECM) turn over, ECM-receptor interaction, focal adhesion and leukocyte trans-endothelial migration. ITGA5 and ITGB5 also affected angiogenesis and endothelial cell function. In addition, ITGA5 was uniquely enriched for actin organization, ITGB5 was uniquely enriched for TGF-β signaling, and ITGB2 was uniquely associated with immune cells activation.Conclusion:Our results implied that integrins, especially ITGA5, ITGB5, ITGB2 participated in the process of inflammation, vasculopathy and fibrosis in SSc. Together, they might render important therapeutic targets for SSc.References:[1]Brown M, O’Reilly S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin Exp Immunol. 2019;195(3):310-321.[2]Gerber, E.E., et al., Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature, 2013. 503(7474): p. 126-30.Disclosure of Interests:None declared
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Wang, Yizhe, Kezuo Hou, Yue Jin, Bowen Bao, Shiying Tang, Jianfei Qi, Yang Yang, et al. "Lung adenocarcinoma-specific three-integrin signature contributes to poor outcomes by metastasis and immune escape pathways." Journal of Translational Internal Medicine 9, no. 4 (December 1, 2021): 249–63. http://dx.doi.org/10.2478/jtim-2021-0046.
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ABSTRACT Background: Inhibitors targeting integrins (ITGs) are applied as a novel strategy for cancers including lung cancer; however, the heterogeneity of ITG subunits might explain why ITG-targeted inhibitors only show limited efficacy for a small group of lung cancer patients. Materials and methods: RNA-Seq data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients were obtained from the TCGA database. Cox regression analysis was performed to construct the prognostic signature and generate the nomogram combined with pathologic stages (pStage). GEO datasets were used for verification. The related biological functions were analyzed by Gene Set Enrichment Analysis (GSEA) software and the TIMER database. Results: By Cox regression analysis of 30 ITG subunits, ITG subunit alpha 5 (ITGA5), ITG subunit alpha 6 (ITGA6), and ITG subunit alpha L (ITGAL) were identified as the prognostic factors in LUAD, which were included in the construction of a LUAD-specific 3-ITG signature. Following the calculation of risk score (RS) of each patient based on 3-ITG signature, patients with high RS in LUAD were found to exhibit worse prognosis, especially in early stage. Nomogram combined with RS and pStage could predict the prognosis of LUAD patients accurately. Mechanism exploration by GSEA showed that metastasis-related microenvironmental pathways were significantly enriched in the high-RS group. An elevated expression of ITGA5 was mainly associated with the promotion of cell migration and invasion, while the high expression of ITGAL had a strong positive correlation with the capability of recognizing and killing cancer cells. Conclusions: Three-ITG signature could improve the prediction ability combined with pStage in LUAD and might contribute to poor prognosis by metastasis and immune escape-related pathways.
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Ząbek, Tomasz, Ewelina Semik, Agnieszka Fornal, Artur Gurgul, and Monika Bugno-Poniewierska. "The Relevance of Methylation Profiles of Equine ITGAL Gene." Annals of Animal Science 16, no. 3 (July 1, 2016): 711–20. http://dx.doi.org/10.1515/aoas-2015-0080.
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AbstractOne of epigenetic features of mammalian genomes is methylation of DNA. This nucleotide modification might exert suppressive effect on gene transcription. We have described putative relevance of methylation of one of immune cells related gene (ITGAL) observed in the set of 11 equine tissues. Comparison between qualitative RT-PCR results and DNA bisulfite sequencing of investigated set of tissues pointed to potential correlations between tissue specific methylation and tissue specific transcription in ITGAL locus. These findings might be important for studies on genetic and epigenetic background of autoimmune disorders in the horse.
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Esmaeili, Behnaz, Behnaz Bayat, Atefe Alirezaee, Mona Delkhah, Mohammad Reza Mehdizadeh, and Zahra Pourpak. "Human Neutrophil Antigen Genotype and Allele Frequencies in Iranian Blood Donors." Journal of Immunology Research 2022 (February 7, 2022): 1–11. http://dx.doi.org/10.1155/2022/4387555.
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Objective. Human neutrophil antigens (HNAs) can be targeted by HNA-allo antibodies and cause a variety of clinical conditions such as transfusion-related acute lung injury (TRALI) and neonatal alloimmune neutropenia (NAIN). The current study is aimed at identifying the genotype and allele frequencies of HNAs in Iranian blood donors. Methods. A total of 150 blood samples were obtained from healthy blood donors. HNA-1, HNA-3, HNA-4, and HNA-5 were genotyped, using the polymerase chain reaction sequence-specific primer (PCR-SSP) technique. The expression of the HNA-2 antigen on the neutrophil surface was evaluated by flow cytometry. Results. The allele frequencies of FCGR3B ∗ 1 (encoding HNA-1a), FCGR3B ∗ 2 (encoding HNA-1b), and FCGR3B ∗ 3 (encoding HNA-1c) were 0.34, 0.63, and 0.03, respectively. For HNA-3, the allele frequencies for SLC44A2 ∗ 1 (encoding HNA-3a) and SLC44A2 ∗ 2 (encoding HNA-3b) were 0.63 and 0.37, respectively. The frequencies of ITGAM ∗ 1 (encoding HNA-4a) and ITGAM ∗ 2 (encoding HNA-4b) alleles were 0.85 and 0.15, respectively. Furthermore, the frequencies of ITGAL ∗ 1 (encoding HNA-5a) and ITGAL ∗ 2 (encoding HNA-5b) alleles were 0.72 and 0.28, respectively. In the studied population, HNA-2 antigen was present on the neutrophil surface in 97.3% of the individuals, while no detectable HNA-2 expression was observed in 2.7% of the individuals. However, no significant difference in HNA-2 expression between different age groups was found. Conclusion. The present study provides the first report of the HNA allele and genotype frequencies among the Iranian population. All HNAs (HNA-1 to HNA-5) were typed using the PCR-SSP and flow cytometer. In the current cohort study, the determined HNA allele frequencies were similar to the previous reports from British, German, and Danish populations. Considering the presence of different Iranian ethnic groups, further studies with a larger sample size are needed to draw a total picture for HNA allele frequencies.
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Skov, Vibe, Mads Thomassen, Lasse Kjær, Caroline Riley, Thomas Stauffer Larsen, Ole Weis Bjerrum, Torben A. Kruse, and Hans Carl Hasselbalch. "Extracellular Matrix-Related Genes Are Deregulated in Peripheral Blood from Patients with Myelofibrosis and Related Neoplasms." Blood 132, Supplement 1 (November 29, 2018): 5491. http://dx.doi.org/10.1182/blood-2018-99-117122.
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Abstract Introduction: The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) which include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) are characterized by varying degrees of bone marrow fibrosis and endothelial proliferation. We and others have previously reported that these stromal alterations are reflected by increased serum levels of matrix derived metabolites, striated collagens type I/III and basement membrane components. The existence of a prefibrotic seromarker profile in MPNs is further evidenced by reports on increased serum levels of matrix metalloproteinase-3 (MMP-3) and decreased tissue inhibitor of metalloproteinase- I (TIMP-I). Using whole blood gene expression profiling, we aimed to provide a comprehensive gene signature of extracellular matrix-related proteins in MPNs with particular focus on genes associated with the regulation of major stromal proteins and MMPs. Methods: Gene expression profiling was performed on whole blood from 21 control subjects, 19 patients with ET, 41 patients with PV, and 9 patients with PMF. RNA was converted to biotin labeled amplified RNA (aRNA) using the MessageAmpTM III RNA amplification kit, and fragmented aRNA was hybridized to Affymetrix HG-U133 Plus 2.0 microarray chips recognizing 54,675 probe sets (38,500 genes). The R statistical software was applied to perform data preprocessing and statistical analysis of microarray data. Results: We identified 20,439, 25,307, and 17,417 probe sets that were differentially expressed between controls and patients with ET, PV, and PMF, respectively (FDR£0.05). These genes included 116 genes encoding extracellular matrix and adhesion molecules (ECM) important for cell-cell and cell-matrix interactions. These genes are represented on the Qiagen Human ECM panel, and in addition, all remaining collagen genes have been included. In patients with ET, COL1A1, COL1A2, COL3A1, COL4A2, COL4A5, LAMA2, LAMB1, MMP1, MMP7, MMP11, MMP12, MMP14, AND TIMP3 were among the 42 upregulated ECM genes (FDR<0.05). In patients with PV, 53 ECM genes were upregulated including COL1A1, COL1A2, COL3A1, COL4A2, LAMA2, LAMB1, MMP1, MMP7, MMP8, MMP9, MMP11, MMP12, MMP14, and TIMP3 (FDR<0.05). In PMF, COL1A2, COL3A1, COL4A2, COL4A5, LAMA2, MMP1, MMP8, MMP9, MMP14, and TIMP3 were among the 26 upregulated genes (FDR<0.05) (Table 1). 17, 14, and 13 ECM genes were significantly downregulated in ET, PV, and PMF, respectively (FDR<0.05) (data not shown). ITGA7, ITGB3, and MMP1 were significantly upregulated from ET over PV to PMF, whereas ITGAL, SPG7, and TGFBI were significantly downregulated from ET over PV to PMF. ADAMTS8, ADAMTS13, COL10A1, COL14A1, COL1A2, COL29A1, COL3A1, COL4A2, COL6A1, ITGA7, ITGB3, ITGB5, LAMA2, MMP1, MMP14, NCAM1, THBS2, and TIMP3 were significantly upregulated in both ET, PV, and PMF (FDR<0.05). COL4A3BP, COL6A2, ITGA4, ITGA5, ITGAL, ITGB1, PECAM1, SPG7, and TGFBI were significantly downregulated in both ET, PV, and PMF (FDR<0.05). In table 2a-b are shown the 10 most significantly up- and downregulated genes. Discussion and conclusions: Bone marrow fibrosis and endothelial proliferation in MPNs are elicited due to the release of fibrogenic and angiogenic growth factors primarily from hyperproliferating megakaryocytes. The connective tissue components of the bone marrow in MPNs include type III collagen, which is deposited in the early disease stages (ET/PV) as "reticulin fibrosis" being accompanied and substituted by mature Van Giesson positive collagen (type I collagen) in the advanced myelofibrosis stage. Increased endothelial cell proliferation is followed by the development of continuous sheets of basement membrane material beneath endothelial cells as assessed by increased deposition of type IV collagen and laminin. Using whole blood gene expression profiling, we provide evidence that abnormal extracellular matrix metabolism is reflected in the gene signature of peripheral blood cells from patients with MPNs. Further studies are needed to determine whether these changes represent local bone marrow fibrogenesis and/or systemic disease manifestations. Disclosures Hasselbalch: Novartis: Research Funding.
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Ратушный, А. Ю., and Л. Б. Буравкова. "ЭКСПРЕССИЯ ГЕНОВ ФОКАЛЬНОЙ АДГЕЗИИ В МУЛЬТИПОТЕНТНЫХ МЕЗЕНХИМАЛЬНЫХ СТРОМАЛЬНЫХ КЛЕТКАХ ПРИ МОДЕЛИРОВАНИИ ЭФФЕКТОВ МИКРОГРАВИТАЦИИ, "Доклады Академии наук"." Доклады Академии Наук, no. 1 (2017): 106–8. http://dx.doi.org/10.7868/s086956521731022x.
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Исследовали экспрессию 84 генов фокальной адгезии мультипотентных мезенхимальных стромальных клеток (ММСК) после 96-часового моделирования эффектов микрогравитации при 3D-клиностатировании. Обнаружили повышение экспрессии ITGA6, ITGA7, BCAR1, GRB2, CAV1, DIAPH1 и снижение ITGA11, ITGAV, ITGB1, PTEN, PTK2 (FAK), ARHGAP5, DOCK1, ROCK2, AKT3. Эти изменения на транскрипционном уровне могут быть одной из причин снижения остеогенного потенциала ММСК и их способности к миграции и адгезии в условиях микрогравитации.
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Hu, Chenyue W., Amina A. Qutub, Yihua Qiu, Suk Young Yoo, Nianxiang Zhang, Naval G. Daver, Maro Ohanian, Kevin Coombes, and Steven M. Kornblau. "Adhesion Signaling States in AML." Blood 124, no. 21 (December 6, 2014): 2386. http://dx.doi.org/10.1182/blood.v124.21.2386.2386.
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Abstract Background Stromal contact in the bone marrow microenvironment is known to affect the resistance of leukemic cells to therapy, in particular the homing and engraftment of leukemic stem cells. This stromal interaction is mediated by the adhesion signaling pathway including extracellular matrix proteins (e.g. FN1, SPP1), cell surface and transmembrane proteins (e.g. CD44, integrin, CAV1), as well as intracellular binding proteins and enzymes (e.g. IGFBP2, PTK2, TGM2). Previous studies mostly examined these proteins in isolation, and hence they were unable to capture the coordination among subpathways and within patient subpopulations. Therefore, it is of key interest to study these proteins in their ensemble and obtain a holistic view of how adhesion signaling pathway gives rise to and affects different AML subpopulations. Methods To profile protein expressions in AML, we made a reverse phase protein array (RPPA) with proteins from leukemia enriched cells from 511 new AML patients. Both bone marrow (n=387) and peripheral blood (n=283) samples were used, with 140 cases having both. The RPPA was probed with 231 strictly validated antibodies, including antibodies against ITGA2, ITGB3, FN1, ITGAL, PTK2, IGFBP2, CD44, SPP1, CAV1 and TGM2. The normal bone marrow derived CD34+ cells were used for comparison. The protein expression data generated from this RPPA was then analyzed by the Standard Proteomic Analysis (SPA), a combination of computational methods including clustering, principal component analysis, network reconstruction (glasso), survival analysis, correlation tests and data mining from public databases. Results Based on the expression levels of ten proteins in the adhesion pathway, we first built a heatmap (Figure A) using “Prototype Clustering” that grouped all patients into six distinct clusters featured by C1) pan low, C2) high SPP1-CD44; C3) high CAV1; C4) high PTK2-ITGA2-ITGB3-FN1-IGFBP2-TGM2; C5) high TGM2; C6) high ITGAL and pan intermediate high expression levels. The adhesion pathway in AML showed literature-consistent patterns, e.g. the coupling between CD44 and SPP1 and the co-expression among integrin subunits, FN1 and PTK2, but also demonstrated new patterns, e.g. independent regulation of CAV1, as well as decoupled expression of TGM2 from the integrins. Each patient cluster represents an adhesion signaling state that can be seen in AML. As shown in this transition map (Figure B), there is an OFF state (C1), two isolated activation states of either CAV1 (C3) or CD44-SPP1 (C2), two intermediate activation states of either TGM2 (C5) or ITGAL (C6), and a combined activation state (C4) from the two intermediate states. By combining both connections inferred from the data and interactions collected from public databases (e.g. String, KEGG), we were able to expand the protein network beyond adhesion pathway and examine their expression levels in each adhesion signaling state. We observed positive co-regulation of SRC and PRKCA with the integrin subunits, connections between IGFBP2 and metabolism/synthesis proteins (e.g. GADPH, EIF4E, GSK), as well as the association of CD44 with histone modification (H3K4Me2, H3K4Me3), most of which have not been reported before. The adhesion activation states are not associated with most clinical correlates, including FLT3 and NPM1 mutation, gender and response status, with the exception of the CAV1 activation state (C3). A significant amount of patients with high CAV1 expression levels are in the favorable cytogenetics group (35% vs. 8% in general, p=0.00001), thus have fewer relapses (relapse rate of 26% vs. 64% in general, p=0.001) and superior overall survival (Figure C) and remission duration (Figure D). Conclusions We have discovered previously unrecognized protein expression patterns and activation states that control stromal contact and adhesion in AML. This includes independent activation of SPP1-CD44 and CAV1, intermediate activation of TGM2 and ITGAL and combined activation of integrin-FN1-PTK2, indicating diverse stromal interaction states in the bone marrow. In particular, the activation of CAV1 is prognostically favorable, suggesting a potential target for future therapeutics in AML. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Zhu, Xueyi, Baojun Liu, Zhenhui Ruan, Mengmeng Chen, Congcong Li, Hanlin Shi, Xi Huang, et al. "TMT-Based Quantitative Proteomic Analysis Reveals Downregulation of ITGAL and Syk by the Effects of Cycloastragenol in OVA-Induced Asthmatic Mice." Oxidative Medicine and Cellular Longevity 2022 (October 25, 2022): 1–20. http://dx.doi.org/10.1155/2022/6842530.
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Background. Cycloastragenol (CAG) has been reported to alleviate airway inflammation in ovalbumin- (OVA-) induced asthmatic mice. However, its specific mechanisms remain unclear. Objective. This study is aimed at investigating the effects of CAG on asthma, comparing its efficacy with dexamethasone (DEX), and elucidating the mechanism of CAG’s regulation. Methods. The asthma mouse model was induced by OVA. CAG at the optimal dose of 125 mg/kg was given every day from day 0 for 20-day prevention or from day 14 for a 7-day treatment. We observed the preventive and therapeutic effects of CAG in asthmatic mice by evaluating the airway inflammation, AHR, and mucus secretion. Lung proteins were used for TMT-based quantitative proteomic analysis to enunciate its regulatory mechanisms. Results. The early administration of 125 mg/kg CAG before asthma happened prevented asthmatic mice from AHR, airway inflammation, and mucus hypersecretion, returning to nearly the original baseline. Alternatively, the administration of CAG during asthma also had the same therapeutic effects as DEX. The proteomic analysis revealed that the therapeutical effects of CAG were associated with 248 differentially expressed proteins and 3 enriched KEGG pathways. We then focused on 3 differentially expressed proteins (ITGAL, Syk, and Vav1) and demonstrated that CAG treatment downregulated ITGAL, Syk, and Vav1 by quantitative real-time PCR, western blot analysis, and immunohistochemical staining. Conclusion. These findings suggest that CAG exerts preventive and protective effects on asthma by inhibiting ITGAL, Syk, and the downstream target Vav1.
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Takashima, Yasuo, Atsushi Kawaguchi, Junya Fukai, Yasuo Iwadate, Koji Kajiwara, Hiroaki Hondoh, and Ryuya Yamanaka. "Survival prediction based on the gene expression associated with cancer morphology and microenvironment in primary central nervous system lymphoma." PLOS ONE 16, no. 6 (June 24, 2021): e0251272. http://dx.doi.org/10.1371/journal.pone.0251272.
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Dysregulation of cell morphology and cell-cell interaction results in cancer cell growth, migration, invasion, and metastasis. Besides, a balance between the extracellular matrix (ECM) and matrix metalloprotease (MMP) is required for cancer cell morphology and angiogenesis. Here, we determined gene signatures associated with the morphology and microenvironment of primary central nervous system lymphoma (PCNSL) to enable prognosis prediction. Next-generation sequencing (NGS) on 31 PCNSL samples revealed gene signatures as follows: ACTA2, ACTR10, CAPG, CORO1C, KRT17, and PALLD in cytoskeleton, CDH5, CLSTN1, ITGA10, ITGAX, ITGB7, ITGA8, FAT4, ITGAE, CDH10, ITGAM, ITGB6, and CDH18 in adhesion, COL8A2, FBN1, LAMB3, and LAMA2 in ECM, ADAM22, ADAM28, MMP11, and MMP24 in MMP. Prognosis prediction formulas with the gene expression values and the Cox regression model clearly divided survival curves of the subgroups in each status. Furthermore, collagen genes contributed to gene network formation in glasso, suggesting that the ECM balance controls the PCNSL microenvironment. Finally, the comprehensive balance of morphology and microenvironment enabled prognosis prediction by a combinatorial expression of 8 representative genes, including KRT17, CDH10, CDH18, COL8A2, ADAM22, ADAM28, MMP11, and MMP24. Besides, these genes could also diagnose PCNSL cell types with MTX resistances in vitro. These results would not only facilitate the understanding of biology of PCNSL but also consider targeting pathways for anti-cancer treatment in personalized precision medicine in PCNSL.
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Li, Chunguang, Li Zhang, Long Zhang, and Guang Zhang. "Correlation between elevated HCLS1 levels and heart failure: A diagnostic biomarker." Medicine 103, no. 23 (June 7, 2024): e38484. http://dx.doi.org/10.1097/md.0000000000038484.
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The correlation between hematopoietic cell-specific lyn substrate 1 (HCLS1) expression levels and heart failure (HF) remains unclear. HF datasets GSE192886 and GSE196656 profiles were generated from GPL24676 and GPL20301 platforms in gene expression omnibus (GEO) database and differentially expressed genes (DEGs) were obtained, which was followed by weighted gene co-expression network analysis, protein-protein interaction (PPI) networks, functional enrichment analysis and comparative toxicogenomics database (CTD) analysis. Heatmaps of gene expression levels were plotted. TargetScan was used to screen miRNAs regulating central DEGs. A total of 500 DEGs were found and mainly concentrated in leukocyte activation, protein phosphorylation, and protein complexes involved in cell adhesion, PI3K Akt signaling pathway, Notch signaling pathway, and right ventricular cardiomyopathy. PPI network identified 15 core genes (HCLS1, FERMT3, CD53, CD34, ITGAL, EP300, LYN, VAV1, ITGAX, LEP, ITGB1, IGF1, MMP9, SMAD2, RAC2). Heatmap shows that 4 genes (EP300, CD53, HCLS1, LYN) are highly expressed in HF tissue samples. We found that 4 genes (EP300, CD53, HCLS1, LYN) were associated with heart diseases, cardiovascular diseases, edema, rheumatoid arthritis, necrosis, and inflammation. HCLS1 is highly expressed in HF and maybe its target.
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Burghardt, Robert C., James R. Burghardt, James D. Taylor, Adele T. Reeder, Bar T. Nguen, Thomas E. Spencer, Kayla J. Bayless, and Greg A. Johnson. "Enhanced focal adhesion assembly reflects increased mechanosensation and mechanotransduction at maternal–conceptus interface and uterine wall during ovine pregnancy." REPRODUCTION 137, no. 3 (March 2009): 567–82. http://dx.doi.org/10.1530/rep-08-0304.
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The integrity of the fetal–maternal interface is critical for proper fetal nourishment during pregnancy. Integrins are important adhesion molecules present at the interface during implantation; however,in vivoevidence for integrin activation and focal adhesion formation at the maternal–conceptus interface is limited. We hypothesized that focal adhesion assembly in uterine luminal epithelium (LE) and conceptus trophectoderm (Tr) results from integrin binding of extracellular matrix (ECM) at this interface to provide increased tensile forces and signaling to coordinate utero-placental development. An ovine model of unilateral pregnancy was used to evaluate mechanotransduction events leading to focal adhesion assembly at the maternal–conceptus interface and within the uterine wall. Animals were hysterectomized on days 40, 80, or 120 of pregnancy, and uteri immunostained for integrins (ITGAV, ITGA4, ITGA5, ITGB1, ITGB3, and ITGB5), ECM proteins (SPP1, LGALS15, fibronectin (FN), and vitronectin (VTN)), cytoskeletal molecules (ACTN and TLN1), and a signal generator (PTK2). Focal adhesion assembly in myometrium and stroma was also studied to provide a frame of reference for mechanical stretch of the uterine wall. Large focal adhesions containing aggregates of ITGAV, ITGA4, ITGA5, ITGB1, ITGB5, ACTN, and PTK2 were detected in interplacentomal uterine LE and Tr of gravid but not non-gravid uterine horns and increased during pregnancy. SPP1 and LGALS15, but not FN or VTN, were present along LE and Tr interfaces in both uterine horns. These data support the idea that focal adhesion assembly at the maternal–conceptus interface reflects adaptation to increasing forces caused by the growing fetus. Cooperative binding of multiple integrins to SPP1 deposited at the maternal–conceptus interface forms an adhesive mosaic to maintain a tight connection between uterine and placental surfaces along regions of epitheliochorial placentation in sheep.
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Yakubets, D. A., Е. А. Markina, and L. B. Buravkova. "DIFFERENTIAL EXPRESSION OF THE ADHESION AND CELL-TO-CELL INTERACTION MOLECULES GENES IN BONE MARROW MICROEXPLANTS UNDER SIMULATED MICROGRAVITY." Aerospace and Environmental Medicine 58, no. 5 (2024): 72–77. http://dx.doi.org/10.21687/0233-528x-2024-58-5-72-77.
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Functional activity of the bone marrow cells is dependent on external signals received from a local microenvironment. In addition to the soluble growth factors and hormones, contacts with neighbor cells and signals from the extracellular matrix are also the most important homeostasis regulators in the bone marrow niche. Purpose of the work is to explore the effects of simulated microgravity on the transcription activity of genes the products of which define the cell-to-cell and cell-to-matrix interactions in bone marrow micro-explants. Femoral marrow cells from male mice BalbC 19-20 wks of age were used in the investigation. After isolation, bone marrow cells were pooled and exposed to simulated microgravity in vitro over 14 days. Following the exposure, bone marrow micro-explants were found to increase expression of genes of the cell adhesion molecules responsible for cell-to-cell interaction (Ncam1, Icam1, Vcam1), and integrins α-М (Itgam) and β-1 (Itgb1). Also, there was a reliable decrease in expression of genes involved in the cell-to-matrix interaction, including integrins β-3 (Itgb3), β-2 (Itgb2), α-Х (Itgax), α-l (Itga1), α-5 (Itga5), receptor CD44 (Cd44), and molecules of the adhesion complexes, such as α- and β-katenins (Ctnna1, Ctnnb1). These changes in the pattern of cells-to-environment interaction may induce disorders in self-renewal, proliferation and differentiation of stromal and hemopoietic precursors which may end up with distortion of hemopoiesis, change in bone homeostasis leading to osteopenia observed after space missions.
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Lu, Qianjin, Donna Ray, David Gutsch, and Bruce Richardson. "Effect of DNA methylation and chromatin structure onITGAL expression." Blood 99, no. 12 (June 15, 2002): 4503–8. http://dx.doi.org/10.1182/blood.v99.12.4503.
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LFA-1 (CD11a/CD18, αLβ2) is an integrin expressed in a tissue-specific fashion and is important in inflammatory and immune responses. Promoter analysis has identified transcription factors that may be involved in CD11a expression, but the mechanisms contributing to its tissue-specific expression are incompletely characterized. In this report we have asked if DNA methylation and/or chromatin structure could contribute to tissue-specific CD11a expression. Bisulfite sequencing was used to compare methylation patterns in the promoter and 5′ flanking regions of the ITGAL gene, encoding CD11a, in normal human T cells, which express LFA-1, and fibroblasts, which do not. The region was found to be heavily methylated in fibroblasts but not T cells, and methylation correlated with an inactive chromatin configuration as analyzed by deoxyribonuclease 1 sensitivity. Patch methylation of the promoter region revealed that promoter activity was methylation-sensitive but that methylation of the 5′ flanking regions more than 500 base pairs 5′ to the transcription start site could also suppress promoter function. Treating fibroblasts with a DNA methylation inhibitor decreased ITGAL promoter methylation and increased CD11a messenger RNA. The results thus indicate that methylation and chromatin structure may contribute to the tissue-specific expression of CD11a.
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Zhang, Zhiyong, Chun Deng, Qianjin Lu, and Bruce Richardson. "Age-dependent DNA methylation changes in the ITGAL (CD11a) promoter." Mechanisms of Ageing and Development 123, no. 9 (May 2002): 1257–68. http://dx.doi.org/10.1016/s0047-6374(02)00014-3.
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Mautone, Lorenza, Carlo Ferravante, Anna Tortora, Roberta Tarallo, Giorgio Giurato, Alessandro Weisz, and Mario Vitale. "Higher Integrin Alpha 3 Beta1 Expression in Papillary Thyroid Cancer Is Associated with Worst Outcome." Cancers 13, no. 12 (June 11, 2021): 2937. http://dx.doi.org/10.3390/cancers13122937.
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Integrins are cell-extracellular matrix adhesion molecules whose expression level undergoes quantitative changes upon neoplastic transformation and are considered functionally related to the development of cancer metastasis. We analyzed the largest mRNA-seq dataset available to determine the expression pattern of integrin family subunits in papillary thyroid carcinomas (PTC). ITGA2, 3, 6, V, and ITGB1 integrin subunits were overexpressed in PTC compared to normal thyroid tissue. The PTC histology variants “classical” and “tall cell” displayed a similar integrin expression profile with a higher level of ITGA3, ITGAV, and ITGB1, which differed from that of the “follicular” variant. Interestingly, compared to RAS mutations, BRAFV600E mutation was associated with a significantly higher expression of integrins. Some integrin subunits were associated with advanced disease stage, lymph node metastasis, extrathyroidal extension, and high-risk groups. Among them, ITGA3 expression displayed the highest correlation with advanced disease and was associated with a negative prognosis. In vitro scratch assay and Matrigel invasion assay in two different PTC cell lines confirmed α3β1 role in cell motility and invasion, supporting its involvement during tumor progression. These results demonstrate the existence of a PTC-specific integrin expression signature correlated to histopathology, specific driver gene mutations, and aggressiveness of the disease.
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Saha, Subbroto Kumar, Tak-Il Jeon, Soo Bin Jang, Se Jong Kim, Kyung Min Lim, Yu Jin Choi, Hyeong Gon Kim, Aram Kim, and Ssang-Goo Cho. "Bioinformatics Approach for Identifying Novel Biomarkers and Their Signaling Pathways Involved in Interstitial Cystitis/Bladder Pain Syndrome with Hunner Lesion." Journal of Clinical Medicine 9, no. 6 (June 21, 2020): 1935. http://dx.doi.org/10.3390/jcm9061935.
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The complexity of interstitial cystitis/bladder pain syndrome (IC/BPS) has led to considerable uncertainty in terms of diagnosis and prevalence of the condition. Here, we try to identify the IC/BPS-associated genes through an integrated analysis of Gene Expression Omnibus (GEO) datasets and confirm experimentally to predict the pathologic diagnosis of IC/BPS. Data mining analysis of GEO datasets (GSE621, GSE11783, GSE28242, and GSE57560) revealed a total of 53 (51 upregulated and two downregulated) common differentially expressed genes (DEGs) in IC/BPS. A protein–protein interaction (PPI) network was then constructed with the 53 common DEGs using Cytoscape v3.7.2, and subsequently, six hub genes (CD5, CD38, ITGAL, IL7R, KLRB1, and IL7R) were identified using cytoHubba v0.1 that were upregulated in IC/BPS. Enrichment analysis of common DEGs revealed that hematopoietic cell lineage, immune system, and T-cell receptor (TCR) signaling in naïve CD4+ T cell signaling pathways were prominently involved with the common 51 upregulated DEGs. The two common downregulated DEGs may enrich linoleic acid metabolism and synthesis of epoxy (EET) and dihydroxyeicosatrienoic acid (DHET) signaling pathways in IC/BPS. Moreover, our RT-PCR data confirmed that the expression of the five hub genes (CD38, ITGAL, IL7R, KLRB1, and IL7R) was significantly augmented in IC/BPS patients’ samples when compared with their normal counterparts. In this study, we systematically predict the significant biomarkers and possible signaling pathways involved in IC/BPS, confirming the differential expression of the hub genes in tissue samples from patients with IC/BPS. Thus, the hub genes might be used as potential diagnostic biomarkers of IC/BPS.
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Shochet, Gali Epstein, Elizabetha Brook, Becky Bardenstein-Wald, Hanna Grobe, Evgeny Edelstein, Lilach Israeli-Shani, and David Shitrit. "Integrin alpha-5 silencing leads to myofibroblastic differentiation in IPF-derived human lung fibroblasts." Therapeutic Advances in Chronic Disease 11 (January 2020): 204062232093602. http://dx.doi.org/10.1177/2040622320936023.
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Background and objective: The term ‘fibroblast’ covers a heterogeneous cell population in idiopathic pulmonary fibrosis (IPF). The fibroblasts are considered as main effector cells, because they promote disease progression by releasing exaggerated amounts of extracellular matrix proteins and modifying cell microenvironment. As IPF-derived human lung fibroblasts (IPF-HLFs) were shown to express higher levels of integrin alpha-5 (ITGA5) than normal derived HLFs (N-HLFs), we explored the importance of ITGA5 to IPF progression. Methods: IPF-HLF and N-HLF primary cultures were established. ITGA5 was silenced by specific small interfering RNA (siRNA)s and its effects on cell phenotype (e.g. cell number, size, cell death, migration) and gene expression (e.g. RNA sequencing, quantitative polymerase chain reaction [qPCR], western blot and immunofluorescence) were tested. Specific integrin expression was evaluated in IPF patient formalin-fixed paraffin embedded sections by immunohistochemistry (IHC). Results: ITGA5-silencing resulted in reduced IPF-HLF proliferation rates and cell migration ( p < 0.05), as well as elevated cell death. transforming growth factor beta (TGF-β) targets (e.g. Fibronectin (FN1), Matrix metalloproteinase 2 (MMP2), TGFB1) were surprisingly elevated following ITGA5 silencing ( p < 0.05). N-HLFs, however, were only slightly affected. Interestingly, ITGA5-silenced cells differentiated into myofibroblasts (e.g. elevated alpha-smooth muscle actin [αSMA], collagen1a, large cell size). RNA-sequencing revealed that following differentiation on 3D-Matrigel for 24 h, ITGA5 levels are reduced while integrin alpha-8 (ITGA8) are elevated in IPF-HLFs. This was confirmed in IPF patients, in which ITGA5 was mainly found in fibroblastic foci, while ITGA8 was mostly observed in old fibrous tissue in the same patient. Conclusions: ITGA5 expression facilitates a more aggressive proliferative phenotype. Downregulation of this integrin results in myofibroblastic differentiation, which is accompanied by elevated ITGA8. Specific targeting could present a therapeutic benefit.
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Oh, William K., Uma Chippada Venkata, Li Wang, Emma Reese, Tiffany Yee, Teena Kochukoshy, Che-Kai Tsao, Matt D. Galsky, Jun Zhu, and Yixuan Gong. "Validation of a whole-blood RNA prognostic signature in metastatic castration-resistant prostate cancer (mCRPC) patients." Journal of Clinical Oncology 32, no. 4_suppl (February 1, 2014): 36. http://dx.doi.org/10.1200/jco.2014.32.4_suppl.36.
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36 Background: We developed a whole-blood RNA transcript-based six gene signature (ABL2, SEMA4D, ITGAL, C1QA, TIMP1, CDKN1A), which separates patients with metastatic castration-resistant prostate cancer (mCRPC) into high- and low-risk survival groups (Ross et al. Lancet Oncology, 2012). In this study, the prognostic utility of the signature is validated on two independent platforms: an updated qPCR platform and an RNA-sequence platform in a new cohort of patients. The dynamic changes in the gene expression are examined during disease progression in serial samples from individual patients. Methods: Whole blood RNA was extracted from PAXgene tubes drawn from 63 patients with prostate cancer representing a range of clinical disease states. Serial samples were collected from a subset of patients (n=34). Survival prediction scores were derived independently based on the RNA-transcript levels of the six genes as quantified by a new ViiA 7 qPCR platform and by Illumina RNA-sequence. Results: The six gene signature scores generated on both qPCR and RNA-sequence platforms remain highly prognostic, separating mCRPC patients into high- and low-risk survival groups (logrank test; p-value for qPCR <0.001; p-value for RNA-seq <0.001). In contrast, prostate-specific antigen (PSA) fails to predict survival in the same cohort. There is a weak correlation between PSA and the six gene score (p-value of spearman correlation=0.14), indicating that the six gene score provides unique information regarding disease status. Patients with serial blood draws demonstrated no relationship with PSA changes. Patients with localized and hormone sensitive prostate cancer had significantly lower six gene scores (p-value=0.036). Individual gene analysis revealed that two genes, ABL2 and ITGAL, as the major contributors to the prognostic score. Conclusions: Our results further validate the prognostic significance of a six gene whole blood RNA signature, using an independent cohort and independent platforms.
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COUSTET, BAPTISTE, SANDEEP K. AGARWAL, PRAVITT GOURH, MICKAEL GUEDJ, MAUREEN D. MAYES, PHILIPPE DIEUDE, JULIEN WIPFF, et al. "Association Study of ITGAM, ITGAX, and CD58 Autoimmune Risk Loci in Systemic Sclerosis: Results from 2 Large European Caucasian Cohorts." Journal of Rheumatology 38, no. 6 (March 1, 2011): 1033–38. http://dx.doi.org/10.3899/jrheum.101053.
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Objective.Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations.Methods.SNP harboring associations with autoimmune diseases, ITGAM rs9937837, ITGAX rs11574637, and CD58 rs12044852, were genotyped in 2 independent cohorts of European Caucasian ancestry: 1031 SSc patients and 1014 controls from France and 1038 SSc patients and 691 controls from the USA, providing a combined study population of 3774 individuals. ITGAM rs1143679 was additionally genotyped in the French cohort.Results.The 4 polymorphisms were in Hardy-Weinberg equilibrium in the 2 control populations, and allelic frequencies were similar to those expected in European Caucasian populations. Allelic and genotypic frequencies for these 3 SNP were found to be statistically similar in SSc patients and controls. Subphenotype analyses for subgroups having diffuse cutaneous subtype disease, specific autoantibodies, or fibrosing alveolitis did not reveal any difference between SSc patients and controls.Conclusion.These results obtained through 2 large cohorts of SSc patients of European Caucasian ancestry do not support the implication of ITGAM, ITGAX, and CD58 genes in the genetic susceptibility of SSc, although they were recently identified as autoimmune disease risk genes.
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Souza, Camila O. S., Jefferson Elias-Oliveira, Caroline Fontanari, Vanderlei Rodriguez, Luiz Gardinassi, and Lucia Faccioli. "CD18 regulates monocyte-macrophage DC progenitors and the differentiation into alternatively activated macrophages during schistosomiasis." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 99.29. http://dx.doi.org/10.4049/jimmunol.206.supp.99.29.
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Abstract Infection with Schistosoma mansoni causes a chronic parasitic disease. Along the course of schistosomiasis, innate immune cells are recruited and accumulate into Th2-granuloma in the liver. Recently, our group demonstrated that the common chain of β2-integrin (CD18) was crucial for monocytopoiesis and resistance to experimental S. mansoni infection. Inside the tissue, inflammatory monocytes (IMs) differentiate and polarize in alternatively activated macrophages (AAMs) in a type 2 microenvironment. In this context, we evaluated the role of CD18 on monocytes progenitors and differentiation into AAMs during chronic schistosomiasis. First, we evaluated the monocyte progenitor cells in the bone marrow from wild-type (WT) and CD18low mice. The low expression of CD18 increased the frequency and absolute number of monocyte-macrophage DC progenitor (MDP), while MFI of Ki-67 were reduced on MDP and common monocytes progenitor (cMoP) at 7 weeks post infection (wpi). Next, we evaluated the integrins family in the liver from S. mansoni-infected mice. We showed increase expression of Itgam when compared to Itgal in the liver at 7 wpi. The frequency of CD11b+cells also increased at 7 wpi, compared to CD11a+ cells. Moreover, compared to WT mice, CD18low animals reduced the MFI of CD11b and CD11c in IMs. The alternative activation markers, Chil3l3 and Arg1 were reduced in CD18low. Indeed, compared to WT mice, CD18low animals reduced the percentage of CD206+PD-L2+ AAMs in the liver at 7 wpi. In addition, the adoptive transference of IMs to CD18low mice reduces the inflammatory infiltrate in the liver at 7 wpi. Overall, our data indicate CD18 coordinated the monocytes differentiation into AAMs during chronic S. mansoni infection.
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Wang, YaoYao, Ye Shu, YangFan Xiao, Qing Wang, Takuro Kanekura, YaPing Li, JiuCun Wang, Ming Zhao, QianJin Lu, and Rong Xiao. "Hypomethylation and overexpression of ITGAL (CD11a) in CD4+ T cells in systemic sclerosis." Clinical Epigenetics 6, no. 1 (2014): 25. http://dx.doi.org/10.1186/1868-7083-6-25.
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Johnson Chacko, Lejo, Hanae Lahlou, Claudia Steinacher, Said Assou, Yassine Messat, József Dudás, Albert Edge, et al. "Transcriptome-Wide Analysis Reveals a Role for Extracellular Matrix and Integrin Receptor Genes in Otic Neurosensory Differentiation from Human iPSCs." International Journal of Molecular Sciences 22, no. 19 (October 7, 2021): 10849. http://dx.doi.org/10.3390/ijms221910849.
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We analyzed transcriptomic data from otic sensory cells differentiated from human induced pluripotent stem cells (hiPSCs) by a previously described method to gain new insights into the early human otic neurosensory lineage. We identified genes and biological networks not previously described to occur in the human otic sensory developmental cell lineage. These analyses identified and ranked genes known to be part of the otic sensory lineage program (SIX1, EYA1, GATA3, etc.), in addition to a number of novel genes encoding extracellular matrix (ECM) (COL3A1, COL5A2, DCN, etc.) and integrin (ITG) receptors (ITGAV, ITGA4, ITGA) for ECM molecules. The results were confirmed by quantitative PCR analysis of a comprehensive panel of genes differentially expressed during the time course of hiPSC differentiation in vitro. Immunocytochemistry validated results for select otic and ECM/ITG gene markers in the in vivo human fetal inner ear. Our screen shows ECM and ITG gene expression changes coincident with hiPSC differentiation towards human otic neurosensory cells. Our findings suggest a critical role of ECM-ITG interactions with otic neurosensory lineage genes in early neurosensory development and cell fate determination in the human fetal inner ear.
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Rokavec, Matjaz, Stephanie Jaeckel, and Heiko Hermeking. "Nidogen-1/NID1 Function and Regulation during Progression and Metastasis of Colorectal Cancer." Cancers 15, no. 22 (November 7, 2023): 5316. http://dx.doi.org/10.3390/cancers15225316.
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We have previously shown that the extracellular matrix and basement membrane protein Nidogen1 (NID1) is secreted by more malignant, mesenchymal-like CRC cells and induces the epithelial–mesenchymal transition (EMT) and promotes the migration and invasion of less malignant, epithelial-like CRC cells. Here, we performed a comprehensive bioinformatics analysis of multiple datasets derived from CRC patients and showed that elevated expression of NID1 and the genes ITGA3, ITGB1, and ITGAV, which encode NID1 receptors, is associated with poor prognosis and advanced tumor stage. Accordingly, the expression of NID1, ITGA3, ITGB1, and ITGAV was associated with an EMT signature, which included SNAIL/SNAI1, an EMT-inducing transcription factor. In CRC cells, ectopic SNAIL expression induced NID1 and SNAIL occupancy was detected at an E-box upstream of the NID1 transcription start site. Therefore, NID1 represents a direct target of SNAIL. Ectopic expression of NID1 or treatment with NID1-containing medium endowed non-metastatic CRC cells with the capacity to form lung metastases after xenotransplantation into mice. Suppression of the NID1 receptor ITGAV decreased cell viability, particularly in CMS/consensus molecular subtype 4 CRC cells. Taken together, our results show that NID1 is a direct target of EMT-TF SNAIL and is associated with and promotes CRC progression and metastasis. Furthermore, the NID1 receptor ITGAV represents a candidate therapeutic target in CMS4 colorectal tumors.
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Tang, Jia, and Takashi Saito. "The Role of Nephronectin on Proliferation and Differentiation in Human Dental Pulp Stem Cells." Stem Cells International 2017 (November 19, 2017): 1–14. http://dx.doi.org/10.1155/2017/2546261.
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Aim. The purpose of the current study was to investigate the effects of nephronectin (Npnt) in human dental pulp stem cells (hDPSCs). Methodology. Npnt was coated to nontissue culture-treated polystyrene (non-PS) plates. The presence of immobilized protein on the surface was detected by polyclonal rabbit primary anti-Npnt antibody. Then the cell number was counted and compared with PBS-, bovine serum albumin- (BSA-), fish scale type I collagen- (FCOL1-), and human fibronectin- (Fn-) coated wells. Cell proliferation was assessed using CCK-8 assay. Cell morphology was observed under light microscopy and fluorescence microscopy. Lastly, the mRNA expression profiles of integrins, dentin sialophosphoprotein (DSPP), bone sialoprotein (BSP), and mineralization capacity of hDPSCs were investigated by real time RT-PCR and alizarin red staining, respectively. Results. Npnt mediates hDPSC adhesion and spreading partially via the Arg-Gly-Asp (RGD) motif. Npnt enhanced the mRNA expression of ITGA1, ITGA4, ITGA7, and ITGB1 on day five. Npnt downregulated DSPP but significantly upregulated BSP mRNA expression at day 28. Further, Npnt and FCOL1 accelerated the matrix mineralization in hDPSCs. Conclusions. The current findings implicate that Npnt would be favorable to recruit hDPSCs and conducive to mineralization in hDPSCs. The combination of Npnt with hDPSCs may offer a promising approach for hard tissue regeneration.
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Tang, Jia, and Takashi Saito. "A Novel Fragment Derived from Laminin-411 Facilitates Proliferation and Differentiation of Odontoblast-Like Cells." BioMed Research International 2018 (May 9, 2018): 1–10. http://dx.doi.org/10.1155/2018/9465383.
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The aim for the present study was to evaluate the in vitro effects of iMatrix-411 in odontoblast-like cells. To that end, iMatrix-411 was coated to both nontissue culture treated- (Non-PS) and tissue culture treated-polystyrene (TCPS) multiwells. MDPC-23 cells were seeded into noncoated (control) or coated wells. Optimal coating density and cell proliferation were assessed by cell counting kit-8 (CCK-8) at day two, day three, and day five. Osteo/odontogenic differentiation was evaluated by real-time RT-PCR and alkaline phosphatase (ALP) activity at days seven and eight, respectively. Calcific deposition of cells was visualized by alizarin red staining. Data were analyzed with post hoc Tukey HSD test (p<0.05). Optimal coating density for iMatrix-411 was 8 μg/cm2. Exposure of MDPC-23 cells to iMatrix-411 in either non-PS or TCPS significantly enhanced proliferative activity. iMatrix-411 elevated ALP activity in both types of culture plates. iMatrix-411 significantly increased the mRNA level of OCN, BSP, OPN, ALP, and DMP-1. Meanwhile, it enhanced the expression of several integrin subunits: ITGA1, ITGA5, ITGAV, ITGB1, and ITGB5. Finally, iMatrix-411 also accelerated the mineralization at day eight in Non-PS. The results indicated iMatrix-411 stimulates proliferation and favours differentiation of odontoblast-like cells.
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Klahan, Sukhontip, Mei-Shin Wu, Edward Hsi, Chi-Cheng Huang, Ming-Feng Hou, and Wei-Chiao Chang. "Computational Analysis of mRNA Expression Profiles Identifies theITGFamily andPIK3R3as Crucial Genes for Regulating Triple Negative Breast Cancer Cell Migration." BioMed Research International 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/536591.
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Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her2/neu). TNBC has worse clinical outcomes than other breast cancer subtypes. However, the key molecules and mechanisms of TNBC migration remain unclear. In this study, we compared two normalized microarray datasets from GEO database between Asian (GSE33926) and non-Asian populations (GSE46581) to determine the molecules and common pathways in TNBC migration. We demonstrated that 16 genes in non-Asian samples and 9 genes in Asian samples are related to TNBC migration. In addition, our analytic results showed that 4 genes,PIK3R3, ITGB1, ITGAL, andITGA6, were involved in the regulation of actin cytoskeleton. Our results indicated potential genes that link to TNBC migration. This study may help identify novel therapeutic targets for drug development in cancer therapy.
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Keum, Sehoon, Han Kyu Lee, Pei-Lun Chu, Matthew J. Kan, Min-Nung Huang, Carol J. Gallione, Michael D. Gunn, Donald C. Lo, and Douglas A. Marchuk. "Natural Genetic Variation of Integrin Alpha L (Itgal) Modulates Ischemic Brain Injury in Stroke." PLoS Genetics 9, no. 10 (October 10, 2013): e1003807. http://dx.doi.org/10.1371/journal.pgen.1003807.
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Leng, Du, Chimedragchaa Chimedtseren, Tegexibaiyin Wang, Ruga Su, Saren Bao, Xiele Mo, Xigesaiyin Ge, et al. "Proteomics analysis of body fluid exosomes of rheumatoid arthritis patients underwent oxhorn cupping therapy." PLOS ONE 19, no. 12 (December 12, 2024): e0311526. https://doi.org/10.1371/journal.pone.0311526.
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Objective The present study was undertaken to understand the multitarget mechanisms of oxhorn cupping therapy (OHCT) in treating rheumatoid arthritis by proteomic analysis. Methods Thirty rheumatoid arthritis patients underwent OHCT and liquid (body fluid) accumulated in the cupping vessels was collected. Exosomes from the body fluid were isolated and characterized by transmission electron microscope (TEM). Particle size analysis, fluorescent labeling, and flow cytometry detection were also performed. Label-free quantitative proteomics analysis was used to detect differentially expressed proteins (DEPs). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, gene ontology (GO) enrichment, clusters of orthologous groups (COG), and protein-protein interaction (PPI) network were used to perform bioinformatics analysis of DEPs. Enzyme-linked immunosorbent assay (ELISA) was used to detect the key targets regulated by OHCT. Results According to TEM images, the average size of exosomes in body fluid of RA patients underwent OHCT was 76.13 nm (5.27E+10 /mL). The positive rates of CD9, CD63, and CD8 were detected on the surface of body fluid exosomes. A total of 300 DEPs (58 up-regulated and 242 down-regulated) were identified between the pre-treatment and post-treatment stages. DEPs were related mostly to protein binding, focal adhesion, extracellular region, post-translational modification and signal transduction. KEGG pathway analysis showed a significant enrichment of DEPs in PI3K-Akt pathway and focal adhesion. Ten DEGs (ITGA5, ITGA4, ENG, MMP14, SERPINH1, THY1, TAGLN, ITGA1, IGF1, and ITGB5) were considered target genes according to PPI network analysis. ELISA showed a slight decrease in the serum levels of CDK1, ITGA5, ITGB5, and CD44 during and after treatment. Conclusions Body fluid samples from RA patients treated with oxhorn cupping contain exosomes. OHCT might exert therapeutic effects in RA through multiple signaling pathways and multiple protein targets.
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Chu, Tian Jiao, and David G. Peters. "Serial analysis of the vascular endothelial transcriptome under static and shear stress conditions." Physiological Genomics 34, no. 2 (July 2008): 185–92. http://dx.doi.org/10.1152/physiolgenomics.90201.2008.
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We have utilized serial analysis of gene expression (SAGE) to analyze the response of human coronary artery endothelial cells (HCAECs) to laminar shear stress (LSS). Primary cultures of HCAECs were exposed to 15 dyn/cm2LSS for 24 h in a parallel plate flow chamber and compared with identical same passage cells cultured under static conditions. The expression levels of a number of functional categories of genes were reduced by shear stress including those encoding proteins involved in cell proliferation (CDC10, CDC20, CDC23, CCND1, CCNB1), angiogenesis (ANGPTL4, CTGF, CYR61, ENG, EPAS1, EGFR, LGALS3, PGK1, and SPARC), extracellular matrix and cell-matrix adhesion (EFEMP1, LOXL2, P4HB, FBN1, FN1, ITGA5, ITGAE, ITGAV, ILK, LAMR1) and ATP synthesis (ATP5G3, ATP5J2, ATP5L, ATP5D). We also observed an increase in the LSS-responsive expression of genes encoding stress response proteins, including HMOX1, which is significant since HMOX1 may have anti-inflammatory and vasodilatory vascular effects. The autosomal dominant polycystic kidney disease (ADPKD) genes PKD1 and PKD2 were also elevated by LSS. ADPKD is associated with vascular malfunction, including the impairment of vasoreactive processes. To our knowledge, this is the first SAGE-based analysis of the shear stress-responsive endothelial cell transcriptome. These immortal data provide a resource for further analyses of the molecular mechanisms underlying the biological response to LSS and contribute to the expanding collection of publicly available SAGE data.
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Boccarelli, Angelina, Nicoletta Del Buono, and Flavia Esposito. "Review of Patient Gene Profiles Obtained through a Non-Negative Matrix Factorization-Based Framework to Determine the Role Inflammation Plays in Neuroblastoma Pathogenesis." International Journal of Molecular Sciences 25, no. 8 (April 17, 2024): 4406. http://dx.doi.org/10.3390/ijms25084406.
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Neuroblastoma is the most common extracranial solid tumor in children. It is a highly heterogeneous tumor consisting of different subcellular types and genetic abnormalities. Literature data confirm the biological and clinical complexity of this cancer, which requires a wider availability of gene targets for the implementation of personalized therapy. This paper presents a study of neuroblastoma samples from primary tumors of untreated patients. The focus of this analysis is to evaluate the impact that the inflammatory process may have on the pathogenesis of neuroblastoma. Eighty-eight gene profiles were selected and analyzed using a non-negative matrix factorization framework to extract a subset of genes relevant to the identification of an inflammatory phenotype, whose targets (PIK3CG, NFATC2, PIK3R2, VAV1, RAC2, COL6A2, COL6A3, COL12A1, COL14A1, ITGAL, ITGB7, FOS, PTGS2, PTPRC, ITPR3) allow further investigation. Based on the genetic signals automatically derived from the data used, neuroblastoma could be classified according to stage rather than as a “cold” or “poorly immunogenic” tumor.
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Li, Xinqi, Muheremu Muhetaer, Jinxian Wu, Xiaoyan Liu, and Fuling Zhou. "Role of ITGA5 in Autophagy, Migration and Invasion of Acute Myeloid Leukemia Cells." Blood 144, Supplement 1 (November 5, 2024): 6091. https://doi.org/10.1182/blood-2024-200621.
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Abstract Introduction: Acute myeloid leukemia is a heterogeneous hematological malignancy characterized by massive proliferation of abnormally differentiated myeloid blasts or promyelocytes. Genetic factors, environmental factors, abnormal bone marrow microenvironment and gene mutations are closely related to the occurrence and development of AML. Integrin family is gradually well known because of its important role in cell adhesion and migration. It is found that integrins, as an important kind of extracellular matrix receptor, participate in the regulation of cell adhesion, migration, proliferation and other physiological processes, and are closely related to the occurrence and development of tumors. Through proteomic sequencing analysis, we found that the expression of integrins ITGA5, ITGA V, and ITGA L in AML leukemia cells was significantly increased. In previous experiments, we verified that ITGA5 is also highly expressed in Molm-13, MV-4-11, and Kasumi-1 cells by QPCR and Western blot, which can effectively promote the chemotherapy of cytarabine. Subsequently, we made related studies on the role of ITGA5 in autophagy, migration and invasion of acute myeloid leukemia cells. Methods: First, we used ITGA5 lentivirus to transfect Molm-13 and MV-4-11 cells, and after successful transfection, we used cytarabine and doxorubicin to verify the chemosensitization effect after knockdown of ITGA5. We collected ITGA5 knockdown Molm-13 cells for transcriptomic sequencing. Then, Western blot was used to detect the expression of apoptosis-related proteins, autophagy-related proteins and pathway proteins in AML cells. We observed the ultrastructural changes of AML cells after knockdown of ITGA5 by transmission electron microscopy. We verified the effect of ITGA5 on the migration and invasion ability of AML cells through migration and invasion experiments. Results: Compared with the previous experimental inhibition, inhibition of ITGA5 can increase the killing effect of chemotherapeutic drugs on AML cells. Subsequently, we collected ITGA5 knockdown Molm-13 cells for transcriptome sequencing, and found that knockdown of ITGA5 can increase the expression of apoptotic protein-related genes, but also reduce the expression of autophagy-related genes. Subsequently, we verified by Western blot that after knocking down ITGA5, the expression of apoptosis-related proteins Cleaved Caspase-3, Cleaved Caspase-9, and Cleaved PARP was more expressed in AML cells treated with chemotherapeutic drugs, and the expression of SQSTM1/p62 and mTOR increased after knocking down ITGA5. The expression of autophagy marker MAP1LC3 was reduced, thus inhibiting autophagy. In addition, we found that inhibition of ITGA5 can significantly inhibit the migration and invasion of AML cells. Conclusion:ITGA5 is highly expressed in AML. Knockdown ITGA5 can play a better role in chemosensitization, that is, enhance the killing effect of cytarabine and doxorubicin on AML cells, and also inhibit the migration and invasion of AML cells. After inhibiting ITGA5, it negatively regulates the phosphorylation of PI3K/AKT, promotes the activation of Caspase 3, Caspase 9, and PARP proteins, and promotes the production of AML cell apoptosis, thus exerting chemosensitization and inhibiting autophagy. ITGA5 is expected to be a target of AML clinical treatment. Disclosures No relevant conflicts of interest to declare.
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Chinchilla-Tábora, Luis Miguel, Juan Carlos Montero, Luis Antonio Corchete, Idalia González-Morais, Edel del Barco Morillo, Alejandro Olivares-Hernández, Marta Rodríguez González, José María Sayagués, and María Dolores Ludeña. "Differentially Expressed Genes Involved in Primary Resistance to Immunotherapy in Patients with Advanced-Stage Pulmonary Cancer." International Journal of Molecular Sciences 25, no. 4 (February 8, 2024): 2048. http://dx.doi.org/10.3390/ijms25042048.
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In the last few years, nivolumab has become the standard of care for advanced-stage lung cancer patients. Unfortunately, up to 60% of patients do not respond to this treatment. In our study, we identified variations in gene expression related to primary resistance to immunotherapy. Bronchoscopy biopsies were obtained from advanced non-small cell lung cancer (NSCLC) patients previously characterized as responders or non-responders after nivolumab treatment. Ten tumor biopsies (from three responders and seven non-responders) were analyzed by the differential expression of 760 genes using the NanoString nCounter platform. These genes are known to be involved in the response to anti-PD1/PD-L1 therapy. All the patients were treated with nivolumab. Examining the dysregulated expression of 24 genes made it possible to predict the response to nivolumab treatment. Supervised analysis of the gene expression profile (GEP) revealed that responder patients had significantly higher levels of expression of CXCL11, NT5E, KLRK1, CD3G, GZMA, IDO1, LCK, CXCL9, GNLY, ITGAL, HLA-DRB1, CXCR6, IFNG, CD8A, ITK, B2M, HLA-B, and HLA-A than did non-responder patients. In contrast, PNOC, CD19, TP73, ARG1, FCRL2, and PTGER1 genes had significantly lower expression levels than non-responder patients. These findings were validated as predictive biomarkers in an independent series of 201 patients treated with nivolumab (22 hepatocellular carcinomas, 14 non-squamous cell lung carcinomas, 5 head and neck squamous cell carcinomas, 1 ureter/renal pelvis carcinoma, 120 melanomas, 4 bladder carcinomas, 31 renal cell carcinomas, and 4 squamous cell lung carcinomas). ROC curve analysis showed that the expression levels of ITK, NT5E, ITGAL, and CD8A were the best predictors of response to nivolumab. Further, 13/24 genes showed an adverse impact on overall survival (OS) in an independent, large series of patients with NSCLC (2166 cases). In summary, we found a strong association between the global GEP of advanced NSCLC and the response to nivolumab. The classification of NSCLC patients based on GEP enabled us to identify those patients who genuinely benefited from treatment with immune checkpoint inhibitors (ICIs). We also demonstrated that abnormal expression of most of the markers comprising the genomic signature has an adverse influence on OS, making them significant markers for therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of these biomarkers.
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Dong, Rui, Rui Zhao, Shan Zheng, Yijie Zheng, Shudao Xiong, and Yiwei Chu. "Abnormal DNA methylation of ITGAL (CD11a) in CD4+ T cells from infants with biliary atresia." Biochemical and Biophysical Research Communications 417, no. 3 (January 2012): 986–90. http://dx.doi.org/10.1016/j.bbrc.2011.12.054.
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Wang, Wei, Zhuohui Li, Guoxiang Xie, Xinmei Li, Zhipei Wu, Manman Li, Anguo Liu, Yan Xiong, and Yu Wang. "Convergent Genomic Signatures of Cashmere Traits: Evidence for Natural and Artificial Selection." International Journal of Molecular Sciences 24, no. 2 (January 6, 2023): 1165. http://dx.doi.org/10.3390/ijms24021165.
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Convergent evolution provides powerful opportunities to investigate the genetic basis of complex traits. The Tibetan antelope (Pantholops hodgsonii) and Siberian ibex (Capra sibirica) belong to different subfamilies in Bovidae, but both have evolved similar superfine cashmere characteristics to meet the cold temperature in plateau environments. The cashmere traits of cashmere goats underwent strong artificial selection, and some traces of domestication also remained in the genome. Hence, we investigated the convergent genomic signatures of cashmere traits between natural and artificial selection. We compared the patterns of convergent molecular evolution between Tibetan antelope and Siberian ibex by testing positively selected genes, rapidly evolving genes and convergent amino acid substitutions. In addition, we analyzed the selected genomic features of cashmere goats under artificial selection using whole-genome resequencing data, and skin transcriptome data of cashmere goats were also used to focus on the genes involved in regulating cashmere traits. We found that molecular convergent events were very rare, but natural and artificial selection genes were convergent enriched in similar functional pathways (e.g., ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway) in a variety of gene sets. Type IV collagen family genes (COL4A2, COL4A4, COL4A5, COL6A5, COL6A6) and integrin family genes (ITGA2, ITGA4, ITGA9, ITGB8) may be important candidate genes for cashmere formation and development. Our results provide a comprehensive approach and perspective for exploring cashmere traits and offer a valuable reference for subsequent in-depth research on the molecular mechanisms regulating cashmere development and fineness.
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Cochrane, Lynne E., Katherine E. Tansey, Michael Gill, Louise Gallagher, and Richard J. L. Anney. "Lack of association between markers in the ITGA3, ITGAV, ITGA6 and ITGB3 and autism in an Irish sample." Autism Research 3, no. 6 (December 2010): 342–44. http://dx.doi.org/10.1002/aur.157.
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Xiong, Hui, Zhixuan Guo, Zengqi Tang, Xuechen Ai, Qing Qi, Xiuting Liu, Danqi Huang, Zhaofeng Li, Suyun Ji, and Qing Guo. "Mesenchymal Stem Cells Activate the MEK/ERK Signaling Pathway and Enhance DNA Methylation via DNMT1 in PBMC from Systemic Lupus Erythematosus." BioMed Research International 2020 (November 17, 2020): 1–8. http://dx.doi.org/10.1155/2020/4174082.
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The defective MEK/ERK signaling pathway and downstream hypomethylation pattern of lymphocytes are crucial for the pathogenesis of systemic lupus erythematosus (SLE). However, the role that the mesenchymal stem cells play in the MEK/ERK signaling pathway and DNA methylation of peripheral blood mononuclear cells (PBMC) from SLE patients remains unknown. In this study, we found that the MEK/ERK signaling pathway of PBMC from SLE patients was activated after the coculture with bone marrow-derived mesenchymal stem cells (BM-MSC) compared with that from the control group. In addition, the expression level of DNA methyltransferase 1 (DNMT1) increased while the levels of CD70, integrin, alpha L (ITGAL), selectin-l, and IL-13 were reduced in PBMC from SLE patients. However, no obvious effect of BM-MSC on PBMC from healthy controls was observed. These findings revealed that BM-MSC might downregulate the expression of methylation-sensitive genes and then suppress the autoactivated PBMC via the MEK/ERK signaling pathway. And it may be one of the mechanisms that BM-MSC ameliorated SLE.
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Huang, Ziyi, Fen Zhou, Mengxuan Shang, Juan Han, Ping Qu, Hui Shi, and Yiren Cheng. "Huaier Inhibits the Stemness and Drug Resistance Via Regulating WNT/β-Catenin and YAP Signaling Pathways in IKZF1del-Ph+ALL." Blood 144, Supplement 1 (November 5, 2024): 5890. https://doi.org/10.1182/blood-2024-209814.
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Background: With the development of TKIs, the prognosis of Ph+ALL has been significantly improved. However, Ph+ALL especially with IKZF1 deletion are more likely to relapse and drug resistance. Huaier is a tranditional Chinese medicine, which has been shown an effective adjuvant of cancer therapy. .Our study aims to explore the effect and mechanism of Huaier on the chemosensitivity of IKZF1del-Ph+-ALL. Methods: Cell viability was analysed by CCK8 and High-throughput Drug Sensitivity Analysis Strategy. Flow cytometry was used to detect cell apoptosis, cell cycle and adhesion markers. RNAseq, RT-PCR and Western blot were conducted to discover the related gene and protein expresson of stemness pathway. Results: Our studies demonstrated that Huaier enhanced the efficacy of chemotherapy. Using the concentration of GI25, GI50 and GI75 of Huaier combined with VDLP, dasatinib, mercaptopurine and methotrexate, it was found that Huaier could improve the cell inhibition rate of these chemotherapy drugs. Huaier combined with dasatinib could significantly increased the apoptosis of Sup-B15 cells (Control group vs. dasatinib group vs. Huaier group vs. Huaier + dasatinib group: 7.70%±0.67% vs. 58.70%±0.35% vs. 60.97%±0.55% vs. 73.17%±0.44%, p < 0.0001), arrested the cell cycle in the G0/G1 phase (Control group vs. dasatinib group vs. Huaier group vs. Huaier + dasatinib group: 46.70%±0.05% vs. 53.74%±0.82% vs. 58.63%±0.01% vs. 63.70%±0.69%, p < 0.0001) and reduced the expression of adhesion-related molecules, such as the mRNA expression of ITGA4, ITGA8, THY-1, ITGA9 (p < 0.0001), ITGA5 (p = 0.0231), and the protein expression of FAK (p < 0.0001) and phosphorylated FAK (p = 0.0026). The result of RNAseq showed that the differentially expressed genes were enriched in stemness-related pathways, among which Wnt/β-catenin and YAP were significantly down-regulated. The mRNA expression of wnt3, wnt3a, DVL-3, c-myc, FZ2, TCF-1, c-jun and cyclinD1 was significantly decreased (P < 0.0001). Also, the WNT pathways downstream of the key moleculars protein expression of β-catenin, c-myc, c-jun, TCF1, TCF3, TCF4 (P < 0.01) and corresponding phosphorylated proteins (P < 0.05) were all decreased. Also the mRNA (P < 0.0001) and protein expression of YAP, CTGF and survivin were significantly decreased (P < 0.01) after Huaier treatment. Conclusions: In our study, we proved that Huaier can inhibit the Wnt/β-catenin and YAP pathway to enhance the chemotherapy sensitivity of Ph+ALL.Therefore, Huaier has great potential for clinical application in the treatment of refractory/relapsed Ph+ALL.
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Sanmukh, Swapnil Ganesh, Nilton J. Santos, Caroline Nascimento Barquilha, Sérgio Alexandre Alcantara dos Santos, Bruno Oliveira Silva Duran, Flávia Karina Delella, Andrei Moroz, Luis Antonio Justulin, Hernandes F. Carvalho, and Sérgio Luis Felisbino. "Exposure to Bacteriophages T4 and M13 Increases Integrin Gene Expression and Impairs Migration of Human PC-3 Prostate Cancer Cells." Antibiotics 10, no. 10 (October 3, 2021): 1202. http://dx.doi.org/10.3390/antibiotics10101202.
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The interaction between bacteriophages and integrins has been reported in different cancer cell lines, and efforts have been undertaken to understand these interactions in tumor cells along with their possible role in gene alterations, with the aim to develop new cancer therapies. Here, we report that the non-specific interaction of T4 and M13 bacteriophages with human PC-3 cells results in differential migration and varied expression of different integrins. PC-3 tumor cells (at 70% confluence) were exposed to 1 × 107 pfu/mL of either lytic T4 bacteriophage or filamentous M13 bacteriophage. After 24 h of exposure, cells were processed for a histochemical analysis, wound-healing migration assay, and gene expression profile using quantitative real-time PCR (qPCR). qPCR was performed to analyze the expression profiles of integrins ITGAV, ITGA5, ITGB1, ITGB3, and ITGB5. Our findings revealed that PC-3 cells interacted with T4 and M13 bacteriophages, with significant upregulation of ITGAV, ITGA5, ITGB3, ITGB5 genes after phage exposure. PC-3 cells also exhibited reduced migration activity when exposed to either T4 or M13 phages. These results suggest that wildtype bacteriophages interact non-specifically with PC-3 cells, thereby modulating the expression of integrin genes and affecting cell migration. Therefore, bacteriophages have future potential applications in anticancer therapies.
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Hildebrand, Carolin, Julia Hollenbach, Bettina Seeger, and Christiane Pfarrer. "β-Hydroxybutyrate Effects on Bovine Caruncular Epithelial Cells: A Model for Investigating the Peri-Implantation Period Disruption in Ketotic Dairy Cows." Animals 13, no. 18 (September 18, 2023): 2950. http://dx.doi.org/10.3390/ani13182950.
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Ketosis is a metabolic disorder arising from a negative energy balance (NEB). It is characterized by high β-Hydroxybutyrate (BHBA) blood levels and associated with reduced fertility in dairy cows. To investigate the impact of BHBA on bovine caruncular epithelial cells (BCEC) in vitro, these cells were stimulated with different concentrations of BHBA. Cell metabolism and motility were examined using an MTT assay and Live-cell imaging. RT-qPCR was used to examine mRNA expressions of TNF, IL6, RELA, prostaglandin E2 synthase (PTGES2) and receptor (PTGER2) as well as integrin subunits ITGAV, ITGA6, ITGB1 and ITGB3. Stimulation with 1.8 and 2.4 mM of BHBA negatively affected cell metabolism and motility. TNF showed increased mRNA expression related to rising BHBA concentrations. IL6, RELA, ITGAV, ITGA6, ITGB1 and ITGB3 as well as PTGER2 showed no changes in mRNA expression. Stimulation with 0.6 and 1.2 mM of BHBA significantly increased the mRNA expression of PTGES2. This does not indicate a negative effect on reproductive performance because low BHBA concentrations are found in steady-state conditions. However, the results of the study show negative effects of high BHBA concentrations on the function of BCECs as well as an inflammatory response. This could negatively affect the feto-maternal communication during the peri-implantation period in ketotic dairy cows.
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Batista-Liz, Joao Carlos, Vanesa Calvo-Río, María Sebastián Mora-Gil, Belén Sevilla-Pérez, Ana Márquez, María Teresa Leonardo, Ana Peñalba, et al. "Mucosal Immune Defence Gene Polymorphisms as Relevant Players in the Pathogenesis of IgA Vasculitis?" International Journal of Molecular Sciences 24, no. 17 (August 22, 2023): 13063. http://dx.doi.org/10.3390/ijms241713063.
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ITGAM–ITGAX (rs11150612, rs11574637), VAV3 rs17019602, CARD9 rs4077515, DEFA (rs2738048, rs10086568), and HORMAD2 rs2412971 are mucosal immune defence polymorphisms, that have an impact on IgA production, described as risk loci for IgA nephropathy (IgAN). Since IgAN and Immunoglobulin-A vasculitis (IgAV) share molecular mechanisms, with the aberrant deposit of IgA1 being the main pathophysiologic feature of both entities, we assessed the potential influence of the seven abovementioned polymorphisms on IgAV pathogenesis. These seven variants were genotyped in 381 Caucasian IgAV patients and 997 matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of these seven polymorphisms when the whole cohort of IgAV patients and those with nephritis were compared to controls. Similar genotype and allele frequencies of all polymorphisms were disclosed when IgAV patients were stratified according to the age at disease onset or the presence/absence of gastrointestinal or renal manifestations. Likewise, no ITGAM–ITGAX and DEFA haplotype differences were observed when the whole cohort of IgAV patients, along with those with nephritis and controls, as well as IgAV patients, stratified according to the abovementioned clinical characteristics, were compared. Our results suggest that mucosal immune defence polymorphisms do not represent novel genetic risk factors for IgAV pathogenesis.
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Venosa, Alessandro, Teresa Musci, and Philip Moos. "Phenotypic Analysis of Fibrogenic Monocyte/Macrophage Subsets in Acute Inflammatory Exacerbations of Lung Disease Driven by Mutant Surfactant Protein-C Expression." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 163.01. http://dx.doi.org/10.4049/jimmunol.210.supp.163.01.
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Abstract Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), COPD, and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. Excess monocyte mobilization during AIE, and their persistence in the lung are linked to poor disease outcome. Guided by clinical evidence, we have developed an inducible model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine mutation at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [SFTPC]. We have previously shown that ablation of CCR2+ monocytes was protective with respect to lung histopathology, mouse survival, and overall inflammation following SP-C mutant induction. Here we identify and phenotypically characterize resident and recruited monocytes/macrophages populations intervening during the initiation and progression of AIE-PF. Single cell sequencing shows pro-inflammatory and pro-fibrotic signatures originating from immature recruited clusters (itgax-itgam+ ccr2+ cx3cr1+)as well as activated macrophages (cd68+ itgax+ itgam+ arg1+)14 d after SP-C I73Tinduction. Using CellChat Explorer database, these cells were predicted to coordinate intense tgfb1, fn1/fibronectinand spp1/osteopontinsignaling. Together, these results provide a clear picture of the fibrogenic role of specific activated monocyte/macrophage subsets responding to alveolar epithelial stress. NIEHS R01ES032553 (AV); ALSAM Foundation for Research Initiatives Grant (AV)
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Ji, Chen, Yuming Li, Kai Yang, Yanwei Gao, Yan Sha, Dong Xiao, Xiaohong Liang, and Zhongqin Cheng. "Identification of four genes associated with cutaneous metastatic melanoma." Open Medicine 15, no. 1 (June 11, 2020): 531–39. http://dx.doi.org/10.1515/med-2020-0190.
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AbstractBackgroundCutaneous melanoma is an aggressive cancer with increasing incidence and mortality rates worldwide. Metastasis is one of the primary elements that influence the prognosis of patients with cutaneous melanoma. This study aims to clarify the potential mechanism underlying the low survival rate of metastatic melanoma and to search for novel target genes to improve the survival rate of patients with metastatic tumors.MethodsGene expression dataset and clinical data were downloaded from The Cancer Genome Atlas portal. Differentially expressed genes (DEGs) were identified, and their functions were studied through gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Survival and multivariate Cox regression analyses were used to screen out candidate genes that could affect the prognosis of patients with metastatic melanoma.ResultsAfter a series of comprehensive statistical analysis, 464 DEGs were identified between primary tumor tissues and metastatic tissues. Survival and multivariate Cox regression analyses revealed four vital genes, namely, POU2AF1, ITGAL, CXCR2P1, and MZB1, that affect the prognosis of patients with metastatic melanoma.ConclusionThis study provides a new direction for studying the pathogenesis of metastatic melanoma. The genes related to cutaneous metastatic melanoma that affect the overall survival time of patients were identified.
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Glawe, J. D., D. R. Patrick, M. Huang, C. D. Sharp, S. C. Barlow, and C. G. Kevil. "Genetic Deficiency of Itgb2 or ItgaL Prevents Autoimmune Diabetes Through Distinctly Different Mechanisms in NOD/LtJ Mice." Diabetes 58, no. 6 (February 17, 2009): 1292–301. http://dx.doi.org/10.2337/db08-0804.
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Qu, Xiaodong, Luyao Zhang, Songbo Li, Tian Li, Xingyu Zhao, Na Wang, and Yongquan Shi. "m6A-Related Angiogenic Genes to Construct Prognostic Signature, Reveal Immune and Oxidative Stress Landscape, and Screen Drugs in Hepatocellular Carcinoma." Oxidative Medicine and Cellular Longevity 2022 (September 30, 2022): 1–24. http://dx.doi.org/10.1155/2022/8301888.
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Background. m6A modification plays a key role in the development of hepatocellular carcinoma (HCC). Angiogenesis-related genes (ARGs) are increasingly being used to define signatures predicting patient prognosis. The correlations between m6A-related ARGs (mARGs), clinical outcomes, and the immune and oxidative stress landscape are unclear. Methods. Univariate Cox regression analysis of 24 mARGs yielded 13 prognostic genes, which were then analyzed for their enriched functions and pathways. After LASSO regression analysis, a prognostic signature was constructed and its reliability validated. Patients were grouped by risk using the signature score, and then the clinical prognosis, the immune landscape, and the oxidative stress landscape between the two groups were analyzed. Drug sensitivity analysis was performed to identify potentially efficient therapeutic agents. Results. Thirteen prognosis-related mARGs consistently clustered patients with HCC into four groups with significantly different prognosis. Four mARGs (EGF, ITGA5, ITGAV, and PLG) were used to construct a prognostic signature and define risk groups. Among them, EGF, ITGA5, and ITGAV, were defined as prognostic risk factors, while PLG was defined as a prognostic protective factor. Compared to low-risk patients, HCC patients in the high-risk group had a poorer prognosis and showed significant differences in clinical characteristics, enriched pathways, tumor stemness, and tumor microenvironment. The drug sensitivity of oxaliplatin and LDK-378 negatively correlated with ITGAV expression. Ten drugs had lower IC50s in the high-risk group, indicating better antitumor efficacy than in the low-risk group, with epothilone B having the lowest IC50 value. Conclusions. A prognostic model consisting of mARGs can be used to predict the prognosis of HCC patients. The risk grouping of our model can be used to reveal differences in the tumor immune microenvironment of patients with HCC. Further in-depth study may provide new targets for future treatment.
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Schmalbach, Barbara, Olga Stepanow, Arne Jochens, Christian Riedel, Günther Deuschl, and Gregor Kuhlenbäumer. "Determinants of Platelet-Leukocyte Aggregation and Platelet Activation in Stroke." Cerebrovascular Diseases 39, no. 3-4 (2015): 176–80. http://dx.doi.org/10.1159/000375396.
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Background: Platelet-leukocyte aggregation (PLA) and platelet activation are found to be on the higher side in ischemic stroke patients. The correlation of PLA with clinical features has not been intensively investigated and the influence of genetic factors on PLA is still unexplored. The interaction of platelets with leukocytes is mainly determined by the proteins encoded by six genes: P-Selectin (SELP encodes CD62P) on the thrombocyte binding to P-Selectin-Glycoprotein-Ligand-1 (PSGL1) on the leukocyte, intracellular-adhesion-molecule 2 (ICAM2) interacting with Integrin alpha M (ITGAM) and Glycoprotein 1b-alpha (GP1BA) binding to Integrin alpha L (ITGAL). Methods: Seventy-nine patients with acute ischemic stroke and 151 controls without vascular disease from a single German center were enrolled. A neurologist and a neuroradiologist ascertained clinical and radiological features. PLA and platelet activation were analyzed using flow cytometry with various antibodies. Coding as well as tagging SNPs in six genes determining PLA were genotyped. Three groups of parameters were correlated with each other: (i) clinical and radiological parameters, (ii) laboratory parameters, (iii) genetic parameters. For the comparisons, robust nonparametric statistical tests were applicable. Results: PLA and platelet activation were higher in ischemic stroke patients compared to controls. Both, anticoagulant and antiplatelet treatment in the patient group affected platelet activation but not PLA. PLA correlated weakly with measures of stroke severity but not with thrombus length or stroke etiology. The association of SNP rs2228315 in the P-Selectin Glycoprotein Ligand-1-gene (PSGL1) with ischemic stroke and platelet activation was significant before correction for multiple testing while a trend was observed for the association with PLA. Regression analysis revealed that (i) platelet activation was an independent determinant of stroke, (ii) that PLA correlated with stroke, sex, age and platelet activation and (iii) that platelet activation correlated only with stroke. None of the SNPs survived in the regression analysis for stroke, PLA or platelet activation as dependent variables. Conclusions: The most important result of our study is that PLA and platelet activation are independent of other vascular risk factors correlated with stroke in our sample. In addition, we identified the missense SNP rs2228315 in the PSGL1-gene as a candidate polymorphism for ischemic stroke-related PLA. Association between this SNP and stroke as well as coronary artery disease has also been shown by two other studies.