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Comprehensive Characterization of Integrin Subunit Genes in Human Cancers.

ABSTRACT: Although integrin subunit genes (ITGs) have been reported to be associated with some human cancer types, a systematic assessment of ITGs across human cancers is lacking. Hence, we performed comprehensive analyses to investigate mRNA expression, copy number variation (CNV), DNA methylation, mutation, and clinical landscapes of ITGs in more than 8000 cancer patients from The Cancer Genome Atlas (TCGA) dataset. Landscapes of ITGs were established across 20 human cancer types. We observed that ITGs are extensively dysregulated with heterogeneity in different system cancer types, part of which are driven by CNV, DNA hypomethylation or mutation. Furthermore, dysregulated prognosis-related ITGs were systematically identified in each cancer type, including ITGA11 in stomach adenocarcinoma (STAD). The models based on dysregulated ITGs with clinical relevance and TNM staging indexes are good indicators in STAD and head and neck squamous cell carcinoma. Finally, ITGA11 is overexpressed and associated with poor survival in STAD cases from the TCGA and additionally Gene Expression Omnibus cohorts. Functionally, ITGA11 knockdown inhibits malignant phenotypes in STAD cell lines AGS and MKN45, demonstrating the oncogenic role of ITGA11 in STAD. Together, this study highlights the important roles of ITGs in tumorigenesis as potential prognostic biomarkers, and provide an effective resource that identifies cancer-related genes of ITGs in human cancers.

SUBMITTER: Cui K

PROVIDER: S-EPMC8242346 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Î±9b1 is the most recent addition to the integrin family of membrane-bound receptors and consequently remains the one which is the least characterized. To better understand how transcription of the human gene encoding the Î±9 subunit is regulated at the molecular level, we cloned the Î±9 promoter and characterized the regulatory elements that are required to ensure its transcription. Transfection of Î±9 promoter/CAT recombinant plasmids in primary cultured cells and uveal melanoma cell lines demonstrated the presence of both negative and positive regulatory elements along the Î±9 promoter and positioned the basal Î±9 promoter to within 118 bp from the Î±9 mRNA start site. In vitro DNaseI footprinting and in vivo ChIP analyses demonstrated the binding of the transcription factors Sp1/Sp3, c-Myb and NFI to the most upstream Î±9 negative regulatory element. The transcription factors Sp1/Sp3 and NFI were found to bind the basal Î±9 promoter individually but Sp1 binding clearly predominates when both transcription factors are present in the same extract. Most of all, addition of tenascin-C (TNC), the ligand of Î±9Î²1, to the tissue culture plates prior to cell seeding increased Î±9 transcription whereas it simultaneously decreased expression of the Î±5 integrin subunit gene. This dual regulatory action of TNC on the transcription of the Î±9 and Î±5 genes suggests that both these integrins must work together to appropriately regulate cell adhesion, migration and differentiation that are hallmarks of tissue wound healing. Primary cultures of human corneal epithelial cells (HCECs; number of replicates: 8), human skin epithelial cells (HSEC; number of replicates: 4), human corneal fibroblast cells (HCFCs; number of replicates: 3), human skin fibroblast cells (HSFCs; number of replicates: 3), human uveal melanocytes (UVM; number of replicates: 3), and various humal uveal melanoma cell lines (T115, T142 and T143; number of replicates: 2-3) were analyzed by gene profiling on microarrays at low culture passages (between passage 2 to 7). HCECs were also cultured on either BSA (number of replicates: 2) or on tenascin-C (number of replicates: 2) and their transcriptome analyzed by gene profiling.

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Comprehensive Characterization of Integrin Subunit Genes in Human Cancers.

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