Targeting the Tumor Stroma: Identifying Crucial Genes in Cancer-Associated Fibroblasts for High-Grade Serous Ovarian Cancer Therapeutics

Ovarian cancer ranks as the eighth leading cause of cancer-related deaths worldwide [۱].Histologically, about ۹۰% of ovarian tumors originate from epithelial cells, with over ۷۰% classified ashigh-grade serous epithelial ovarian cancer (HGSOC) and a less than ۳۵% five-year survival rate [۲].Recent reports emphasize the critical role of the tumor microenvironment in cancer progression, withcancer-associated fibroblasts (CAFs) being a pivotal cell type [۳]. Therefore, pinpointing key genesexpressed in CAFs for potential therapeutic targeting is of utmost importance. In this study, a metaanalysisof gene expression associated with CAFs was conducted using microarray data from the GEOdatasets, GSE۱۲۶۱۳۲ and GSE۴۰۵۹۵ were extracted, normalized, and subjected to PCA analysis usingR programming. Differentially expressed genes (DEGs) with significant expression differences in CAFsisolated from HGSOC tumor tissues compared to normal ovarian fibroblasts (NOFs) were identified inhuman samples. To unravel interactions between DEGs, String software was utilized, and hub geneswere identified using Centiscape and Cytohubba. Additionally, a weighted gene co-expression networkanalysis (WGCNA) was performed to identify hub genes from co-expressed genes. This comprehensiveapproach resulted in the identification of ۲۸ hub genes from String analysis and ۳۰ top hub genes usingthe WGCNA package. Our results underscore the significance of genes associated with the mTORC۱signaling pathway, MYC Target v۱, and Complement pathways in the function of CAFs promotingHGSOC. Specifically, genes CCT۶A, PSMD۱۲, and COPS۵ in the mTORC۱ signaling pathway,SYNCRIP, COPS۵, and PWP۱ in the MYC Target v۱ signaling pathway, and USP۱۴, USP۱۶ in theComplement signaling pathway in CAFs were linked to metabolic changes promoting the survival oftumor cells. The identified key genes may present potential targets in the treatment of high-grade serousovarian cancer, warranting experimental validation.

کلیدواژه ها:

Cancer-associated fibroblasts ، High grade serous ovarian cancer ، Hub genes ، WGCNA analysis ، Metabolic pathways