Identification of hub genes and compounds controlling ovarian cancer stem cell characteristics via stemness indices analysis

Background: Ovarian cancer (OC) is the most lethal gynecological malignancy. It has been reported that cancer stem cells (CSCs) play a crucial role in disseminated metastases in abdominal cavity and chemotherapy resistance of high-grade serous OC. However, the overall gene expression features of OC stem cells have not been clarified.

Methods: Expression datasets of 379 OC samples and 88 normal tissues were downloaded from The Cancer Genome Atlas (TCGA) and the Genotype Tissue Expression (GTEx) project. Differentially expressed genes (DEGs) were screened using the "limma" package in R software. Among the DEGs, modules and hub genes that were highly related to messenger RNA expression-based stemness index (mRNAsi) and epigenetically regulated mRNAsi indices were identified via weighted gene co-expression network analysis (WGCNA). These hub genes were considered to be associated with OC stem cells. The Gene Ontology (GO) project and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to identify the main biological processes that hub genes participated in. Finally, Connectivity Map (CMap) was used to predict compounds that disturb the hub genes.

Results: We identified 2,253 DEGs; of these, 31 had a significantly positive correlation to mRNAsi indices and were upregulated in OC, while 41 of them had a significantly negative correlation with mRNAsi indices and were downregulated in OC. Correlation analysis indicated that hub genes from the same module composed a dense interaction network. GO and KEGG enrichment analysis demonstrated that hub genes primarily play roles in cell division and proliferation. Moreover, the compounds that may disturb hub genes were identified. Of these, 11 compounds, including MS-275, DL-thiorphan, and GW-8510, which have never been studied in OC stem cells, were screened as underlying treatments targeting OC stem cells.

Conclusions: Altogether, 72 hub genes that were closely linked to OC stem cell characteristics were found to mainly participate in cell division and proliferation. Moreover, compounds that disturb these hub gens were identified and can be considered underlying targets for inhibiting OC stem cells.