Identification of key genes and pathways related to cancer-associated fibroblasts in chemoresistance of ovarian cancer cells based on GEO and TCGA databases.

BACKGROUND: Studies have revealed the implications of cancer-associated fibroblasts (CAFs) in tumor progression, metastasis, and treatment resistance. Here, in silico analyses were performed to reveal the key genes and pathways by which CAFs affected chemoresistance in ovarian cancer.

METHODS: Candidate genes were obtained from the intersected differentially expressed genes in ovarian cancer, ovarian cancer chemoresistance, and ovarian CAF-related microarrays and chemoresistance-related genes from GeneCards databases. Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis were employed to identify the pathways engaged in ovarian cancer chemoresistance and ovarian CAF-related pathways. The top genes with high Degree in the protein-protein interaction network were intersected with the top genes enriched in the key pathways, followed by correlation analyses between key genes and chemotherapeutic response. The expression profiles of key genes were obtained from Human Protein Atlas database and TCGA-ovarian cancer data.

RESULTS: p53, cell cycle, PI3K-Akt, and MAPK pathways were the key pathways related to the implication of CAFs in ovarian cancer chemoresistance. 276 candidate genes differentially expressed in CAFs were associated with ovarian cancer chemoresistance. MYC, IGF1, HRAS, CCND1, AKT1, RAC1, KDR, FGF2, FAS, and EGFR were enriched in the key chemoresistance-related ways. Furthermore, MYC, EGFR, CCND1 exhibited close association with chemotherapeutic response to platinum and showed a high expression in ovarian cancer tissues and platinum-resistant ovarian cancer cells.

CONCLUSION: The study suggests the key genes (MYC, EGFR, and CCND1) and pathways (p53, cell cycle, PI3K-Akt, and MAPK) responsible for the effect of CAFs on ovarian cancer chemoresistance.