<p>Identification of Chemoresistance-Associated Key Genes and Pathways in High-Grade Serous Ovarian Cancer by Bioinformatics Analyses</p>

Abstract

High-grade serous ovarian cancer (HGSOC) is the leading cause of death among gynecological malignancies. This is mainly attributed to its high rates of chemoresistance. To date, few studies have investigated the molecular mechanisms underlying this resistance to treatment in ovarian cancer patients. In this study, we aimed to explore these molecular mechanisms using bioinformatics analysis. Methods: We analyzed microarray data set GSE51373, which included 16 platinumsensitive HGSOC samples and 12 platinum-resistant control samples. Differentially expressed genes (DEGs) were identified using RStudio. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using DAVID, and a DEG-associated protein-protein interaction (PPI) network was constructed using STRING. Hub genes in the PPI network were identified, and the prognostic value of the top ten hub genes was evaluated. MGP, one of the hub genes, was verified by immunohistochemistry. Results: All samples were confirmed to be of high quality. A total of 109 DEGs were identified, and the top ten enriched GO terms and four KEGG pathways were obtained. Specifically, the PI3K-AKT signaling pathway and the Rap1 signaling pathway were identified as having significant roles in chemoresistance in HGSOC. Furthermore, based on the PPI network, KIT, FOXM1, FGF2, HIST1H4D, ZFPM2, IFIT2, CCNO, MGP, RHOBTB3, and CDC7 were identified as hub genes. Five of these hub genes could predict the prognosis of HGSOC patients. Positive immunostaining signals for MGP were observed in the chemoresistant samples. Conclusion: Taken together, the findings of this study may provide novel insights into HGSOC chemoresistance and identify important therapeutic targets.

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

“…In agreement, we observed that almost half of HGSC patients have increased FOXM1 expression in recurrent chemoresistant tumors [ 256 ]. Bioinformatic analysis led to the identification of FOXM1 as one of the top three hub genes for which overexpression leads to platinum-based chemotherapy resistance [ 257 ]. Furthermore, cisplatin-resistant ovarian cancer tissues and cells were reported to have increased FOXM1 [ 232 ] and FOXM1 was an independent indicator of shorter time to progression in platinum-resistant EOC [ 222 ].…”

Identification of GNA12‑driven gene signatures and key signaling networks in ovarian cancer

“…Next, the hub and bottleneck genes upregulated in GNA12-silenced cells were examined (Table VI). These nodes, representing the genes that would have been suppressed by GNA12, were found to be associated with proteasome-mediated context-specific apoptotic pathways and therapy resistance in numerous cancer types (46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57). Taken together, the functional analyses of the hub and bottleneck genes indicated that the genes downregulated in GNA12-silenced cells coded for pro-tumorigenic proteins, while the genes upregulated upon silencing of GNA12 encoded anti-tumorigenic proteins (Fig.…”

FOXM1 Inhibition in Ovarian Cancer Tissue Cultures Affects Individual Treatment Susceptibility Ex Vivo

“…Here, the tissue model was used to investigate the potency of FOXM1 inhibition in ovarian cancer specimens, as the transcription factor network is altered in 87% of ovarian cancer patients [ 48 ]. Overexpression of FOXM1 in high-grade ovarian cancer patients was shown to correlate with resistance against platinum-agents and poor prognosis, with patients quickly building up resistance to standard therapy which was also observed with ovarian cancer cell lines in vitro [ 23 , 49 , 50 , 51 ]. Thiostrepton treatment downregulated FOXM1 expression on mRNA level in ovarian tissue cultures, confirming results of cell culture experiments [ 16 , 17 ].…”