Emerging roles of the Hippo signaling pathway in cisplatin-resistant ovarian cancer cells

Background and Aim: Ovarian cancer, the fifth lethal cancer in women, has a low survival rate due to its poor prognosis and relapse. The palliative cure by the platinum-based chemotherapy approach is the backbone of this cancer treatment. Recent studies have explicated the roles of the Hippo signaling pathway in the development and progression of multiple cancer types, including ovarian cancer.Moreover, some of the Hippo members can collaborate in a cisplatin resistance state and decrease the survival rate of patients due to recurrence and abdominal cavity diffusion. We found that Hippo members' expression can be utilized as potential markers to predict the relapse and patients' survival in the treatment process.Methods: Microarray data of five ovarian cancer cell lines were obtained from the GEO database (GSE۴۷۸۵۶). The screening of gene expression profile, evaluation of the data quality, and extraction of differentially expressed genes (DEGs) was accomplished between cisplatin-treated and untreated cell lines using TAC software. Furthermore, the Hippo members and their function in cisplatin-treated and untreated cell lines were recognized through the EnrichR database, which enrolls gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genome analysis (KEGG). Expression and survival analysis by Kaplan-Meier plot was conducted in order to screen and validate key genes.Results: A total of ۱۴ DEGs, between five cell lines, including FU-OV-۱, HeyA۸, HeyC۲, IGROV-۱, and OV۹۰, were recognized as Hippo pathway potential core components for treatment prediction. These potential markers of the Hippo pathway were mainly classified as pathways in cancer, PI۳K-Akt Signaling Pathway, Ras Signaling Focal Adhesion-PI۳K-Akt-mTOR-signaling pathway, Gap junction, Proteoglycans in cancer, and focal adhesion proteins. ITGA۲, CDH۲, INSR, CD۴۴, and CDH۱۰ genes were also identified as regulatory nodes of the Hippo-Merlin Signaling pathway, which are downregulated after cisplatin treatment leading a low survival rate. Additionally, the upregulation of FOXM۱, PRKACA, PDGFRA genes in mentioned cell lines after cisplatin treatment, suggests their predictive roles in low survival and drug resistance after cisplatin therapy.Conclusion: In conclusion, our study demonstrates new insights into the regulatory mechanisms of the Hippo pathway in platinum-based chemotherapy resistance. Identification of key genes as candidate players in ovarian cancer may be reflected as potential new targets to improve the low survival rate and treatment strategies in ovarian malignancy.

کلیدواژه ها:

Ovarian cancer ، cisplatin ، drug resistance ، Hippo signaling ، survival rate