Identification of Three Potential Prognostic Genes in Platinum-Resistant Ovarian Cancer via Integrated Bioinformatics Analysis

Abstract

Purpose

Ovarian cancer is the most lethal gynecologic malignancy. Resistance to platinum-based chemotherapy affects the overall survival of patients. This study used an integrated bioinformatics to find the poorly understood molecular mechanisms underlying platinum resistance in ovarian cancer.

Methods

Based on the RNA-seq data of tissues in The Cancer Genome Atlas (TCGA) and RNA-seq data of cells from the Cancer Cell Encyclopedia (CCLE), we integrated differentially expressed genes (DEGs) in ovarian cancer tissue and cells. After screening for DEGs related to platinum resistance, we conducted survival analysis and built protein interaction networks to identify genes that may affect prognosis and interact with each other. Least absolute shrinkage and selection operator (Lasso) regression analysis was used to construct a predictive model. Immunohistochemistry and Western blot were used to validate the results. Finally, gene set enrichment analysis (GSEA) was performed on the expression of genes individually.

Results

We found that ATPase Na⁺/K⁺ transporting subunit alpha 2 (ATP1A2), calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) interacted with each other and could predict resistance to platinum-based therapy, correlating negatively with prognosis. Moreover, we constructed a predictive model based on nine genes, including ATP1A2 and CASQ2. Immunohistochemistry and Western blot validated the upregulation of these genes in ovarian cancer tissue samples and cell lines. The immunohistochemistry results also confirmed the prognostic value of ATP1A2, CASQ2 and RYR2. GSEA predicted that ATP1A2, CASQ2 and RYR2 may act on the KRAS and mTORC1 pathways and participate in metabolic reprogramming and regulation of calcium homeostasis in platinum-resistant cells.

Conclusion

ATP1A2, CASQ2 and RYR2 were highly expressed in platinum-resistant ovarian cancer. ATP1A2 and CASQ2 were related to the prognosis of platinum-resistant ovarian cancer patients. These genes might act on KARS and mTORC1 pathways and participate in metabolic reprogramming and regulation of calcium homeostasis in platinum-resistant cells.

Keywords:

• ovarian cancer
• platinum resistance
• prognosis
• metabolic reprogramming
• calcium homeostasis

Acknowledgments

The authors thank the patients that provided tissue samples used in this research for their contribution to our work.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Qilu Hospital of Shandong University. All patients provided informed consent before data collection.

Data Sharing Statement

RNA-seq data and clinical information of TCGA cohort was downloaded from TCGA website (https://portal.gdc.cancer.gov/). IC₅₀ information of cell lines was accessed in the GDSC database (https://www.cancerrxgene.org/) and their RNA-seq data was downloaded from the CCLE database (https://portals.broadinstitute.org/ccle).

Disclosure

The authors declare no conflict of interest.