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Updated: Oct 12, 2025
Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Identification of Three Potential Prognostic Genes in Platinum-Resistant Ovarian Cancer via Integrated Bioinformatics
Xue Zhang1,2,3, Xuan Wei1,2,3, Gaigai Bai1,2,3
1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
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.
Insights
This study identified ATP1A2, CASQ2, and RYR2 as key genes in platinum-resistant ovarian cancer. These genes are upregulated and linked to poor prognosis, potentially impacting KRAS and mTORC1 pathways.
Area of Science:
- Oncology
- Genomics
- Bioinformatics
Background:
- Ovarian cancer is a leading cause of gynecologic cancer deaths.
- Platinum-based chemotherapy resistance significantly impacts patient survival.
- Molecular mechanisms of platinum resistance in ovarian cancer remain poorly understood.
Purpose of the Study:
- To elucidate the molecular mechanisms of platinum resistance in ovarian cancer using integrated bioinformatics.
- To identify novel biomarkers for predicting platinum resistance and patient prognosis.
Main Methods:
- Integrated analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Encyclopedia (CCLE) RNA-seq data.
- Differential gene expression analysis, survival analysis, and protein-protein interaction network construction.
- Least Absolute Shrinkage and Selection Operator (Lasso) regression for predictive model development, validated by immunohistochemistry and Western blot.
- Gene Set Enrichment Analysis (GSEA) to explore pathway involvement.
Main Results:
- Identified ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2), calsequestrin 2 (CASQ2), and ryanodine receptor 2 (RYR2) as interacting genes predicting platinum resistance.
- These genes (ATP1A2, CASQ2, RYR2) negatively correlated with patient prognosis.
- A nine-gene predictive model, including ATP1A2 and CASQ2, was constructed and validated.
- GSEA suggested ATP1A2, CASQ2, and RYR2 involvement in KRAS and mTORC1 pathways, metabolic reprogramming, and calcium homeostasis regulation.
Conclusions:
- ATP1A2, CASQ2, and RYR2 are significantly upregulated in platinum-resistant ovarian cancer.
- ATP1A2 and CASQ2 are associated with the prognosis of platinum-resistant ovarian cancer.
- These genes may influence platinum resistance through KRAS and mTORC1 signaling, affecting cellular metabolism and calcium balance.
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