Upregulation of the Long Noncoding RNA CASC10 Promotes Cisplatin Resistance in High-Grade Serous Ovarian Cancer

• Published in: International journal of molecular sciences 2022-07, Vol.23 (14), p.7737
• Main Authors: Noriega-Rivera, Ricardo, Rivera-Serrano, Mariela, Rabelo-Fernandez, Robert J, Pérez-Santiago, Josué, Valiyeva, Fatima, Vivas-Mejía, Pablo E
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - genetics; Carcinoma, Ovarian Epithelial - drug therapy; Cell cycle; Cell division; Cell growth; Cell Line, Tumor; Cell proliferation; Chemotherapy; Cisplatin; Cisplatin - metabolism; Cisplatin - pharmacology; Cisplatin - therapeutic use; Deoxyribonucleic acid; DNA; Drug Resistance, Neoplasm; Female; Gene expression; Humans; Kinases; Metastases; Mice; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Patients; Proteins; RNA, Long Noncoding - genetics; RNA, Long Noncoding - therapeutic use; RNA, Small Interfering - pharmacology; siRNA; Survival analysis; Tumors; Up-Regulation - genetics
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23147737

Despite initial responses to first-line treatment with platinum and taxane-based combination chemotherapy, most high-grade serous ovarian carcinoma (HGSOC) patients will relapse and eventually develop a cisplatin-resistant fatal disease. Due to the lethality of this disease, there is an urgent need to develop improved targeted therapies against HGSOC. Herein, we identified CASC10, a long noncoding RNA upregulated in cisplatin-resistant ovarian cancer cells and ovarian cancer patients. We performed RNA sequencing (RNA-seq) in total RNA isolated from the HGSOC cell lines OVCAR3 and OV-90 and their cisplatin-resistant counterparts. Thousands of RNA transcripts were differentially abundant in cisplatin-sensitive vs. cisplatin-resistant HGSOC cells. Further data filtering unveiled CASC10 as one of the top RNA transcripts significantly increased in cisplatin-resistant compared with cisplatin-sensitive cells. Thus, we focused our studies on CASC10, a gene not previously studied in ovarian cancer. SiRNA-mediated CASC10 knockdown significantly reduced cell proliferation and invasion; and sensitized cells to cisplatin treatment. SiRNA-mediated CASC10 knockdown also induced apoptosis, cell cycle arrest, and altered the expression of several CASC10 downstream effectors. Multiple injections of liposomal CASC10-siRNA reduced tumor growth and metastasis in an ovarian cancer mouse model. Our results demonstrated that CASC10 levels mediate the susceptibility of HGSOC cells to cisplatin treatment. Thus, combining siRNA-mediated CASC10 knockdown with cisplatin may represent a plausible therapeutic strategy against HGSOC.