期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 14, 页码 -出版社
MDPI
DOI: 10.3390/ijms23147737
关键词
ovarian cancer; cisplatin resistance; RNA-seq; bioinformatics; long noncoding RNAs
资金
- RCMI grant (National Institute on Minority Health and Health Disparities) [U54 MD007600]
- National Institute of General Medical SciencesResearch Training Initiative for Student Enhancement (NIGMS-RISE) Program [R25GM061838, 5R25GM061151-20]
- Institutional Development Award (IDeA) INBRE Grant from the National Institute of General Medical Sciences (NIGMS) [P20GM103475]
- Bioinformatics Research Core of the INBRE program
In this study, it was found that the long noncoding RNA CASC10 is upregulated in cisplatin-resistant ovarian cancer cells and patients. Knockdown of CASC10 reduces cell proliferation and invasion, and increases sensitivity to cisplatin treatment. Moreover, liposomal CASC10-siRNA can inhibit tumor growth and metastasis.
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.
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