Long Non-coding RNA CCAT1 Sponges miR-454 to Promote Chemoresistance of Ovarian Cancer Cells to Cisplatin by Regulation of Surviving

• Published in: Cancer research and treatment Vol. 52; no. 3; pp. 798 - 814
• Main Authors: Wang, De-Ying, Li, Na, Cui, Yu-Lan
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Cancer Association 01.07.2020; 대한암학회
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Proliferation; Cisplatin - pharmacology; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; Original; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; RNA, Long Noncoding - genetics; Survivin - genetics; Survivin - metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; 의학일반; miR-454; LncRNA; CCAT1; Survivin; Epithelial ovarian carcinoma; Chemoresistance
• ISSN: 1598-2998; 2005-9256
• DOI: 10.4143/crt.2019.498

Colon cancer-associated transcript 1 (CCAT1) was identified as an oncogenic long non-coding RNA (lncRNA) in a variety of cancers. However, there was a lack of understanding of the mechanism by which CCAT1 conferred cisplatin (also known as DDP) resistance in ovarian cancer cells. Cell viability of A2780, SKOV3, A2780/DDP, and SKOV3/DDP cells upon cisplatin treatment was monitored by MTT assay. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected the expression levels of CCAT1 and miR-454. The effect of sh-CCAT1 on cisplatin response was investigated in xenografts study. Bioinformatic analysis, luciferase reporter assay and qRT-PCR were conducted to validate the direct interaction among CCAT1, miR-454, and survivin. Apoptosis was determined by flow cytometry after dual staining of Annexin-V-FITC/propidium iodide, and the expression of apoptosis-related proteins Bcl-2, Bax and survivin were detected by qRT-PCR and Western blotting. Xenograft study was conducted to monitor in vivo tumor formation. CCAT1 was highly expressed in cisplatin-resistant ovarian cancer cell line A2780/DDP and SKOV3/DDP. Knockdown of CCAT1 restored sensitivity to cisplatin in vitro and in vivo. Our data revealed that silencing of CCAT1 promoted cisplatin-induced apoptosis via modulating the expression of pro- or anti-apoptotic proteins Bax, Bcl-2, and survivin. CCAT1 directly interacted with miR-454, and miR-454 overexpression potentiated cisplatin-induced apoptosis. Survivin was identified as a functional target of miR-454, restoration of survivin attenuated the effect of miR-454 on cisplatin response. In addition, miR-454 inhibitor or overexpression of survivin was found to abolish sh-CCAT1-induced apoptosis upon cisplatin treatment. CCAT1/miR-454/survivin axis conferred cisplatin resistance in ovarian cancer cells.