Journal
RNA BIOLOGY
Volume 17, Issue 11, Pages 1576-1589Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15476286.2019.1709296
Keywords
Cisplatin; Gastric cancer; CRAL; CYLD; Drug resistance
Categories
Funding
- National Natural Science Foundation of China [81773383, 81370078, 81903085]
- Science Foundation for Distinguished Young Scholars of Jiangsu Province [BK20170047]
- Fundamental Research Funds for the Central Universities [021414380439]
- Foundation of Priority Academic Program Development (PAPD)
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX17_1294]
- United Fund of Nanjing Medical University
- United Fund of Southeast University
- China Postdoctoral Science Foundation [2019M651808]
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Emerging evidence has suggested that long noncoding RNAs (lncRNAs) play an essential role in the tumorigenesis of multiple types of cancer including gastric cancer (GC). However, the potential biological roles and regulatory mechanisms of lncRNA in response to cisplatin, which may be involved in cisplatin resistance, have not been fully elucidated. In this study, we identified a novel lncRNA, cisplatin resistance-associated lncRNA (CRAL), that was downregulated in cisplatin-resistant GC cells, impaired cisplatin-induced DNA damage and cell apoptosis and thus contributed to cisplatin resistance in GC cells. Furthermore, the results indicated that CRAL mainly resided in the cytoplasm and could sponge endogenous miR-505 to upregulate cylindromatosis (CYLD) expression, which further suppressed AKT activation and led to an increase in the sensitivity of gastric cancer cells to cisplatin in vitro and in preclinical models. Moreover, a specific small molecule inhibitor of AKT activation, MK2206, effectively reversed the cisplatin resistance in GC caused by CRAL deficiency. In conclusion, we provide the first evidence that a novel lncRNA, CRAL, could function as a competing endogenous RNA (ceRNA) to reverse GC cisplatin resistance via the miR-505/CYLD/AKT axis, which suggests that CRAL could be considered a potential predictive biomarker and therapeutic target for cisplatin resistance in gastric cancer.
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