The long noncoding RNA CRAL reverses cisplatin resistance via the miR-505/CYLD/AKT axis in human gastric cancer cells.

Abstract

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.

• Authors: Zhangding Wang, Qiang Wang, Guifang Xu, Na Meng, Xinli Huang, Zerun Jiang, Chen Chen, Yan Zhang, Junjie Chen, Aiping Li, Nan Li, Xiaoping Zou, Jianwei Zhou, Qingqing Ding, Shouyu Wang
• Journal: RNA biology (RNA Biol) Vol. 17 Issue 11 Pg. 1576-1589 (11 2020) ISSN: 1555-8584 [Electronic] United States
• PMID: 31885317 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antineoplastic Agents
• MIRN505 microRNA, human
• MicroRNAs
• RNA, Long Noncoding
• Proto-Oncogene Proteins c-akt
• CYLD protein, human
• Deubiquitinating Enzyme CYLD
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Cisplatin (pharmacology)
• DNA Damage
• Deubiquitinating Enzyme CYLD (genetics)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Humans
• MicroRNAs (genetics)
• Phosphatidylinositol 3-Kinases (metabolism)
• Prognosis
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Long Noncoding (genetics)
• Signal Transduction
• Stomach Neoplasms (drug therapy, genetics, metabolism, pathology)