The long noncoding RNA CRAL reverses cisplatin resistance via the miR-505/CYLD/AKT axis in human gastric cancer cells
The long noncoding RNA CRAL reverses cisplatin resistance via the miR-505/CYLD/AKT axis in human gastric cancer cells
复制标题
长非编码 RNA CRAL 通过 miR-505/CYLD/AKT 轴逆转人胃癌细胞中的顺铂耐药性
DOI：
10.1080/15476286.2019.1709296
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发表时间：
2020-01-08
期刊：
影响因子：
4.1
通讯作者：
Wang, Shouyu
中科院分区：
文献类型：
--
作者：
Wang, Zhangding;Wang, Qiang;Wang, Shouyu
越来越多的证据表明，长非编码RNA(LncRNAs)在包括胃癌(GC)在内的多种癌症的发生发展中起着重要作用。然而，lncRNA对顺铂的潜在生物学作用和调控机制尚未完全阐明，这可能与顺铂耐药有关。在本研究中，我们发现了一种新的LncRNA，即顺铂耐药相关的LncRNA(CRAL)，它在顺铂耐药的GC细胞中表达下调，削弱了顺铂诱导的DNA损伤和细胞凋亡，从而参与了GC细胞对顺铂的耐药。此外，结果表明，CRAL主要存在于细胞质中，并可结合内源性miR-505上调圆柱瘤病(CyLD)的表达，从而进一步抑制AKT的激活，导致体外和临床前模型胃癌细胞对顺铂的敏感性增加。此外，AKT激活的特异性小分子抑制剂MK2206有效地逆转了CRAL缺乏引起的GC对顺铂的耐药。综上所述，我们首次提供证据表明，一个新的内源性RNA CRAL可以通过miR-505/CyLD/AKT轴作为竞争内源性RNA(CerNA)逆转GC顺铂耐药，这表明CRAL可能被认为是胃癌顺铂耐药的潜在预测生物标志物和治疗靶点。
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.