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

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 <i>in vitro</i> 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.

越来越多的研究证据表明，长链非编码RNA（long noncoding RNAs，lncRNAs）在包括胃癌（gastric cancer，GC）在内的多种癌症的发生发展中发挥关键作用。然而，长链非编码RNA在顺铂应答过程中的潜在生物学功能与调控机制，尤其是其与顺铂耐药的关联，尚未完全阐明。本研究中，我们鉴定出一种新型长链非编码RNA——顺铂耐药相关长链非编码RNA（cisplatin resistance-associated lncRNA，CRAL），该分子在顺铂耐药胃癌细胞中呈低表达，可抑制顺铂诱导的DNA损伤与细胞凋亡，进而促进胃癌细胞的顺铂耐药性。进一步研究发现，CRAL主要定位于细胞质，可通过海绵吸附内源性miR-505，上调圆柱瘤蛋白（CYLD）的表达，进而抑制AKT通路激活，最终在体外实验及临床前模型中提升胃癌细胞对顺铂的敏感性。此外，特异性AKT激活小分子抑制剂MK2206可有效逆转CRAL缺失所诱导的胃癌顺铂耐药。综上，本研究首次证实，新型长链非编码RNA CRAL可作为内源竞争RNA（competing endogenous RNA，ceRNA），通过miR-505/CYLD/AKT信号轴逆转胃癌顺铂耐药，这表明CRAL有望成为胃癌顺铂耐药的潜在预测性生物标志物与治疗靶点。