Dai Qingqiang, Zhang Tianqi, Pan Jiaomeng, Li Chen
Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032 China.
J Cancer. 2020 Apr 6;11(13):3882-3892. doi: 10.7150/jca.43446. eCollection 2020.
: Drug resistance of cancer cells is one of the major causes of chemotherapy failure. Recently research demonstrated that long non-coding RNA Urothelial cancer associated 1 (UCA1) could promote tumor cisplatin resistance. In this study, we aim to investigate the role of UCA1 in the cisplatin treatment of gastric cancer and its underlying mechanism. : Cell counting kit-8 (CCK-8) assay and apoptosis assay were used to detect the effects of different doses of cisplatin on the proliferation and apoptosis of gastric cancer. We examined the expression relationship between the Enhancer of Zeste Homologue 2 (EZH2) and UCA1 by quantitative Real-time polymerase chain reaction (qRT-PCR) and western blot analysis. Western blot analysis was also performed to detect the expression levels of apoptosis-related proteins, EZH2 and key genes in PI3K/AKT signaling pathway, RIP and RNA pull down assays were performed to explore the interaction between UCA1 and EZH2. : We demonstrated that higher the UCA1 expression levels in GC tissues correlated with the poorer the prognosis of patients according to the TCGA database, the GEO database. Moreover, overexpression of UCA1 promotes GC cell proliferation and inhibits cisplatin-induced apoptosis. Knockdown of UCA1 showed the opposite results. Besides, UCA1 exerted its function through interacting with EZH2 and regulates EZH2 expression, knockdown of EZH2 decreased cisplatin resistance of GC cells. Hence, UCA1 promotes cisplatin resistance of GC via recruiting EZH2 and activating PI3K/AKT pathway. : Our research revealed the lncRNA UCA1 promoted the cisplatin resistance of GC by recruiting EZH2 and activating PI3K/AKT pathway to modulate cell apoptosis, indicating treatments targeting UCA1 or EZH2 might provide meaningful therapeutic strategies for cisplatin-resistance GC patients.
癌细胞的耐药性是化疗失败的主要原因之一。最近的研究表明，长链非编码RNA尿路上皮癌相关1（UCA1）可促进肿瘤顺铂耐药。在本研究中，我们旨在探讨UCA1在胃癌顺铂治疗中的作用及其潜在机制。
采用细胞计数试剂盒-8（CCK-8）法和凋亡检测法检测不同剂量顺铂对胃癌细胞增殖和凋亡的影响。通过定量实时聚合酶链反应（qRT-PCR）和蛋白质免疫印迹分析检测增强子结合蛋白2（EZH2）与UCA1之间的表达关系。蛋白质免疫印迹分析还用于检测凋亡相关蛋白、EZH2以及PI3K/AKT信号通路关键基因的表达水平，进行RIP和RNA下拉实验以探讨UCA1与EZH2之间的相互作用。
根据TCGA数据库和GEO数据库，我们证明胃癌组织中UCA1表达水平越高，患者预后越差。此外，UCA1的过表达促进胃癌细胞增殖并抑制顺铂诱导的凋亡。敲低UCA1则出现相反的结果。此外，UCA1通过与EZH2相互作用发挥其功能并调节EZH2表达，敲低EZH2可降低胃癌细胞的顺铂耐药性。因此，UCA1通过招募EZH2并激活PI3K/AKT通路促进胃癌的顺铂耐药。
我们的研究表明，lncRNA UCA1通过招募EZH2并激活PI3K/AKT通路调节细胞凋亡，从而促进胃癌的顺铂耐药，这表明针对UCA1或EZH2的治疗可能为顺铂耐药的胃癌患者提供有意义的治疗策略。
