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Silencing of long non-coding RNA XIST represses gastric cancer progression through blocking NFκB pathway via inhibiting HNF4A-mediated transcription of EPHA1
Cancer Gene Therapy ( IF 6.4 ) Pub Date : 2020-11-16 , DOI: 10.1038/s41417-020-00220-5
Ping Li 1, 2, 3 , Liuhua Wang 4 , Pengfei Li 1, 2 , Fangyong Hu 1, 2 , Yi Cao 3 , Dong Tang 4 , Gang Ye 5 , Hongbo Li 5 , Daorong Wang 4
Affiliation  

Gastric cancer (GC) is a common cancer and a leading cause of cancer-related deaths worldwide. Recent studies have supported the important role of long non-coding RNAs (lncRNAs) in GC progression. This study identified functional significance of X inactive specific transcript (XIST) in GC. The expression of XIST and EPHA1 in GC tissues and cells was measured. Then, dual luciferase reporter gene assay, RNA immunoprecipitation (RIP) assay and Chromatin Immunoprecipitation (ChIP) assay were performed to explore the interaction among XIST, EPHA1 and HNF4A. The effects of XIST on GG progression were evaluated by determining expression of proliferation- and invasion-related proteins (Ki67, PCNA, MMP-2, and MMP-9). Further, the functional role of XIST in GC with the involvement of NFκB pathway was also analyzed. Subsequently, the tumor growth in nude mice was evaluated. High expression of XIST and EPHA1 was observed in GC. XIST elevated EPHA1 expression by recruiting HNF4A. In addition, silencing of XIST inhibited GC progression in vitro and in vivo. Overexpressed XIST and EPHA1 yielded a reversed effect on cell proliferation and invasion. SN50 treatment (inhibitor of NFκB pathway) counteracted the promotive effect on GC cell proliferation and invasion mediated by XIST. The present study unveils that XIST increases the enrichment of HNF4A in the promoter region of EPHA1, thus promoting the deterioration of GC.



中文翻译:

长非编码RNA XIST的沉默通过抑制HNF4A介导的EPHA1转录阻断NFκB通路来抑制胃癌进展

胃癌(GC)是一种常见癌症,也是全球癌症相关死亡的主要原因。最近的研究支持长链非编码 RNA (lncRNA) 在 GC 进展中的重要作用。本研究确定了 X 失活特异性转录本 (XIST) 在 GC 中的功能意义。检测GC组织和细胞中XIST和EPHA1的表达。然后,进行双荧光素酶报告基因测定、RNA免疫沉淀(RIP)测定和染色质免疫沉淀(ChIP)测定来探讨XIST、EPHA1和HNF4A之间的相互作用。通过测定增殖和侵袭相关蛋白(Ki67、PCNA、MMP-2 和 MMP-9)的表达来评估 XIST 对 GG 进展的影响。此外,还分析了 XIST 在 GC 中涉及 NFκB 通路的功能作用。随后,评估裸鼠中的肿瘤生长。在 GC 中观察到 XIST 和 EPHA1 高表达。XIST 通过招募 HNF4A 来提高 EPHA1 表达。此外,XIST 的沉默在体外和体内抑制了 GC 进展。过表达的 XIST 和 EPHA1 对细胞增殖和侵袭产生相反的影响。SN50 治疗(NFκB 通路抑制剂)抵消了 XIST 介导的对 GC 细胞增殖和侵袭的促进作用。本研究表明,XIST 增加了 EPHA1 启动子区域 HNF4A 的富集,从而促进 GC 恶化。

更新日期:2020-11-16
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