lncRNA HAGLROS通过mTOR信号抑制自噬介导胃癌恶性表型的机制研究

LncRNAs are closely associated with gastric tumorigenesis, but their role in the molecular mechanisms are unclear. Our previous studies have found that lncRNA HAGLROS is highly expressed in gastric cancer tissue, and level of its expression was positively correlated with the stage and size of tumor. With the silence of HAGLROS in the gastric cancer cell line, the cell proliferation and migration were inhibited, while autophagy signal mTOR was down-regulated, autophagy-associated genes ATG9A and ATG9B were up-regulated, etc. These results showed that silence of HAGLROS could induce the autophagy. When autophagy was inhibited by 3-MA, the cell proliferation and migration were strengthened. Therefore, we suggest that HAGLROS may regulate the malignant phonotype by activating the mTOR signals. The present study intends to evaluate whether HAGLROS could be associated with clinical parameters of gastric cancer first; then to demonstrate HAGLROS’s biological functions on the gastric cancer cell both in vitro and in vivo. After that, the present study will explore the molecular mechanisms of HAGLROS to impact the gastric cancer phonotypes through activating mTOR to inhibit autophagy. Finally, we will clarify the association between the HAGLROS, mTOR and autophagy-associated molecules. Our study would provide important experimental evidence for precision diagnosis and treatment for gastric cancer.

LncRNA异常表达与胃癌发生发展密切相关，但确切机制亟待阐明。前期研究发现lncRNA HAGLROS在胃癌组织中高表达，表达水平与胃癌分期、肿瘤大小呈正相关；在胃癌细胞株中沉默HAGLROS，细胞增殖和迁移能力明显抑制，自噬负调控信号mTOR下调、自噬相关基因ATG9A、ATG9B上调，自噬标志分子LC3II增加、P62减少，表明沉默HAGLROS自噬被诱导；应用3-MA抑制自噬细胞增殖和迁移能力增强；推测HAGLROS可能通过激活mTOR信号抑制自噬以调控胃癌恶性表型。本项目首先研究HAGLROS与胃癌临床参数的关系；继而从细胞株和动物水平揭示HAGLROS对胃癌生物学功能的影响；进一步在分子水平揭示HAGLROS通过激活mTOR信号抑制自噬介导胃癌恶性表型的机制；最后通过组织样本验证HAGLROS与mTOR信号、自噬相关分子之间的关系及其生物学功能，为胃癌的精准诊疗提供实验依据。

LncRNA异常表达与胃癌发生发展密切相关，但确切机制亟待阐明。前期研究发现lncRNAHAGLROS在胃癌组织中高表达，表达水平与胃癌分期、肿瘤大小呈正相关；在胃癌细胞株中沉默HAGLROS，细胞增殖和迁移能力明显抑制，自噬负调控信号mTOR下调、自噬相关基因ATG9A、ATG9B上调，自噬标志分子LC3II增加、P62减少，表明沉默HAGLROS自噬被诱导；应用3-MA抑制自噬细胞增殖和迁移能力增强；推测HAGLROS可能通过激活mTOR信号抑制自噬以调控胃癌恶性表型。本项目首先研究HAGLROS与胃癌临床参数的关系；继而从细胞株和动物水平揭示HAGLROS对胃癌生物学功能的影响；进一步在分子水平揭示HAGLROS通过激活mTOR信号抑制自噬介导胃癌恶性表型的机制；最后通过组织样本验证HAGLROS与mTOR信号、自噬相关分子之间的关系及其生物学功能，为胃癌的精准诊疗提供实验依据。