STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells via mTOR signal-mediated inhibition of autophagy.
STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells via mTOR signal-mediated inhibition of autophagy.
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STAT3诱导的lncRNA HAGLROS过表达通过mTOR信号介导的自噬抑制促进胃癌细胞的恶性进展
DOI：
10.1186/s12943-017-0756-y
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发表时间：
2018-01-12
期刊：
影响因子：
37.3
通讯作者：
Yang F
中科院分区：
文献类型：
--
作者：
Chen JF;Wu P;Xia R;Yang J;Huo XY;Gu DY;Tang CJ;De W;Yang F
长链非编码RNA（longnoncodingRNAs，lncRNA）是一类重要的功能调节因子，参与了包括胃癌（gastriccancer，GC）在内的多种肿瘤的发生发展。研究异常表达的lncRNA可能通过作为癌基因或抑癌基因为胃癌的发生发展提供新的认识。在这项研究中，我们的目的是研究lncRNA HAGLROS在GC中的表达模式及其临床意义，以及其在肿瘤进展中的生物学作用。通过生物信息学分析和qRT-PCR检测HAGLROS在胃癌组织和胃癌细胞系中的相对表达量。使用功能获得或丧失方法来研究HAGLROS的生物学功能。采用MTT法、集落形成实验和裸鼠移植瘤模型观察HAGLROS对细胞增殖的影响。采用创伤愈合实验和Transwell实验研究胃癌细胞的侵袭和迁移能力。通过FISH、RIP、RNA-seq、荧光素酶报告分析、RNA pulldown和Western blot检测分子机制。结果显示为平均值± S. D。并使用Student’s t检验（双尾）检验差异的显著性。我们通过公开的lncRNA表达谱和整合分析筛选出HAGLROS，其表达显著增加并且与GC患者的结果相关。外源性下调HAGLROS表达可显著抑制细胞增殖、侵袭和迁移。机制研究表明，HAGLROS是转录因子STAT 3的直接靶点。此外，HAGLROS敲低降低mTOR表达并增加自噬相关基因ATG 9A和ATG 9 B表达。进一步的研究表明，HAGLROS以两种方式调节mTOR信号。一方面，HAGLROS通过拮抗miR-100 - 5 p介导的mTOR mRNA抑制来竞争性地吸收miR-100 - 5 p以增加mTOR表达。另一方面，HAGLROS与mTORC 1组分相互作用，激活mTORC 1信号通路，这是已知的自噬的重要负信号。HAGLROS激活mTORC 1信号通路可抑制自噬，从而促进过度增殖并维持GC细胞的恶性表型。目前的研究表明，HAGLROS过表达有助于GC的发展和不良预后，并将成为GC治疗的靶点，并进一步发展为潜在的预后生物标志物。本文的在线版本（10.1186/s12943-017-0756-y）包含补充材料，可供授权用户使用。
Long noncoding RNAs (lncRNAs) are an important class of functional regulators involved in human cancers development, including gastric cancer (GC). Studying aberrantly expressed lncRNAs may provide us with new insights into the occurrence and development of gastric cancer by acting as oncogenes or tumor suppressors. In this study, we aim to examine the expression pattern of lncRNA HAGLROS in GC and its clinical significance as well as its biological role in tumor progression. Bioinformatics analysis and qRT-PCR were performed to detect the relative expression of HAGLROS in GC tissues and cell lines. Gain or loss of function approaches were used to investigate the biological functions of HAGLROS. The effect of HAGLROS on proliferation was evaluated by MTT, colony formation assay and nude mouse xenograft model. Wound healing and Transwell assays were used to study the invasion and migration of GC cells. FISH, RIP, RNA-seq, Luciferase report assays, RNA pulldown and Western blot were fulfilled to measure molecular mechanisms. Results are shown as means ± S.D. and differences were tested for significance using Student’s t-test (two-tailed). We screened out HAGLROS, whose expression was significantly increased and correlated with outcomes of GC patients by publicly available lncRNAs expression profiling and integrating analyses. Exogenous down-regulation of HAGLROS expression significantly suppressed the cell proliferation, invasion and migration. Mechanistic investigations showed that HAGLROS was a direct target of transcriptional factor STAT3. Moreover, HAGLROS knockdown decreased mTOR expression and increased autophagy-related genes ATG9A and ATG9B expression. Further investigation showed that HAGLROS regulated mTOR signals in two manners. In the one hand, HAGLROS competitively sponged miR-100-5p to increase mTOR expression by antagonizing miR-100-5p-mediated mTOR mRNA inhibition. On the other hand, HAGLROS interacted with mTORC1 components to activate mTORC1 signaling pathway which was known to be an important negative signal of autophagy. Here activation of mTORC1 signaling pathway by HAGLROS inhibited autophagy, thereby promoted excessive proliferation and maintained the malignant phenotype of GC cells. The present study demonstrates that HAGLROS overexpression contributes to GC development and poor prognosis and will be a target for GC therapy and further develop as a potential prognostic biomarker. The online version of this article (10.1186/s12943-017-0756-y) contains supplementary material, which is available to authorized users.
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