LncRNA-HGBC stabilized by HuR promotes gallbladder cancer progression by regulating miR-502-3p/SET/AKT axis

被引：181

作者：

Hu, Yun-ping ^{[1
,2
,3
,4
]}

Jin, Yun-peng ^{[1
,2
,3
]}

Wu, Xiang-song ^{[1
,2
,3
]}

Yang, Yang ^{[1
,2
,3
]}

Li, Yong-sheng ^{[1
,2
,3
]}

Li, Huai-feng ^{[1
,2
,3
]}

Xiang, Shan-shan ^{[1
,2
,3
]}

Song, Xiao-ling ^{[1
,2
,3
]}

Jiang, Lin ^{[1
,2
,3
]}

Zhang, Yi-jian ^{[1
,2
,3
]}

Huang, Wen ^{[1
,2
,3
]}

Chen, Shi-li ^{[1
,2
,3
]}

Liu, Fa-tao ^{[1
,2
,3
]}

Chen, Chen ^{[1
,2
,3
]}

Zhu, Qin ^{[1
,2
,3
]}

Chen, Hong-zhuan ^{[4
]}

Shao, Rong ^{[1
,4
]}

Liu, Ying-bin ^{[1
,2
,3
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Gen Surg, Bldg 25,Room 513,1665 Kongjiang Rd, Shanghai 200092, Peoples R China

[2] Shanghai Key Lab Biliary Tract Dis Res, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China

[3] Shanghai Res Ctr Biliary Tract Dis, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China

[4] Shanghai Jiao Tong Univ, Sch Med, Dept Pharmacol, W Bldg 3,Room 407,280 Chongqi Rd, Shanghai 200025, Peoples R China

来源：

MOLECULAR CANCER | 2019年 / 18卷 / 01期

基金：

中国国家自然科学基金;

关键词：

Gallbladder cancer; lncRNA-HGBC; miR-502-3p; SET; HuR; LONG NONCODING RNA; COMPETING ENDOGENOUS RNA; HEPATOCELLULAR-CARCINOMA; CELL-PROLIFERATION; EXPRESSION; SET; INFLAMMATION; MIGRATION; LEUKEMIA; INVASION;

D O I：

10.1186/s12943-019-1097-9

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Backgrounds Long non-coding RNAs (lncRNAs) are essential factors that regulate tumor development and metastasis via diverse molecular mechanisms in a broad type of cancers. However, the pathological roles of lncRNAs in gallbladder carcinoma (GBC) remain largely unknown. Here we discovered a novel lncRNA termed lncRNA Highly expressed in GBC (lncRNA-HGBC) which was upregulated in GBC tissue and aimed to investigate its role and regulatory mechanism in the development and progression of GBC. Methods The expression level of lncRNA-HGBC in GBC tissue and different cell lines was determined by quantitative real-time PCR. The full length of lncRNA-HGBC was obtained by 5 ' and 3 ' rapid amplification of the cDNA ends (RACE). Cellular localization of lncRNA-HGBC was detected by fluorescence in situ hybridization (FISH) assays and subcellular fractionation assay. In vitro and in vivo assays were preformed to explore the biological effects of lncRNA-HGBC in GBC cells. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation (RIP) assay were used to identify lncRNA-HGBC-interacting proteins. Dual luciferase reporter assays, AGO2-RIP, and MS2-RIP assays were performed to verify the interaction between lncRNA-HGBC and miR-502-3p. Results We found that lncRNA-HGBC was upregulated in GBC and its upregulation could predict poor survival. Overexpression or knockdown of lncRNA-HGBC in GBC cell lines resulted in increased or decreased, respectively, cell proliferation and invasion in vitro and in xenografted tumors. LncRNA-HGBC specifically bound to RNA binding protein Hu Antigen R (HuR) that in turn stabilized lncRNA-HGBC. LncRNA-HGBC functioned as a competitive endogenous RNA to bind to miR-502-3p that inhibits target gene SET. Overexpression, knockdown or mutation of lncRNA-HGBC altered the inhibitory effects of miR-502-3p on SET expression and downstream activation of AKT. Clinically, lncRNA-HGBC expression was negatively correlated with miR-502-3p, but positively correlated with SET and HuR in GBC tissue. Conclusions Our study demonstrates that lncRNA-HGBC promotes GBC metastasis via activation of the miR-502-3p-SET-AKT cascade, pointing to lncRNA-HGBC as a new prognostic predictor and a therapeutic target.

引用

页数：18

共 49 条

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HuR Regulates Gap Junctional Intercellular Communication by Controlling β-Catenin Levels and Adherens Junction Integrity [J].