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

Author:

Hu Yun-ping,Jin Yun-peng,Wu Xiang-song,Yang Yang,Li Yong-sheng,Li Huai-feng,Xiang Shan-shan,Song Xiao-ling,Jiang Lin,Zhang Yi-jian,Huang Wen,Chen Shi-li,Liu Fa-tao,Chen Chen,Zhu Qin,Chen Hong-zhuan,Shao Rong,Liu Ying-binORCID

Abstract

Abstract 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.

Funder

National Natural Science Foundation of China

the Emerging Frontier Program of Hospital Development Center

the General Surgery Construction Program of Shanghai Municipal Health Commission

Xinhua Hospital PI-startup funds

the Project of Excellent Young Scholars from Shanghai Municipal Health and Family Planning Commission

the Talent Development Fund from Shanghai Municipal Human Resources and Social Security Bureau

Shanghai Pujiang Program

Shanghai Key Laboratory of Biliary Tract Disease Research Foundation

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology,Molecular Medicine

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