1. Academic Validation
  2. LncRNA-HGBC stabilized by HuR promotes gallbladder cancer progression by regulating miR-502-3p/SET/AKT axis

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

  • Mol Cancer. 2019 Nov 21;18(1):167. doi: 10.1186/s12943-019-1097-9.
Yun-Ping Hu  # 1 2 3 4 Yun-Peng Jin  # 1 2 3 Xiang-Song Wu  # 1 2 3 Yang Yang 1 2 3 Yong-Sheng Li 1 2 3 Huai-Feng Li 1 2 3 Shan-Shan Xiang 1 2 3 Xiao-Ling Song 1 2 3 Lin Jiang 1 2 3 Yi-Jian Zhang 1 2 3 Wen Huang 1 2 3 Shi-Li Chen 1 2 3 Fa-Tao Liu 1 2 3 Chen Chen 1 2 3 Qin Zhu 1 2 3 Hong-Zhuan Chen 5 Rong Shao 6 7 Ying-Bin Liu 8 9 10
Affiliations

Affiliations

  • 1 Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China.
  • 2 Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China.
  • 3 Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China.
  • 4 Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, W. Building 3, Room 407, 280 Chongqi Road, Shanghai, 200025, China.
  • 5 Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, W. Building 3, Room 407, 280 Chongqi Road, Shanghai, 200025, China. [email protected].
  • 6 Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China. [email protected].
  • 7 Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, W. Building 3, Room 407, 280 Chongqi Road, Shanghai, 200025, China. [email protected].
  • 8 Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China. [email protected].
  • 9 Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China. [email protected].
  • 10 Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China. [email protected].
  • # Contributed equally.
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.

Keywords

Gallbladder cancer; HuR; SET; lncRNA-HGBC; miR-502-3p.

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