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
  • 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.
PMID: 31752906 DOI: 10.1186/s12943-019-1097-9
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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