Abstract
BackgroundsLong 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.MethodsThe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Gallbladder cancer (GBC) is a rare, but is an extremely aggressive carcinoma developed from the biliary tract [1]
We were focused on this uncharacterized Long non-coding RNAs (lncRNAs) and named lncRNA-HGBC
To further validate the increased level of lncRNA-HGBC in GBC, we examined lncRNA-HGBC expression in another set of 43 cases containing both cancer and adjacent non-tumor tissues, and found that lncRNA-HGBC level was significantly higher in GBC tissues than in benign tissues (P = 0.0074; Fig. 1a)
Summary
Gallbladder cancer (GBC) is a rare, but is an extremely aggressive carcinoma developed from the biliary tract [1]. Regardless of the relatively higher incidence in Asia than in Western countries [2], almost GBC cases are diagnosed at advanced stages due to the lack of early symptoms. Most of those patients fall into unexpected contraindication of the resection, while the rest need immediately surgical removal [3,4,5]. Adjunctive therapy including chemo- and radiotherapy is an indispensable regimen to treat the majority of GBC patients. Over the last decades large effort has been made in identification of tumor-promoting oncogenes and tumor suppressors in GBC, there is still lack of independent biomarkers that can be routinely used in clinical practice [9, 10].
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