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NDRG1 promotes growth of hepatocellular carcinoma cells by directly interacting with GSK-3? and Nur77 to prevent ?-catenin degradation.

ABSTRACT: The N-myc downstream regulated gene 1 (NDRG1) is significantly associated with advanced tumor stages and poor survival of hepatocellular carcinoma (HCC), thereby implicating it as a potential target for HCC treatment. We aim to further understand its biological roles in hepatocarcinogenesis, as a means to exploit it for therapeutic purposes. By screening using the ProtoArray® Human Protein Microarrays, we identified glycogen synthase kinase 3? (GSK-3?) and the orphan nuclear receptor (Nur77) as potential interaction partners of NDRG1. These interactions were confirmed in HCC cell lines in vitro by co-immunoprecipitation; and co-localizations of NDRG1 with GSK-3? and Nur77 were observed by immunofluorescence staining. Additionally, high levels of NDRG1 competitively bind to GSK-3? and Nur77 to allow ?-catenin to escape degradation, with consequent elevated levels of downstream oncogenic genes. In vivo, we consistently observed that NDRG1 suppression in HCC xenografts decreased ?-catenin levels and its downstream target Cyclin D1, with concomitant tumor growth inhibition. Clinically, the over-expression of NDRG1 in HCC patient samples is positively correlated with GSK-3?-9ser (|?? R | = 0.28, p = 0.01), Nur77 (|?? R | = 0.42, p < 0.001), and ?-catenin (| R |= 0.32, p = 0.003) expressions. In conclusion, we identified GSK-3? and Nur77 as novel interaction partners of NDRG1. These protein-protein interactions regulate the turnover of ?-catenin and subsequent downstream signaling mediated by ?-catenin in HCC cells, and provides potential targets for future therapeutic interventions.

SUBMITTER: Lu WJ

PROVIDER: S-EPMC4745767 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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NDRG1 promotes growth of hepatocellular carcinoma cells by directly interacting with GSK-3β and Nur77 to prevent β-catenin degradation.

Lu Wen-Jing WJ Chua Mei-Sze MS Wei Wei W So Samuel K SK

Oncotarget 20151001 30

The N-myc downstream regulated gene 1 (NDRG1) is significantly associated with advanced tumor stages and poor survival of hepatocellular carcinoma (HCC), thereby implicating it as a potential target for HCC treatment. We aim to further understand its biological roles in hepatocarcinogenesis, as a means to exploit it for therapeutic purposes. By screening using the ProtoArray® Human Protein Microarrays, we identified glycogen synthase kinase 3β (GSK-3β) and the orphan nuclear receptor (Nur77) as ...[more]

PMID: 26359353

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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence. Accumulating evidence shows that CD58-expressing tumor cell is implicated in development of various cancers. The present study aimed to reveal the functional significance of CD58 in HCC progression and the underlying mechanisms.MethodsImmunohistochemical staining (IHC), and western blotting were used to detect the expression of CD58 in HCC tissues and cells. The levels of sCD58 (a soluble form of CD58) in the cell supernatants and serum were assessed by ELISA. CCK-8, colony formation, and xenograft assays were used to detect the function of CD58 on proliferation in vitro and in vivo. Transwell assay and sphere formation assay were performed to evaluate the effect of CD58 and sCD58 on metastasis and self-renewal ability of HCC cells. Western blotting, immunofluorescence (IF), TOP/FOP Flash reporter assay, and subcellular fractionation assay were conducted to investigate the molecular regulation between CD58/sCD58 and AKT/GSK-3β/β-catenin axis in HCC cells.ResultsCD58 was significantly upregulated in HCC tissues. Elevation of CD58 expression correlated with more satellite foci and vascular invasion, and poorer tumor-free and overall survival in HCC patients. Higher sCD58 levels were in HCC patients' serum compared to healthy individuals. Functionally, CD58 promotes the proliferation of HCC cells in vitro and in vivo. Meanwhile, CD58 and sCD58 induce metastasis, self-renewal and pluripotency in HCC cells in vitro. Mechanistically, CD58 activates the AKT/GSK-3β/β-catenin signaling pathway by increasing phosphorylation of AKT or GSK3β signaling, promoting expression of Wnt/β-catenin target proteins and TCF/LEF-mediated transcriptional activity. Furthermore, AKT activator SC-79 or inhibitor LY294002 abolished the inhibitory effect of CD58 silencing on the proliferation, metastasis, and stemness of HCC cells.ConclusionsTaken together, CD58 promotes HCC progression and metastasis via activating the AKT/GSK-3β/β-catenin pathway, suggesting that CD58 is a novel prognostic biomarker and therapeutic target for HCC.

Dataset Information

NDRG1 promotes growth of hepatocellular carcinoma cells by directly interacting with GSK-3? and Nur77 to prevent ?-catenin degradation.

Publications

NDRG1 promotes growth of hepatocellular carcinoma cells by directly interacting with GSK-3β and Nur77 to prevent β-catenin degradation.

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