Oncotarget

Research Papers:

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

Wen-Jing Lu _, Mei-Sze Chua, Wei Wei and Samuel K. So

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Oncotarget. 2015; 6:29847-29859. https://doi.org/10.18632/oncotarget.4913

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Abstract

Wen-Jing Lu1, Mei-Sze Chua1, Wei Wei1, Samuel K. So1

1Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA

Correspondence to:

Mei-Sze Chua, e-mail: mchua@stanford.edu

Keywords: NDRG1, β-catenin, GSK-3β, Nur77, liver cancer

Abbreviations: NDRG1, N-Myc downstream regulated gene 1; HCC, Hepatocellular carcinoma; GSK-3β, glycogen synthase kinase-3β; Nur77, Orphan nuclear receptor

Received: June 08, 2015     Accepted: August 07, 2015     Published: August 20, 2015

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 3β (GSK-3β) 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-3β and Nur77 were observed by immunofluorescence staining. Additionally, high levels of NDRG1 competitively bind to GSK-3β and Nur77 to allow β-catenin to escape degradation, with consequent elevated levels of downstream oncogenic genes. In vivo, we consistently observed that NDRG1 suppression in HCC xenografts decreased β-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-3β-9ser (│R│= 0.28, p = 0.01), Nur77 (│R│= 0.42, p < 0.001), and β-catenin (│R│= 0.32, p = 0.003) expressions. In conclusion, we identified GSK-3β and Nur77 as novel interaction partners of NDRG1. These protein-protein interactions regulate the turnover of β-catenin and subsequent downstream signaling mediated by β-catenin in HCC cells, and provides potential targets for future therapeutic interventions.


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