Oncotarget

Research Papers:

Hepatitis B virus X protein amplifies TGF-β promotion on HCC motility through down-regulating PPM1a

Yuan Liu, Yong Xu, Hongxin Ma, Bo Wang, Leiqi Xu, Hualin Zhang, Xiaojia Song, Lifen Gao, Xiaohong Liang _ and Chunhong Ma

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Oncotarget. 2016; 7:33125-33135. https://doi.org/10.18632/oncotarget.8884

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Abstract

Yuan Liu1, Yong Xu1, Hongxin Ma1, Bo Wang1, Leiqi Xu1, Hualin Zhang1, Xiaojia Song1, Lifen Gao1, Xiaohong Liang1, Chunhong Ma1

1Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China

Correspondence to:

Xiaohong Liang, e-mail: Liangxiaohong@sdu.edu.cn

Chunhong Ma, e-mail: machunhong@sdu.edu.cn

Keywords: HCC, HBx, PPM1a, TGF-β, tumorigenenesis

Received: September 22, 2015     Accepted: April 02, 2016     Published: April 21, 2016

ABSTRACT

Over-activation of transforming growth factor-β (TGF-β) signaling pathway promotes cell migration and invasion in hepatocellular carcinoma (HCC). The Hepatitis B virus X protein (HBx) is involved in the enhancement of TGF-β signaling pathway in HCC while the mechanism remains unclear. Protein phosphatase magnesium dependent 1A (PPM1a) functions as a phosphatase essential for terminating the TGF-β signaling pathway by dephosphorylating p-Smad2/3. In this study, we found that HBx dose-dependently downregulated PPM1a protein level in the presence of TGF-β, while having no effect on its mRNA level. Further study showed that HBx increased the ubiquitination of PPM1a and accelerated its proteasomal degradation. Restoration of PPM1a almost completely abrogated HBx mediated promotion on HCC migration and invasion. This involvement of PPM1a in HBx-related HCC was further confirmed with immunohistochemical analysis in HCC tissue. Compared with paired pericarcinous tissue, HCC tissue showed decreased PPM1a level. Besides, PPM1a level is negatively correlated with HBx expression. Taken together, our present study suggests that HBx-induced degradation of PPM1a is a novel mechanism for over-activation of TGF-β pathway in HCC development, which might provide potential candidates for clinical diagnosis and treatment.


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