한빛사 논문
Abstract
Eun-Sook Park1,2, Yong Kwang Park1, ChanYoung Shin1,2, Seung Hwa Park3, Sung Hyun Ahn1, Doo Hyun Kim1, Keo-Heun Lim1, So Young Kwon4, Kwang Pyo Kim5, Sung-Il Yang1, Baik L. Seong6, Kyun-Hwan Kim1,2,*
1 Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Republic of Korea
2 Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Republic of Korea
3 Department of Anatomy, Konkuk University School of Medicine, Seoul, Republic of Korea
4 Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea
5 Department of Molecular Biotechnology, WCU program, Konkuk University, Seoul, Republic of Korea
6 Department of Biotechnology, College of Life Science and Biotechnology, and Translational Research Center for Protein Function Control, Yonsei University,Seoul, Republic of Korea
* Corresponding author
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.26379
Abstract
Liver regeneration after liver damage caused by toxins and pathogens is critical for liver homeostasis. Retardation of liver proliferation was reported in hepatitis B virus (HBV) X protein (HBx)-transgenic mice. However, the underlying mechanism of the HBx-mediated disturbance of liver regenerationis unknown.We investigated the molecular mechanismof the inhibition of liver regeneration using liver cell lines and a mouse model. The mouse model of acute HBV infection was established by hydrodynamic injection of viral DNA.Liver regeneration after partial hepatectomy was significantly inhibited in the HBV DNA-treatedmice. Mechanism studies have revealed that the expression of urokinase-type plasminogen activator (uPA), which regulates the activation of hepatocyte growth factor (HGF), was significantly decreased in the liver tissues of HBV or HBx-expressing mice. The down-regulation of uPA was further confirmed using liver cell lines transiently or stably transfected with HBx and the HBV genome. HBx suppresseduPA expression through the epigenetic regulationof the uPA promoter in mice liver tissues and human liver cell lines. Expression of HBx strongly induced hyper-methylation of the uPA promoter byrecruiting DNA methyltransferase (DNMT) 3A2.Conclusions:Taken together,these resultssuggest that infection of HBV impairs liver regeneration throughthe epigenetic dysregulation of liver regeneration signals by HBx. (HEPATOLOGY 2013.)
Keywords: HBx; liver regeneration; Epigenetic regulation; uPA
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