Subcellular Mislocalization of Mutant Hepatitis B X Proteins Contributes to Modulation of STAT/SOCS Signaling in Hepatocellular CarcinomaBock C.-T. · Toan N.L. · Koeberlein B. · Song L.H. · Chin R. · Zentgraf H. · Kandolf R. · Torresi J.
aDepartment of Molecular Pathology, Institute of Pathology, University Hospital of Tuebingen, Tuebingen, Germany; bDepartment of Pathophysiology, Vietnam Military Medical University, Hadong City, and cDepartment of Infectious Diseases, Tran Hung Dao Hospital, Hanoi, Vietnam; dDepartment of Medicine, Victorian Infectious Diseases Service, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Vic., Australia; eGerman Cancer Research Center, Applied Tumor Virology, Heidelberg, Germany
Objective: The hepatitis B virus X (HBx) protein plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). One potential mechanism by which HBx can cause liver cancer may involve intracellular distribution and consecutively modulation of the proliferative important STAT/SOCS signaling with upregulation of STAT3. Methods: 153 Vietnamese HBV-infected patients, including 48 patients with HCC, were analyzed. HBx sequences were determined by sequencing and subcloned for functional experiments. Intracellular localization of HBx mutants was determined by immunofluorescence assays. The impact of HBx mutants on JAK/STAT/SOCS signaling was investigated using Western blot and PCR analyses. Results: In 4/48 HCC patients, truncated HBx together with full-length mutated HBx proteins were observed. Expression of HBx mutant proteins demonstrated an atypical nuclear and perinuclear localization. Functional experiments to determine the effect of HBx mutants on STAT/SOCS signaling demonstrated a significantly increased upregulation of STAT3 activation (p > 0.001) in comparison to wild-type (wt)-HBx. STAT1 was not activated either by wt-HBx or HBx mutants. Interestingly, SOCS1 and SOCS3 expression was not activated by wt-HBx and HBx mutants. Conclusions: Our results suggest that atypical nuclear/perinuclear localization of HBx mutants might be responsible for an enhanced activation of STAT3, inhibition of STAT1 and silencing of SOCS1/SOCS3 expression. This observation points to an active role of HBx mutants in hepatocarcinogenesis that involves dysregulation of STAT/SOCS signaling.
C.-Thomas Bock, PhD
Department of Molecular Pathology, Institute of Pathology
University Hospital of Tuebingen, DE–72076 Tuebingen (Germany)
Tel. +49 7071 29 86889, Fax +49 7071 29 5334
C.-T.B. and N.L.T. contributed equally to this work and share first authorship.
Received: September 18, 2008
Accepted: February 11, 2009
Published online: March 26, 2009
Number of Print Pages : 12
Number of Figures : 6, Number of Tables : 2, Number of References : 53
Intervirology (International Journal of Basic and Medical Virology)
Vol. 51, No. 6, Year 2008 (Cover Date: April 2009)
Journal Editor: Liebert U.G. (Leipzig)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)
For additional information: http://www.karger.com/INT