TY - JOUR
T1 - Aberrant cyclin a expression and centrosome overduplication induced by hepatitis B virus pre-S2 mutants and its implication in hepatocarcinogenesis
AU - Wang, Lily Hui Ching
AU - Huang, Wenya
AU - Lai, Ming Derg
AU - Su, Ih Jen
N1 - Funding Information:
1Institute of Molecular and Cellular Biology and 2Department of Medical Science, National Tsing Hua University, Hsinchu 300, Taiwan, 3Center of Infectious Diseases and Signaling Research, 4Department of Medical Technology, 5Department of Biochemistry and 6Department of Pathology, National Cheng-Kung University Medical College and Hospital, 701 Tainan, Taiwan and 7Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, 704 Tainan, Taiwan *To whom correspondence should be addressed. National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, 367, Sheng-Li Road, Tainan 704, Taiwan. Tel: +886 6 2083426; Fax: +886 6 2083466; Email: suihjen@nhri.org.tw
Funding Information:
National Science Council Taiwan (NSC 99-2311-B-007-010, NSC 100-2320-B-007-001 to L.H.-C.W. and NSC 99-2320-B-400-010-MY3 to I.-J.S.); Center of Infectious Diseases and Signal Transduction, National Cheng Kung University, Tainan, Taiwan.
PY - 2012
Y1 - 2012
N2 - Ground glass hepatocytes harboring hepatitis B virus (HBV) pre-S2 mutants have been recognized as pre-neoplastic lesions of hepatocellular carcinoma (HCC). The pre-S2 mutants accumulated in endoplasmic reticulum (ER) can induce ER stress, upregulate cyclin A and promote hepatocyte proliferation. Notably, cyclin A was aberrantly detected in the cytoplasm, instead of nucleus, of pre-S2 mutant-transgenic mice livers, thereby raising the potential role of cytoplasmic cyclin A in HBV hepatocarcinogenesis. In this study, we confirmed that cyclin A was detected in the cytoplasm in the majority of HBV-related HCC tissues. In vitro, the pre-S2 mutant-initiated ER stress could induce cytoplasmic cyclin A mediated via cleavage by the calcium-dependent protease μ-calpain, resulting in an N-terminal truncated product which was preferentially located in the cytoplasm. The aberrant cyclin A expression subsequently induced centrosome overduplication, and this effect was abolished by calpain-specific inhibitors or RNA interference targeting to cyclin A. Overall, our data indicate that HBV pre-S2 mutant may elicit aberrant cyclin A expression and centrosome overduplication through ER stress induction and thereby represent a potential mechanism for the chromosome instability in HBV hepatocarcinogenesis.
AB - Ground glass hepatocytes harboring hepatitis B virus (HBV) pre-S2 mutants have been recognized as pre-neoplastic lesions of hepatocellular carcinoma (HCC). The pre-S2 mutants accumulated in endoplasmic reticulum (ER) can induce ER stress, upregulate cyclin A and promote hepatocyte proliferation. Notably, cyclin A was aberrantly detected in the cytoplasm, instead of nucleus, of pre-S2 mutant-transgenic mice livers, thereby raising the potential role of cytoplasmic cyclin A in HBV hepatocarcinogenesis. In this study, we confirmed that cyclin A was detected in the cytoplasm in the majority of HBV-related HCC tissues. In vitro, the pre-S2 mutant-initiated ER stress could induce cytoplasmic cyclin A mediated via cleavage by the calcium-dependent protease μ-calpain, resulting in an N-terminal truncated product which was preferentially located in the cytoplasm. The aberrant cyclin A expression subsequently induced centrosome overduplication, and this effect was abolished by calpain-specific inhibitors or RNA interference targeting to cyclin A. Overall, our data indicate that HBV pre-S2 mutant may elicit aberrant cyclin A expression and centrosome overduplication through ER stress induction and thereby represent a potential mechanism for the chromosome instability in HBV hepatocarcinogenesis.
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U2 - 10.1093/carcin/bgr296
DO - 10.1093/carcin/bgr296
M3 - Article
C2 - 22159224
AN - SCOPUS:84863076138
VL - 33
SP - 466
EP - 472
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 2
ER -