| Co-Investigator(Kenkyū-buntansha) |
FUJIE Hajime THE UNIVERSITY OF TOKYO, FACULTY OF MEDICINE, RESEARCH ASSOClATE, 医学部附属病院, 助手 (90332577)
SHINTANI Yoshizumi THE UNIVERSITY OF TOKYO, FACULTY OF MEDICINE, RESEARCH ASSOCIATE, 医学部附属病院, 助手 (80261965)
MORIYA Kyoji THE UNIVERSITY OF TOKYO, FACULTY OF MEDICINE, LECTURER, 医学部附属病院, 講師 (00272550)
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| Budget Amount *help |
¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2002: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2001: ¥8,200,000 (Direct Cost: ¥8,200,000)
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| Research Abstract |
The mechanism of hepatocarcinogenesis in hepatitis C virus (HCV) infection is still undefined. One possibility is the involvement of oxidative stress, which can produce genetic mutations as well as gross chromosomal alterations and contribute to cancer development. We recently showed that the core protein of HCV induces, after a long period, hepatocellular carcinoma (HCC) in transgenic mice with marked hepatic steatosis but without inflammation, indicating a direct involvement of HCV in hepatocarcinogenesis. PCOOH level was increased by 180% in old core gene transgenic mice aged over 16 months. Concurrently, there was a significant increase in the catalase activity, and decreases in the levels of total and reduced glutathione in the same mice. Interestingly, alcohol caused a marked increase in PCOOH level in transgenic mice, suggesting synergism between alcohol and HCV in hepatocarcinogenesis. The HCV core protein thus afters the oxidant/antioxidant state in the liver in the absence of
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inflammation, and thereby may contribute to or facilitate, at least partly, the development of HCC in HCV infection. Since previous studies indicated that ROS is closely associated with mitogen-activated protein kinases (MAPK), we examined activities of c-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinase (ERK) in the liver of core-transgenic and nontransgenic mice with short-term ethanol feeding. Activity of ERK and p38 MAPK was increased in core-transgenic mice compared with nontransgenic mice, whereas neither ERK nor p38 MAPK was activated hi core-transgenic mice with normal diets. In addition, activity of cyclic-AMP and serum responsive element, downstream pathways of p38 MAPK and ERK, was also increased. Comparison of gene expression profiles by cDNA microarray and real-time PCR revealed that galectin-1, which is associated with cell transformation, was significantly increased in ethanol-fed core-transgenic mice. On the other hand, glutathione S-transferase, which plays a key role in protecting cells from oxidative stress, was decreased. In conclusion, these results suggest that HCV core protein cooperates with ethanol for the activation of some MAPK pathways, and leads to the modulation of several genes, contributing to pathogenesis observed in livers of HCV-infected patients with high ethanol consumption. Less
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