| Project/Area Number |
16590646
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Gastroenterology
|
|---|
| Research Institution | Kansai Medical University |
|---|
Principal Investigator |
MATSUZAKI Koichi Kansai Medical University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (70278638)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SEKI Toshihito Kansai Medical University, Faculty of Medicine, Professor, 医学部, 教授 (70163087)
|
|---|
| Project Period (FY) |
2004 – 2005
|
| Project Status |
Completed (Fiscal Year 2005)
|
| Budget Amount *help |
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥2,900,000 (Direct Cost: ¥2,900,000)
|
|---|
| Keywords | Hepatocellular Carcinoma / TGF-β / Smad / TGF-β |
|---|
| Research Abstract |
Most patients suffered from chronic hepatitis attributed to hepatitis C virus (HCV) infection develop liver fibrosis with a high risk for hepatocellular carcinoma. However, little information is available on the molecular mechanisms by which chronic inflammation causes progressive liver fibrosis and hepatocellular carcinoma simultaneously. On the other hand, transforming growth factor β(TGF-β) activates not only TGF-β type I receptor (TβRI) but also c-Jun N-terminal kinase (JNK), changing unphosphorylated Smad3 to its phosphoisoforms : C-terminally phosphorylated Smad3 (pSmad3C) and linker phosphorylated Smad3 (pSmad3L). TβRI/pSmad3C pathway involves tumor suppressive action by up-regulating p21^<WAF1> transcript, whereas JNK/pSmad3L-mediated signaling promotes extracellular matrix deposition, in part, by increasing plasminogen activator inhibitor 1 (PAI-1). As the HCV-infected livers progressed from chronic hepatitis through cirrhosis to hepatocellular carcinoma, pSmad3L/PAI-1 gradually increased while pSmad3C/p21^<WAF1> decreased in the hepatocytes, leading to loss of epithelial homeostasis and acquisition of an invasive, mesenchymal phenotype. JNK activated by pro-inflammatory cytokine interleukin-1β acted as a regulator of TGF-β signaling by increasing the level of pSmad3L/PAI-1 available for fibrogenic action in the hepatocytes, in the meantime reducing TGF-β-dependent tumor suppressive activity of pSmad3C/p21^<WAF1>. In conclusion, chronic inflammation associated with HCV infection shifts human hepatic TGF-β signaling from tumor suppression to fibrogenesis with the progress of liver diseases, thereby accelerating liver fibrosis with higher risk for hepatocellular carcinoma.
|
