2002 Fiscal Year Final Research Report Summary
Autocrine TGF-β Signal Transaction and Regulalion in Hepatocellular Carcinoma.
| Project/Area Number |
13670573
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Kansai Medical University |
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Principal Investigator |
MATSUZAKI Koichi Kansai Medical University, Third Department of Internal Medicine, Assistant Professor, 医学部, 講師 (70278638)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAHASHI Yoshitsugu Kansai Medical University, Third Department of Internal Medicine, Research Assistant, 医学部, 助手 (70247930)
SEKI Toshihito Kansai Medical University, Third Department of Internal Medicine, Associate Professor, 医学部, 助教授 (70163087)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Hepatocellular Carcinoma / TGF-β / Smad |
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| Research Abstract |
Resistance to growth inhibitory effects of TGF-β is a frequent consequence of malignant transformation. On the other hand, serum concentrations of TGF-b, plasminogen activator inhibitor type 1 (PAI-1), and vascular endothelial growth factor (VEGF) are elevated as tumor progresses. The molecular mechanism of autocrine TGF-β signaling and its effects on PAI-1 and VEGF production in human hepatocellular carcinoma (HCC) is unknown. TGF-b signaling involves TGF-β type I receptor-mediated phosphorylation of serine residues within the conserved SSXS motif at the C-terminus of Smad2 and Smad3. To investigate the involvement of autocrine TGF-β signal in cell growth, PAI-1 and VEGF production of HCC, we made stable transfectants of human HCC line (HuH-7 cells) to express a mutant Smad2(3S-A), in which serine residues of SSXS motif were changed to alanine. The transfectants demonstrated an impaired Smad2 signaling. Along with the resistance to growth inhibition by TGF-β, forced expression of Smad2(3S-A) induced endogenous TGF-β secretion. Moreover, this increased TGF-β enhanced ligand-dependent signaling through the activated Smad3 and Smad4 complex, and transcriptional activities of PAI-1 and VEGF genes. In conclusion, distortion of autocrine TGF-β signals in human HCC accelerates their malignant potential by enhancing cell growth as well as PAI-1 and VEGF production (Oncogene in press).
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[Publications] Furukawa F., Matsuzaki K., Mori S., Tahashi Y, Yoshida K., Sugano Y., Yamagata H., Matsushita M., Seki t., Nishizawa M., Fujisawa j and Inoue K.: "p38 MAPK Mediates Fibrogenic Signal through Smad3 Phosphorylation in Rat Myofibroblasts"Hepatology. in press.
Description
「研究成果報告書概要(欧文)」より
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