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J. Biol. Chem., Vol. 276, Issue 42, 38781-38786, October 19, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/42/38781    most recent M104944200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, K.-Y. Articles by Nam, M.-J. Search for Related Content PubMed PubMed Citation Articles by Kim, K.-Y. Articles by Nam, M.-J. Social Bookmarking                      What's this?

Induction of Angiogenesis by Expression of Soluble Type II Transforming Growth Factor- Receptor in Mouse Hepatoma^*

Kye-Young Kim, So-Young Jeong, Jonghwa Won^§, Pan-Dong Ryu^¶, and Myeong-Jin Nam

From the  Central Genome Center, National Institute of Health, Seoul 122-701, Korea, the ^§ Mogam Biotechnology Research Institute, Kyonggi-do, 449-910, Korea, and the ^¶ Department of Pharmacology, College of Veterinary Medicine, Seoul National University, Suwon 441-744, Korea

The biological effect of transforming growth factor- (TGF-) is cell type-specific and complex. The precise role of TGF- is not clear in vivo. To elucidate the regulation mechanism of endogenous TGF- on hepatoma progression, we modified the MH129F mouse hepatoma cell with a retroviral vector encoding the extracellular region of type II TGF- receptor (TRII). Soluble TRII (TRIIs) blocked TGF- binding to TRII on the membrane of hepatoma cells. Growth of MH129F cells was inhibited by TGF-1 treatment; however, soluble TRII-overexpressing cells (MH129F/TRIIs) did not show any change in proliferation after TGF-1 treatment. MH129F/TRIIs cells also increased vascular endothelial growth factor (VEGF) expression, endothelial cell migration, and tube formation. Implantation of MH129F/TRIIs cells into C3H/He mice showed the significantly enhanced tumor formation. According to Western blot and protein kinase C assay, the expression of VEGF, KDR/flk-1 receptor, and endothelial nitric-oxide synthase was enhanced, and the phosphorylation activity of protein kinase C was increased up to 3.7-fold in MH129F/TRIIs tumors. Finally, a PECAM-1-stained intratumoral vessel was shown to be 4.2-fold higher in the MH129F/TRIIs tumor. These results indicate that VEGF expression is up-regulated by a blockade of endogenous TGF- signaling in TGF--sensitive hepatoma cells and then stimulates angiogenesis and tumorigenicity. Therefore, we suggest that endogenous TGF- is a major regulator of the VEGF/flk-1-mediated angiogenesis pathway in hepatoma progression.

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