Autocrine stimulatory mechanism by transforming growth factor β in human hepatocellular carcinoma

Koichi Matsuzaki, Masataka Date, Fukiko Furukawa, Yoshiya Tahashi, Masanori Matsushita, Kazushige Sakitani, Noriyo Yamashiki, Toshihito Seki, Hidetsugu Saito, Mikio Nishizawa, Junichi Fujisawa, Kyoichi Inoue

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86 Citations (Scopus)


The serum concentration of transforming growth factor β (TGF-β) is elevated as tumors progress in hepatocellular carcinoma (HCC) patients. In this study, we examined whether modulation of tumor-derived TGF-β signal transduction contributes to malignant progression. We investigated the production of TGF-β1, the biological effects of TGF-β and neutralizing antibody on HCC cells, activation of Smad 2, Smad 3, and Smad 4, induction of antagonistic Smads (Smad 6 and Smad 7), and promoter activities of two target genes, plasminogen activator inhibitor type 1 (PAI-1) and p15(INK4B). In human cell lines HCC-M and HCC-T, TGF-β accelerates their proliferation. Smad 2 was activated constitutively by an autocrine mechanism, because in the absence of exogenous TGF-β, a high level of Smad 2 phosphorylation, induction of PAI-1 transcripts, and nuclear localization of Smad 2 were observed. This constitutive activation of Smad 2 was, at least in part, attributable to the lack of induction of antagonistic Smads by TGF-β. However, Smads activated by tumor-derived TGF-β constantly suppressed p15(INK4B) expression. In addition, 3 of 10 human HCC tissues showed nuclear localization of Smad 2 and low mRNA levels of p15(INK4B) and antagonistic Smads but a high level of PAI-I. Our observations suggest that this constant suppression of the p15(INK4B) gene could be involved in the malignant progression of HCC.

Original languageEnglish
Pages (from-to)1394-1402
Number of pages9
JournalCancer Research
Issue number5
Publication statusPublished - 2000 Mar 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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