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

Research output: Contribution to journalArticle

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Abstract

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
Volume60
Issue number5
Publication statusPublished - 2000 Mar 1

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Transforming Growth Factors
Hepatocellular Carcinoma
Plasminogen Activator Inhibitor 1
Neoplasms
Neutralizing Antibodies
Genes
Signal Transduction
Phosphorylation
Cell Line
Messenger RNA
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Matsuzaki, K., Date, M., Furukawa, F., Tahashi, Y., Matsushita, M., Sakitani, K., ... Inoue, K. (2000). Autocrine stimulatory mechanism by transforming growth factor β in human hepatocellular carcinoma. Cancer Research, 60(5), 1394-1402.

Autocrine stimulatory mechanism by transforming growth factor β in human hepatocellular carcinoma. / Matsuzaki, Koichi; Date, Masataka; Furukawa, Fukiko; Tahashi, Yoshiya; Matsushita, Masanori; Sakitani, Kazushige; Yamashiki, Noriyo; Seki, Toshihito; Saito, Hidetsugu; Nishizawa, Mikio; Fujisawa, Junichi; Inoue, Kyoichi.

In: Cancer Research, Vol. 60, No. 5, 01.03.2000, p. 1394-1402.

Research output: Contribution to journalArticle

Matsuzaki, K, Date, M, Furukawa, F, Tahashi, Y, Matsushita, M, Sakitani, K, Yamashiki, N, Seki, T, Saito, H, Nishizawa, M, Fujisawa, J & Inoue, K 2000, 'Autocrine stimulatory mechanism by transforming growth factor β in human hepatocellular carcinoma', Cancer Research, vol. 60, no. 5, pp. 1394-1402.
Matsuzaki K, Date M, Furukawa F, Tahashi Y, Matsushita M, Sakitani K et al. Autocrine stimulatory mechanism by transforming growth factor β in human hepatocellular carcinoma. Cancer Research. 2000 Mar 1;60(5):1394-1402.
Matsuzaki, Koichi ; Date, Masataka ; Furukawa, Fukiko ; Tahashi, Yoshiya ; Matsushita, Masanori ; Sakitani, Kazushige ; Yamashiki, Noriyo ; Seki, Toshihito ; Saito, Hidetsugu ; Nishizawa, Mikio ; Fujisawa, Junichi ; Inoue, Kyoichi. / Autocrine stimulatory mechanism by transforming growth factor β in human hepatocellular carcinoma. In: Cancer Research. 2000 ; Vol. 60, No. 5. pp. 1394-1402.
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AU - Sakitani, Kazushige

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AU - Seki, Toshihito

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