TY - JOUR
T1 - Autocrine stimulatory mechanism by transforming growth factor β in human hepatocellular carcinoma
AU - Matsuzaki, Koichi
AU - Date, Masataka
AU - Furukawa, Fukiko
AU - Tahashi, Yoshiya
AU - Matsushita, Masanori
AU - Sakitani, Kazushige
AU - Yamashiki, Noriyo
AU - Seki, Toshihito
AU - Saito, Hidetsugu
AU - Nishizawa, Mikio
AU - Fujisawa, Junichi
AU - Inoue, Kyoichi
PY - 2000/3/1
Y1 - 2000/3/1
N2 - 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.
AB - 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.
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M3 - Article
C2 - 10728705
AN - SCOPUS:0034163388
SN - 0008-5472
VL - 60
SP - 1394
EP - 1402
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -
