Autocrine stimulatory mechanism by transforming growth factor beta in human hepatocellular carcinoma.


The serum concentration of transforming growth factor beta (TGF-beta) is elevated as tumors progress in hepatocellular carcinoma (HCC) patients. In this study, we examined whether modulation of tumor-derived TGF-beta signal transduction contributes to malignant progression. We investigated the production of TGF-beta1, the biological effects of TGF-beta 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 p15INK4B. In human cell lines HCC-M and HCC-T, TGF-beta accelerates their proliferation. Smad 2 was activated constitutively by an autocrine mechanism, because in the absence of exogenous TGF-beta, 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-beta. However, Smads activated by tumor-derived TGF-beta constantly suppressed p151NK4B expression. In addition, 3 of 10 human HCC tissues showed nuclear localization of Smad 2 and low mRNA levels of p15INK4B and antagonistic Smads but a high level of PAI-1. Our observations suggest that this constant suppression of the p15INK4B gene could be involved in the malignant progression of HCC.

Citations per Year

262 Citations

Semantic Scholar estimates that this publication has 262 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Matsuzaki2000AutocrineSM, title={Autocrine stimulatory mechanism by transforming growth factor beta in human hepatocellular carcinoma.}, author={Koichi Matsuzaki and Masataka Date and Fukiko Furukawa and Yoshiya Tahashi and Masahiro Matsushita and Katumi Sakitani and Noriyo Yamashiki and Toshihito Seki and Hidetsugu Saito and M Nishizawa and Jun - Ichi Fujisawa and Kazuo Inoue}, journal={Cancer research}, year={2000}, volume={60 5}, pages={1394-402} }