title: Autocrine stimulatory mechanism by transforming growth factor beta in human hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan. matsuzak@takii.kmu.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Matsuzaki
authors.forename: M
authors.initials: M
authors.lastname: Date
authors.forename: F
authors.initials: F
authors.lastname: Furukawa
authors.forename: Y
authors.initials: Y
authors.lastname: Tahashi
authors.forename: M
authors.initials: M
authors.lastname: Matsushita
authors.forename: K
authors.initials: K
authors.lastname: Sakitani
authors.forename: N
authors.initials: N
authors.lastname: Yamashiki
authors.forename: T
authors.initials: T
authors.lastname: Seki
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: M
authors.initials: M
authors.lastname: Nishizawa
authors.forename: J
authors.initials: J
authors.lastname: Fujisawa
authors.forename: K
authors.initials: K
authors.lastname: Inoue
mesh_terms: D019898:Autocrine Communication; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D016212:Transforming Growth Factor beta