title: Distortion of autocrine transforming growth factor beta signal accelerates malignant potential by enhancing cell growth as well as PAI-1 and VEGF production in human hepatocellular carcinoma cells.
abstract: Resistance to growth inhibitory effects of transforming growth factor (TGF)-beta is a frequent consequence of malignant transformation. On the other hand, serum concentrations of TGF-beta, plasminogen activator inhibitor type 1 (PAI-1), and vascular endothelial growth factor (VEGF) are elevated as tumor progresses. The molecular mechanism of autocrine TGF-beta signaling and its effects on PAI-1 and VEGF production in human hepatocellular carcinoma (HCC) is unknown. TGF-beta signaling involves TGF-beta type I receptor-mediated phosphorylation of serine residues within the conserved SSXS motif at the C-terminus of Smad2 and Smad3. To investigate the involvement of autocrine TGF-beta signal in cell growth, PAI-1 and VEGF production of HCC, we made stable transfectants of human HCC line (HuH-7 cells) to express a mutant Smad2(3S-A), in which serine residues of SSXS motif were changed to alanine. The transfectants demonstrated an impaired Smad2 signaling. Along with the resistance to growth inhibition by TGF-beta, forced expression of Smad2(3S-A) induced endogenous TGF-beta secretion. Moreover, this increased TGF-beta enhanced ligand-dependent signaling through the activated Smad3 and Smad4 complex, and transcriptional activities of PAI-1 and VEGF genes. In conclusion, distortion of autocrine TGF-beta signals in human HCC accelerates their malignant potential by enhancing cell growth as well as PAI-1 and VEGF production.
authors.affiliation: Third Department of Internal Medicine, 10-15 Fumizonocho, Mariguchi, Osaka 570-8507, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sugano
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuzaki
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tahashi
authors.forename: Fukiko
authors.initials: F
authors.lastname: Furukawa
authors.forename: Shigeo
authors.initials: S
authors.lastname: Mori
authors.forename: Hideo
authors.initials: H
authors.lastname: Yamagata
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yoshida
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsushita
authors.forename: Mikio
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Fujisawa
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Inoue
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D019898:Autocrine Communication / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D046911:Macromolecular Substances; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000509:alpha-Fetoproteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D017395:Plasminogen Activator Inhibitor 1; D011993:Recombinant Fusion Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000509:alpha-Fetoproteins