Distortion of autocrine transforming growth factor β signal accelerates malignant potential by enhancing cell growth as well as PAI-1 and VEGF production in human hepatocellular carcinoma cells

• Published in: Oncogene Vol. 22; no. 15; pp. 2309 - 2321
• Main Authors: SUGANO, Yasushi, MATSUZAKI, Koichi, INOUE, Kyoichi, TAHASHI, Yoshiya, FURUKAWA, Fukiko, MORI, Shigeo, YAMAGATA, Hideo, YOSHIDA, Katsunori, MATSUSHITA, Masanori, NISHIZAWA, Mikio, FUJISAWA, Junichi
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 17-04-2003; Nature Publishing Group
• Subjects: Alanine; alpha-Fetoproteins - biosynthesis; alpha-Fetoproteins - genetics; Amino Acid Motifs; Amino Acid Substitution; Autocrine Communication - physiology; Autocrine signalling; Biological and medical sciences; C-Terminus; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell growth; Classical genetics, quantitative genetics, hybrids; Disease Progression; DNA Replication; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endothelial Growth Factors - biosynthesis; Endothelial Growth Factors - genetics; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic - drug effects; Genetics of eukaryotes. Biological and molecular evolution; Hepatocellular carcinoma; Human; Humans; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - genetics; Kinases; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lymphokines - biosynthesis; Lymphokines - genetics; Macromolecular Substances; Medical sciences; Mutagenesis, Site-Directed; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Phosphorylation; Plasminogen Activator Inhibitor 1 - biosynthesis; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen activator inhibitors; Recombinant Fusion Proteins - physiology; Serine; Signal Transduction; Smad2 Protein; Smad3 Protein; Smad4 Protein; Trans-Activators - chemistry; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription; Transfection; Transforming Growth Factor beta - physiology; Transforming growth factor-b; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Human; Growth; Transforming growth factor β; VEGF; Hepatic disease; Hepatocellular carcinoma; Distortion; HCC; Malignant tumor; Production; Digestive diseases; PAI-1; TGF-β; Smad
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206305

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.