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  • Original Paper
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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

Oncogene volume 22, pages 2309–2321 (2003)Cite this article

Abstract

Resistance to growth inhibitory effects of transforming growth factor (TGF)-β is a frequent consequence of malignant transformation. On the other hand, serum concentrations of TGF-β, plasminogen activator inhibitor type 1 (PAI-1), and vascular endothelial growth factor (VEGF) are elevated as tumor progresses. The molecular mechanism of autocrine TGF-β signaling and its effects on PAI-1 and VEGF production in human hepatocellular carcinoma (HCC) is unknown. TGF-β signaling involves TGF-β 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-β 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-β, forced expression of Smad2(3S-A) induced endogenous TGF-β secretion. Moreover, this increased TGF-β 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-β signals in human HCC accelerates their malignant potential by enhancing cell growth as well as PAI-1 and VEGF production.

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Acknowledgements

We thank Dr SW Qian (National Cancer Institute, Bethesda, MD, USA), Dr R Derynck (University of California at San Francisco, San Francisco, CA, USA), Drs CH Heldin, and K Miyazono (Ludwig Institute for Cancer Research) for providing us with cDNAs of rat TGF-β1, human Smad2, Smad3, Smad4, and human TβRI in this study.

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Author notes

  1. Kyoichi Inoue: Deceased

Authors and Affiliations

  1. Third Department of Internal Medicine, 10–15 Fumizonocho, Moriguchi, Osaka, 570–8507, Japan

    Yasushi Sugano, Koichi Matsuzaki, Yoshiya Tahashi, Fukiko Furukawa, Shigeo Mori, Hideo Yamagata, Katsunori Yoshida, Masanori Matsushita & Kyoichi Inoue

  2. Department of Medical Chemistry, 10–15 Fumizonocho, Moriguchi, Osaka, 570–8507, Japan

    Mikio Nishizawa

  3. Department of Microbiology, Kansai Medical University, 10–15 Fumizonocho, Moriguchi, Osaka, 570–8507, Japan

    Junichi Fujisawa

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  1. Yasushi Sugano
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Correspondence to Koichi Matsuzaki.

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Sugano, Y., Matsuzaki, K., Tahashi, Y. et al. 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. Oncogene 22, 2309–2321 (2003). https://doi.org/10.1038/sj.onc.1206305

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