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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.
Oncogene. 2003 Apr 17; 22(15):2309-21.O

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+Show Affiliations

Third Department of Internal Medicine, 10-15 Fumizonocho, Mariguchi, Osaka 570-8507, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12700666

Citation

Sugano, Yasushi, et al. "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." Oncogene, vol. 22, no. 15, 2003, pp. 2309-21.
Sugano Y, Matsuzaki K, Tahashi Y, et al. 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. Oncogene. 2003;22(15):2309-21.
Sugano, Y., Matsuzaki, K., Tahashi, Y., Furukawa, F., Mori, S., Yamagata, H., Yoshida, K., Matsushita, M., Nishizawa, M., Fujisawa, J., & Inoue, K. (2003). 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. Oncogene, 22(15), 2309-21.
Sugano Y, et al. 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. Oncogene. 2003 Apr 17;22(15):2309-21. PubMed PMID: 12700666.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Sugano,Yasushi, AU - Matsuzaki,Koichi, AU - Tahashi,Yoshiya, AU - Furukawa,Fukiko, AU - Mori,Shigeo, AU - Yamagata,Hideo, AU - Yoshida,Katsunori, AU - Matsushita,Masanori, AU - Nishizawa,Mikio, AU - Fujisawa,Junichi, AU - Inoue,Kyoichi, PY - 2003/4/18/pubmed PY - 2003/5/15/medline PY - 2003/4/18/entrez SP - 2309 EP - 21 JF - Oncogene JO - Oncogene VL - 22 IS - 15 N2 - 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. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/12700666/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_ L2 - https://doi.org/10.1038/sj.onc.1206305 DB - PRIME DP - Unbound Medicine ER -