Autocrine TGF-β Signal Transaction and Regulalion in Hepatocellular Carcinoma.

肝细胞癌中自分泌 TGF-β 信号传输和调节。

• 批准号: 13670573
• 负责人: MATSUZAKI Koichi
• 金额: $ 2.3万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670573/
• 关键词: Hepatocellular Carcinoma; TGF-β; Smad

Resistance to growth inhibitory effects of TGF-β is a frequent consequence of malignant transformation. On the other hand, serum concentrations of TGF-b, 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-b 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 (Oncogene in press).

对TGF-β生长抑制作用的抵抗是恶性转化的常见后果。另一方面，随着肿瘤的进展，血清中TGF-b、纤溶酶原激活物抑制剂1型（PAI-1）和血管内皮生长因子（VEGF）的浓度升高。自分泌TGF-β信号的分子机制及其对人肝细胞癌（HCC）中PAI-1和VEGF产生的影响尚不清楚。TGF-b信号通路涉及TGF-β I型受体介导的Smad2和Smad3 c端保守的SSXS基序内丝氨酸残基的磷酸化。为了研究自分泌TGF-β信号在HCC细胞生长、PAI-1和VEGF生成中的作用，我们利用人HCC细胞系（hh -7细胞）稳定转染表达突变体Smad2(3S-A)，其中SSXS基序的丝氨酸残基变为丙氨酸。转染显示Smad2信号通路受损。在抵抗TGF-β生长抑制的同时，强制表达Smad2（3S-A）诱导内源性TGF-β分泌。此外，通过激活Smad3和Smad4复合体，以及PAI-1和VEGF基因的转录活性，TGF-β的增加增强了配体依赖性信号传导。总之，在人类HCC中，自分泌TGF-β信号的扭曲通过促进细胞生长以及PAI-1和VEGF的产生来加速其恶性潜能。

项目成果

松崎恒一: "肝線維化とTGF-βシグナル伝達機構"Bio Clinica. 16. 304-309 (2001)

Koichi Matsuzaki：“肝纤维化和 TGF-β 信号传导机制”Bio Clinica 16. 304-309 (2001)。

Furukaw F, Matsuzaki K et al.: "TGF-β Propagates Fibrogeniz Signal through p38 MAPK-Dependent Smad3 phosphorylation in Rat Myofibroblaste"Hepatology. (in press).

Furukaw F、Matsuzaki K 等人：“TGF-β 在大鼠肌成纤维细胞中通过 p38 MAPK 依赖性 Smad3 磷酸化传播 Fibrogeniz 信号”（正在出版）。

Tohashi Y, Matsuzaki K et al.: "Differential regulation of Autocrine TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injuries"Hepatology. 35. 49-61 (2002)

Tohashi Y、Matsuzaki K 等人：“急性和慢性大鼠肝损伤之间肝星状细胞中自分泌 TGF-β 信号的差异调节”肝病学。

Matsuzaki Koichi: "Oxford University Press"Davis J.M.. 47 (2001)

松崎浩一：《牛津大学出版社》Davis J.M.. 47 (2001)

松崎恒一: "肝線維化の病態の把握と治療への展望"細胞. 33. 422-423 (2001)

Koichi Matsuzaki：“了解肝纤维化的病理学和治疗前景”Cell 33. 422-423 (2001)。