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STUDIES OF DEDIFFERENTIATION MECHANISMS IN HEPATOCELLULAR CRCINOMA

肝细胞癌去分化机制的研究

基本信息

批准号：
06670244
负责人：
KOJIRO Masamichi
金额：
$ 1.15万
依托单位：
KURUME UNIVRSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06670244/
关键词：
Hepatocellular carcinoma Dedifferentiation Growth factor Autocrine mechanism Basic fibroblast growth factor Fibroblast growth factor receptor Apoptosis Fas antigen 血管新生

项目摘要

1. Growth Stimulating Factors of Hepatocellular Carcinoma (HCC) Cells. We examined the effects of known growth factors on the proliferation of two clonally related HCC cell lines (HAK-1A & HAK-1B). HAK-1A is morphologically more differentiated and biologically less malignant than HAK-1B.The two HCC cell lines expressed the proteins and mRNAs of basic fibroblast growth factor (bFGF) and its receptor, FGFR.In vitro and in vivo experiments by using anti-bFGF neutralizing antibody and exogenous bFGF revealed that : (1) well-differentiated HCC cell line, HAK-1A,possessed a proliferation mechanism regulated by a paracrine mechanism, mediated by bFGF/FGFR ; (2) poorly differentiated HCC cell line, HAK-1B,possessed both autocrine and paracrine proliferatio mechanisms mediated by bFGF/FGFR ; and (3) bFGF/FGFR system also plays an important role in cell growth, but does not relate to angiogenesis in vivo. As to other growth factos and their receptors, the two cell lines expressed transforming growth factor (TGF) -alpha and its receptor, epidermal growth factor receptor (EGFR). Anti-EGFR neutralizing antibody showed growth suppressive effect on the cell lines, but anti-TGF-alpha neutralizing antibody showed no effect. This suggested involvement of the other EGFR ligands (EGF,heparin binding-EGF,amphiregulin, beta-cellulin etc.) in the HCC cell proliferation.2. Growth Inhibition and Apoptosis Inducing Factors of HCC Cells. TGF-beta showed no significant effects on the two cell lines. As to the expression of Fas antigen, which is a apoptosis inducing protein, HAK-1B showed lower level of Fas antigen expression and resistance to anti-Fas-mediated apoptosis.In conclusion, HCC cells may acquire more efficient cell proliferaton mechanisms (autocrine/paracrine) mediated by bFGF/FGFR in their dedifferentiation process. Also, loss of Fas system after clonal cell dedifferentiation is favorable for HCC cells to escape apoptosis.

1.肝细胞癌细胞的生长刺激因子我们研究了已知的生长因子对两个克隆相关的肝癌细胞系(Hak-1A和Hak-1B)增殖的影响。两种肝癌细胞系均表达碱性成纤维细胞生长因子及其受体FGFR的蛋白和mRNAs。用抗碱性成纤维细胞生长因子中和抗体和外源性bFGFR进行的体内外实验表明：(1)高分化肝癌细胞株Hak-1A具有由bFGF/FGFR介导的旁分泌机制调节的增殖机制，(2)低分化肝癌细胞株Hak-1B同时具有由bFGF/FGFR介导的自分泌和旁分泌增殖机制；(3)bFGF/FGFR系统在细胞生长中也起重要作用，但与体内血管生成无关。对于其他生长因子及其受体，两株细胞均表达转化生长因子-α及其受体--表皮生长因子受体。抗EGFR中和抗体对细胞生长有抑制作用，而抗转化生长因子-α中和抗体无此作用。这表明其他EGFR配体(EGF、肝素结合-EGF、两用调节素、β-细胞蛋白等)参与了这一过程。结论：1.在肝癌细胞增殖过程中。肝癌细胞的生长抑制和凋亡诱导因素。转化生长因子-β对两种细胞株均无明显影响。对于凋亡诱导蛋白Fas抗原的表达，Hak-1B细胞表现出较低的Fas抗原表达水平和对抗Fas介导的细胞凋亡的抵抗。结论：肝癌细胞在其去分化过程中可能获得了更有效的细胞增殖机制(自分泌/旁分泌)。克隆细胞去分化后Fas系统的缺失有利于肝癌细胞逃避细胞凋亡。