Expression of transforming growth factor alpha epidermal growth factor receptor, hepatocyte growth factor c-met and acidic fibroblast growth factor fibroblast growth factor receptors during hepatocarcinogenesis
Expression of transforming growth factor alpha epidermal growth factor receptor, hepatocyte growth factor c-met and acidic fibroblast growth factor fibroblast growth factor receptors during hepatocarcinogenesis
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DOI：
10.1093/carcin/17.5.931
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发表时间：
1996-05-01
期刊：
影响因子：
4.7
通讯作者：
Thorgeirsson, SS
中科院分区：
文献类型：
--
作者：
Hu, ZY;Evarts, RP;Thorgeirsson, SS
人们普遍认为，多肽生长因子的异常产生，以及其他分子的改变，在肿瘤的发展中发挥重要作用。转化生长因子α（TGF α）、肝细胞生长因子（HGF）和酸性成纤维细胞生长因子（aFGF）是有助于通过肝细胞复制和卵圆细胞增殖发生肝再生的三种主要生长因子。然而，目前尚不清楚这些生长因子是否以及在多大程度上也参与了肝癌的发生。本研究应用北方印迹和原位杂交技术检测了Solt-Farber法诱导的大鼠肝癌发生过程中TGF α、HGF和aFGF及其相应受体的基因表达。所有三种生长因子/受体系统，TGF α/表皮生长因子受体（EGFR），HGF/c-met和aFGF/FGF受体（bek和bek）在卵圆细胞增殖的早期时间点显著升高。它们各自的表达在1个月后下降，并保持在低水平，直到肝肿瘤的发展。在所有肝细胞癌（HCC）检查，TGF α和aFGF的转录高表达，而HGF的低。关于肿瘤中的受体表达，EGFR以不同的水平存在，c-met以较高的水平表达，而bek显著增加，而bek保持在低水平。这些数据表明，TGF α和aFGF是参与HCC进展的主要生长因子，并且aFGF的信号在HCC中主要由受体TGF β转导。此外，HCC细胞在生长因子/受体系统的基因表达方面与卵圆细胞表型非常相似。这些结果，沿着发现所有HCC细胞对卵圆细胞抗原OV 6呈阳性，并且细胞角蛋白19在肿瘤和卵圆细胞中都大量表达，强烈地表明至少一些由Solt-Farber方案诱导的HCC可能来源于卵圆细胞。
It is widely believed that abnormal production of polypeptide growth factors, together with other molecular alterations, play an important role in neoplastic development. Transforming growth factor alpha (TGF alpha), hepatocyte growth factor (HGF) and acidic fibroblast growth factor (aFGF) are the three major growth factors that contribute to liver regeneration occurring via both hepatocyte replication and oval cell proliferation. It is not clear, however, whether and to what extent these growth factors are also involved in hepatocarcinogenesis. In the present study, the gene expression of TGF alpha, HGF and aFGF and their corresponding receptors was examined by Northern blotting and in situ hybridization during hepatocarcinogenesis induced by the Solt-Farber protocol. All three growth factor/receptor systems, TGF alpha/epidermal growth factor receptor (EGFR), HGF/c-met and aFGF/FGF receptors (flg and bek) were significantly elevated at early time points when oval cells were proliferating. Their respective expression decreased after 1 month and remained at a low level until the development of liver tumors. In all hepatocellular carcinomas (HCC) examined, the transcripts of TGF alpha and aFGF were highly expressed, while those of HGF were low. With regard to the receptor expression in the tumors, EGFR was present at varying levels, c-met was expressed at higher levels and flg increased significantly, whereas bek remained at low levels. These data suggest that TGF alpha and aFGF are the major growth factors involved in the progression of HCC, and that the signal of aFGF is mainly transduced by the receptor flg in HCC. Furthermore, HCC cells were phenotypically very similar to oval cells with regard to the gene expression of growth factor/receptor systems. These results, along with the finding that all the HCC cells are positive for the oval cell antigen OV6, and that cytokeratin 19 is heavily expressed in both tumor and oval cells, strongly suggest that at least some of the HCC induced by the Solt-Farber protocol may be derived from oval cells.