Ito Y, Sasaki Y, Horimoto M, Wada S, Tanaka Y, Kasahara A, Ueki T, Hirano T, Yamamoto H, Fujimoto J, Okamoto E, Hayashi N, Hori M
First Department of Medicine, Osaka University School of Medicine, Suita, Japan.
Hepatology. 1998 Apr;27(4):951-8. doi: 10.1002/hep.510270409.
Mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) is a key molecule in intracellular signal transducing pathways that transport extracellular stimuli from cell surface to nuclei. MAPK/ERK has been revealed to be involved in the physiological proliferation of mammalian cells and also to potentiate them to transform. However, its role in the outgrowth of human hepatocellular carcinoma (HCC) has yet to be clarified. Therefore, in this study, we investigated the activation of MAPK/ERK and its associated gene expression in HCC. MAPK/ERK was activated in 15 of 26 cases of HCC we examined (58%), and its activity level was significantly higher in HCC than in the adjacent non-cancerous lesions. Besides, MAPK/ERK activation in HCC was positively correlated with protein expression of transcription factor c-Fos. Furthermore, in 25 of 26 cases of HCC which genomic DNA was available, 22 cases without genomic DNA amplification exhibited positive correlation, not only between protein expression of c-Fos and cyclin D1, but also between MAPK/ERK activation and cyclin D1 expression. Concerning the relationship between MAPK/ERK activation and the clinicohistopathological features of HCC, the tumor (HCC) versus non-tumor (non-cancerous counterpart) ratio (T/N) of MAPK/ERK activity was positively correlated with tumor size, but neither with the stage of HCC nor the degree of differentiation of HCC. In conclusion, these findings suggest that MAPK/ERK activation in human HCC may play an important role in multistep hepatocarcinogenesis, especially in the progression of HCC; at least in part, through cyclin D1 up-regulation primarily induced by MAPK/ERK via c-Fos.
丝裂原活化蛋白激酶/细胞外信号调节蛋白激酶（MAPK/ERK）是细胞内信号转导通路中的关键分子，该通路可将细胞外刺激从细胞表面传递至细胞核。已有研究表明，MAPK/ERK参与哺乳动物细胞的生理增殖，并促使细胞发生转化。然而，其在人类肝细胞癌（HCC）发生发展中的作用尚待阐明。因此，在本研究中，我们调查了HCC中MAPK/ERK的激活情况及其相关基因表达。在我们检测的26例HCC病例中，有15例（58%）的MAPK/ERK被激活，且其活性水平在HCC中显著高于相邻的非癌性病变。此外，HCC中MAPK/ERK的激活与转录因子c-Fos的蛋白表达呈正相关。此外，在可获取基因组DNA的26例HCC病例中，有25例在无基因组DNA扩增的情况下，不仅c-Fos的蛋白表达与细胞周期蛋白D1之间呈正相关，而且MAPK/ERK的激活与细胞周期蛋白D1的表达之间也呈正相关。关于MAPK/ERK激活与HCC临床组织病理学特征的关系，MAPK/ERK活性的肿瘤（HCC）与非肿瘤（非癌对应物）比值（T/N）与肿瘤大小呈正相关，但与HCC的分期及分化程度均无关。总之，这些发现表明，人类HCC中MAPK/ERK的激活可能在肝癌多步骤发生过程中发挥重要作用，尤其是在HCC的进展中；至少部分是通过MAPK/ERK经由c-Fos主要诱导细胞周期蛋白D1上调来实现的。
