Molecular mechanism of hypercarcinogenic state -inflammation-induced hepatocarcinogenesis-

点击翻译按钮获取中文摘要

Cancer is a heritable disorder of somatic cells. Carcinogenesis looks like an opened Japanese fan, because initiated cells grow in several directions and tumors suggest the edge of the fan having many gene abnormalities.Development of hepatocellular carcinoma (HCC) is associated with the chronic inflammation of the liver caused by various factors such as hepatitis B or C virus infection. We reported DNA binding protein A (dbpA) as a candidate molecule that can accelerate the inflammation-induced hepatocarcinogenesis DbpA belongs to the Y box binding protein family, and YB-1, the prototype member of this family, is reported to be a prognostic marker of malignant diseases other than HCC. The purpose of this study was to examine the significance of the expression of dbpA, or of the T to G transversion in the dbpA promoter region which enhances the promoter activity in vitro, for the progression of HCC.(1)The dbpA expression was associated with the advanced stages of HCC, and the cases wit … More h the nuclear dbpA expression had a poor prognosis.(2)DbpA contributed more significantly to this association than YB-1.(3)The T to G transversion in the dbpA promoter region was related to the nuclear localization of dbpA.We reported that dbpA transcription is positively regulated by E2F1 which is also implicated in hepatocarcinogenesis. To study the in vivo effect of dbpA on the hepatocarcinogenesis, we generated the dbpA-transgenic mouse that specifically expressed a transgene in hepatocytes. We studied the effect of dbpA on the expression of other cellular genes by using microarray analyses. The expression profiles from livers of 31 and 32 week-old male transgenic mice (Tg (+)) that did not show any morphological changes and from livers of their male wild-type littermates (Tg (-)) were compared.(4)The 11 up-regulated genes included 7 carcinogenesis-related genes (Igfbp1, Tff3, Hpx, Orm2, Cts1, Plg, Jdp1), and the 9 down-regulated genes included Car3 that was associated with the protection of cells from attack by oxygen radicals. As for Igfbp1 (insulin like growth factor binding protein 1), we confirmed that its expression was reduced by siRNA targeting dbpA in the human HCC cell line. Less