Molecular mechanism of hypercarcinogenic state -inflammation-induced hepatocarcinogenesis-

癌症是一种可遗传的体细胞疾病。肝癌的发生过程看起来像一个打开的日本扇子，因为启动的细胞向几个方向生长，肿瘤表明扇子的边缘有许多基因异常。肝细胞癌（HCC）的发生与各种因素如B或C病毒感染引起的肝脏慢性炎症有关。我们报道了DNA结合蛋白A（dbpA）作为一种促进炎症诱导的肝癌发生的候选分子。DbpA属于Y盒结合蛋白家族，YB-1是该家族的原型成员，据报道它是肝癌以外的恶性疾病的预后标志物。本研究的目的是检查dbpA的表达，或在dbpA启动子区域的T到G的颠换，在体外增强启动子的活性，HCC的进展的意义。（1）dbpA的表达与肝癌的分期有关， ...更多信息 核dbpA表达预后差。（2）DbpA比YB-1对这种关联的贡献更大。（3）dbpA基因启动子区的T → G颠换与dbpA基因的核定位有关，我们发现dbpA基因的转录受E2 F1的正调控，E2 F1也参与了肝癌的发生。为了研究dbpA对肝癌发生的体内作用，我们产生了在肝细胞中特异性表达转基因的dbpA转基因小鼠。我们通过使用微阵列分析研究了dbpA对其他细胞基因表达的影响。比较了未显示任何形态学变化的31和32周龄雄性转基因小鼠（Tg（+））肝脏的表达谱及其雄性野生型同窝仔（Tg（-））肝脏的表达谱。（4）上调的11个基因中有7个与肿瘤发生相关，分别为Igfbp 1、Tff 3、Hpx、Orm 2、Cts 1、Plg、Jdp 1;下调的9个基因中有与保护细胞免受氧自由基攻击相关的Car 3。至于Igfbp 1（胰岛素样生长因子结合蛋白1），我们证实，它的表达减少siRNA靶向dbpA在人肝癌细胞系。少

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