Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis  

作　　者：Francesco Feo Maddalena Frau Rosa Maria Pascale 

机构地区：[1]Department of Biomedical Sciences,Division of Experimental Pathology and Ontology,University of Sassari,Sassari 07100,Italy

出　　处：《World Journal of Gastroenterology》2008年第43期6601-6615,共15页世界胃肠病学杂志（英文版）

基　　金：Supported by Grants from the"Associazione Italiana Ricerche sul Cancro"

摘　　要：Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma （HCC）. Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway （BN） rats. Unrestrained extracellular signal-regulated kinase （ERK） activity linked to proteasomal degradation of dual-specificity phosphatase 1 （DUSP1）, a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-KB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-α transgenic mice. iNOS, IKK/NF-κB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.啮齿类动物和人上的研究表明继承倾向到肝细胞癌(HCC ) 。涉及对 hepatocarcinogenesis 抵抗或易受影响的显型的获得的分子的改变的分析证明在遗传上易受影响的 F344 老鼠和 G1-S 的 HCC 的 G1 和 S 阶段的解除管制在抵抗布朗也不方法(BN ) 的损害堵住老鼠。连接到双特性的磷酸酶的 proteasomal 降级的无限制的细胞外的调整信号的激酶(英皇家空军之阶级最低之兵) 活动 1 (DUSP1 ) ，一个特定的英皇家空军之阶级最低之兵禁止者，由 CKS1-SKP2 ubiquitin ligase，建筑群发生在 F344 老鼠和人的更好攻击的 HCC。这机制与更好的预后在 BN 老鼠的 HCC 和人的 HCC 是不太活跃的。有 IKK/NF-kappaB 和地岬 / 英皇家空军之阶级最低之兵小径的 i Nos 串音的 Upregulation 在 F344 老鼠和 c-Myc-TGF-alpha 的 HCC 代表的最好攻击的模型在高水平发生在啮齿类动物肝损害转基因的老鼠。在规定上面的 i NOS， IKK/NF-kappaB，和地岬 / 英皇家空军之阶级最低之兵在有更差的预后的人的 HCC 是最高级的并且断然与肿瘤增长， genomic 不稳定性和 microvascularization 相关，并且否定地与 apoptosis。因此，房间周期规定和信号转导变异小径的活动似乎被 HCC 修饰词基因调制，并且在他们的效率的差别影响危险性到 hepatocarcinogenesis 并且可能人的 HCC 的预后。

关 键 词：HEPATOCARCINOGENESIS Genetic predisposition Polygenic disease  Redifferentiation Signal transduction pathways Cell cycle Cell proliferation Apoptosis Proteasomal degradation 

分 类 号：R735.7[医药卫生—肿瘤]