Tsunedomi Ryouichi, Iizuka Norio, Hamamoto Yoshihiko, Uchimura Shunji, Miyamoto Takanobu, Tamesa Takao, Okada Toshimasa, Takemoto Norikazu, Takashima Motonari, Sakamoto Kazuhiko, Hamada Kenji, Yamada-Okabe Hisafumi, Oka Masaaki
Department of Surgery II, Yamaguchi University School of Medicine, Ube, Yamaguchi 755-8505, Japan.
Int J Oncol. 2005 Sep;27(3):661-7.
Cytochrome P450 (CYP) genes are involved in the pathogenesis of hepatocellular carcinoma (HCC). To examine changes in expression of CYPs in HCC arising from hepatitis C virus (HCV)-infected liver, we used oligonucleotide array data of 27 CYPs from samples of 50 HCV-associated HCCs, five HCV-infected non-tumorous livers, and six HCV-negative normal livers. Progression of primary HCC can be characterized by decrease in the grade of tumor differentiation, increased frequency of venous invasion and increased tumor size. On the basis of tumor differentiation, the self-organizing map (SOM) classified the 27 CYPs into four groups. The first group contained 11 CYPs, including the CYP2C and CYP4F families, that showed decreased expression in parallel with progression of HCV-infected liver to HCC with less differentiation. The second group contained CYP-IID, CYP3A7 and CYP27A1, genes that showed high levels of expression specific to well differentiated HCC. The third group contained 5 sterol-metabolizing CYPs with levels lower in HCV-infected livers than in HCV-uninfected livers. The last group included the CYP2E1 and CYP3A families. Among the 27 CYPs, levels of 7 (CYP2B6, CYP-IIC, CYP2C9, CYP2C19, CYP3A5, CYP4F3 and CYP27A1) were significantly lower and levels of 2 (CYP2E1 and CYP4F2) were slightly lower in HCC with venous invasion than in HCC without venous invasion. Levels of CYP-IIC and CYP2C9 were inversely associated with tumor size. In contrast, levels of CYP51A1 were positively associated with tumor size. Our present study revealed that expression of specific CYPs was altered in conjunction with progression of HCV-associated HCC. These CYPs may serve as markers of progression and molecular targets for treatment of HCV-associated HCC.
细胞色素P450（CYP）基因参与肝细胞癌（HCC）的发病机制。为了研究丙型肝炎病毒（HCV）感染肝脏引发的HCC中CYPs表达的变化，我们使用了来自50例HCV相关HCC样本、5例HCV感染的非肿瘤肝脏样本和6例HCV阴性正常肝脏样本的27种CYPs的寡核苷酸阵列数据。原发性HCC的进展可以通过肿瘤分化程度降低、静脉侵犯频率增加和肿瘤大小增加来表征。基于肿瘤分化，自组织映射（SOM）将27种CYPs分为四组。第一组包含11种CYPs，包括CYP2C和CYP4F家族，它们的表达随着HCV感染肝脏向低分化HCC的进展而降低。第二组包含CYP-IID、CYP3A7和CYP27A1基因，这些基因在高分化HCC中表现出高水平的特异性表达。第三组包含5种固醇代谢CYPs，其在HCV感染肝脏中的水平低于未感染HCV的肝脏。最后一组包括CYP2E1和CYP3A家族。在27种CYPs中，有7种（CYP2B6、CYP-IIC、CYP2C9、CYP2C19、CYP3A5、CYP4F3和CYP27A1）在有静脉侵犯的HCC中的水平显著低于无静脉侵犯的HCC，有2种（CYP2E1和CYP4F2）的水平略低。CYP-IIC和CYP2C9的水平与肿瘤大小呈负相关。相反，CYP51A1的水平与肿瘤大小呈正相关。我们目前的研究表明，特定CYPs的表达随着HCV相关HCC的进展而改变。这些CYPs可能作为HCV相关HCC进展的标志物和治疗的分子靶点。
