Dysregulation of hedgehog pathway signaling in hepatocellular carcinoma
Dysregulation of hedgehog pathway signaling in hepatocellular carcinoma
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发表时间：
2006-04
期刊：
影响因子：
11.2
通讯作者：
E. Lemmer;Yingbei Chen;S. Yea;E. Wurmbach;M. Schwartz;G. Khitrov;A. Villanueva;G. Narla;S. Waxman;S. Friedman;J. Llovet
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作者：
E. Lemmer;Yingbei Chen;S. Yea;E. Wurmbach;M. Schwartz;G. Khitrov;A. Villanueva;G. Narla;S. Waxman;S. Friedman;J. Llovet
2676肝细胞癌是世界范围内的主要癌症，由于终末期慢性丙型肝炎病毒感染，其发病率正在迅速上升。晚期肝细胞癌尚无一线系统治疗方法。了解肝细胞癌发生/发展过程中的信号通路将为设计新的分子靶向药物提供理论基础。为了研究丙型肝炎病毒相关性肝细胞癌发生发展过程中基因表达的变化，我们收集了78例接受肝细胞癌手术切除或肝移植的丙型肝炎肝硬变患者的样本。采用实时荧光定量RT-PCR方法检测56条候选肿瘤通路基因在代表肝细胞癌进展期病变(10例正常、10例肝硬变、18例异型增生、40例肝癌)中的表达。其中，Hhedgehog(HH)信号通路的关键成分显著失调，HH信号通路是一种以前在肝细胞癌中未被研究的促癌途径。HH途径对于正常的胚胎发育至关重要；然而，成人HH信号的重新激活与几个散发性肿瘤有关。我们发现，24/40(60%)的丙型肝炎病毒相关的肝细胞癌中，印度刺猬(IHH，HH配体)的表达上调了一倍或更多，而在肝硬变和异型增生病变中，这一比例为1/28(3.6%)(p
2676 Hepatocellular carcinoma (HCC) is major cancer worldwide whose incidence is rapidly increasing due to end-stage chronic hepatitis C virus (HCV) infection. There is no first line systemic treatment for advanced HCC. Knowledge of of the signaling pathways involved in the initiation/progression of HCC will provide a rationale for the design of new molecular targeting agents. In order to characterize the changes in gene expression during the development of HCV-associated HCC, we collected samples from 78 HCV-cirrhotic patients undergoing surgical resection or liver transplantation for HCC. Gene expression of 56 candidate tumor pathway mRNAs were analyzed by real-time RT-PCR in lesions representing progressive histologic stages (10 normal, 10 cirrhosis, 18 dysplastic lesions, 40 HCCs) of HCC. Among these, key components of the hedgehog (Hh) signaling pathway, a tumor promoting pathway not previously studied in HCC, were, significantly dysregulated. The Hh pathway is crucial for normal embryonic development; however, reactivation of Hh signaling in adults is associated with several sporadic tumors. We found that 24/40 (60%) of HCV-associated HCCs displayed two-fold or more upregulation of Indian Hedgehog (IHH, Hh ligand) expression compared to 1/28 (3.6%) of cirrhotic livers and dysplastic lesions (p