Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma
Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma
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乙型肝炎病毒X蛋白诱导的FoxM1表达上调促进乙型肝炎病毒相关肝细胞癌的肿瘤转移并提示不良预后
DOI：
10.1016/j.jhep.2012.04.020
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发表时间：
2012-09-01
影响因子：
25.7
通讯作者：
Wu, Kaichun
中科院分区：
文献类型：
--
作者：
Xia, Limin;Huang, Wenjie;Wu, Kaichun
背景与目的：叉头盒M1(Forkhead box M1，FOXM1)是肿瘤转移的主要调节因子，在肝细胞癌的发生发展中起着重要作用。然而，FOXM1是否促进了乙肝病毒相关性肝细胞癌的进展仍不清楚。因此，本研究旨在探讨FOXM1在乙肝肝细胞癌中的临床病理意义及其在乙型肝炎病毒X(HBX)介导的侵袭转移中的作用。方法：采用免疫组织化学方法检测FOXM1及其功能靶点基质金属蛋白酶-7(MMP7)、RhoC和Rho-kinase1(ROCK1)在人乙肝肝细胞癌组织中的表达。用荧光素酶报告、染色质免疫沉淀和凝胶迁移率改变实验检测HBx对FOXM1启动子转录调控的影响。通过Transwell分析和原位转移模型分析FOXM1在HBx介导的侵袭和转移中的作用。结果：FOXM1的过度表达与多种恶性特征相关，提示HBV肝细胞癌患者预后不良。FOXM1表达是影响肝细胞癌术后复发和生存的独立因素。FOXM1通过促进MMP-7、RhoC和ROCK1的表达促进肝癌细胞的侵袭和转移，而FOXM1的过度表达与这些蛋白在乙肝-肝细胞癌组织中的表达升高有关。HBX通过ERK/CREB途径上调FOXM1的表达，抑制FOXM1可显著降低HBX增强的肝癌细胞体外侵袭和体内肺转移。结论：HBX通过ERK/CREB途径激活FOXM1的表达，从而导致肝癌细胞的侵袭和转移，是乙肝相关肝癌发生的新的分子机制。Crown版权所有(C)2012欧洲肝脏研究协会。爱思唯尔出版公司版权所有。
Background & Aims: Forkhead box M1 (FoxM1) is a master regulator of tumor metastasis that plays an important role in the development of hepatocellular carcinoma (HCC). However, whether or not FoxM1 contributes to the progression of HBV-associated HCC (HBV-HCC) remains unknown. Therefore, we aimed at investigating the clinicopathologic significance of FoxM1 in HBV-HCC and the potential role of FoxM1 in hepatitis B virus X (HBx)-mediated invasiveness and metastasis.Methods: The expression of FoxM1 and its functional targets matrix metalloproteinase-7 (MMP-7), RhoC, and Rho-kinase 1 (ROCK1) in human HBV-HCC tissues was detected by immunohistochemistry. Luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were used to measure the transcriptional regulation of FoxM1 promoter by HBx. The effect of FoxM1 on HBx-mediated invasiveness and metastasis was analyzed by transwell assays and an orthotopic metastatic model.Results: FoxM1 overexpression correlated with multiple malignant characteristics and indicated poor prognosis of HBV-HCC patients. FoxM1 expression was an independent factor affecting the recurrence and survival of patients with HBV-HCC after surgical resection. FoxM1 promoted hepatoma cell invasion and metastasis by promoting MMP-7, RhoC, and ROCK1 expression, while FoxM1 overexpression was associated with elevated expressions of these proteins in HBV-HCC tissues. HBx upregulated FoxM1 expression through the ERK/CREB pathway, and FoxM1 inhibition significantly decreased HBx-enhanced hepatoma cell invasion in vitro and lung metastasis in vivo.Conclusions: We report a new molecular mechanism for HBV-associated hepatocarcinogenesis that involves the activation of FoxM1 expression by HBx through the ERK/CREB pathway, thereby leading to invasion and metastasis of hepatoma cells. Crown copyright (C) 2012 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.