Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China.
Oncogene. 2011 Oct 27;30(43):4410-27. doi: 10.1038/onc.2011.149. Epub 2011 May 2.
Epithelial-mesenchymal transition (EMT) induced by transforming growth factor-β (TGF-β) is implicated in hepatocarcinogenesis and hepatocellular carcinoma (HCC) metastasis. HAb18G/CD147, which belongs to the CD147 family, is an HCC-associated antigen that has a crucial role in tumor invasion and metastasis. The goal of this study was to investigate the role of HAb18G/CD147 during EMT in hepatocarcinogenesis. Human normal hepatic cell lines QZG and L02, primary mouse hepatocytes and nude mouse models were used to determine the role of HAb18G/CD147 in EMT, and the involvement of the TGF-β-driven pathway. A dual-luciferase reporter assay and ChIP were used to investigate the transcriptional regulation of the CD147 gene. Samples from patients with liver disease were assessed to determine the relationship between HAb18G/CD147 and typical markers for EMT. Our results show that upregulation of HAb18G/CD147 is induced by TGF-β coupled with downregulation of E-cadherin and upregulation of N-cadherin and vimentin. The expression of HAb18G/CD147 is controlled by the cell survival PI3K/Akt/GSK3β signaling pathway, and is directly regulated by the transcription factor Slug. Transfection of CD147 also induces an elevated expression of TGF-β. CD147-transfected hepatocytes have mesenchymal phenotypes that accelerate tumor formation and tumor metastasis in vivo. Immunohistochemistry analysis shows a negative correlation between HAb18G/CD147 and E-cadherin expression (r(s)=-0.3622, P=0.0105), and a positive correlation between HAb18G/CD147 and Slug expression (r(s)=0.3064, P=0.0323) in human HCC tissues. Our study uncovers a novel role of HAb18G/CD147 in mediating EMT in the process of HCC progression and showed that CD147 is a Slug target gene in the signaling cascade TGF-β→PI3K/Akt→GSK3β→Snail→Slug→CD147. Our results suggest that CD147 may be a potential target for the treatment and prevention of HCC.
上皮-间充质转化（EMT）由转化生长因子-β（TGF-β）诱导，与肝癌发生和肝细胞癌（HCC）转移有关。HAb18G/CD147 属于 CD147 家族，是一种与 HCC 相关的抗原，在肿瘤侵袭和转移中起关键作用。本研究旨在探讨 HAb18G/CD147 在肝癌发生过程中 EMT 中的作用。使用人正常肝细胞系 QZG 和 L02、原代小鼠肝细胞和裸鼠模型来确定 HAb18G/CD147 在 EMT 中的作用，以及 TGF-β 驱动途径的参与。双荧光素酶报告基因检测和 ChIP 用于研究 CD147 基因的转录调控。评估肝病患者的样本，以确定 HAb18G/CD147 与 EMT 的典型标志物之间的关系。我们的结果表明，TGF-β 诱导 HAb18G/CD147 的上调，同时下调 E-钙粘蛋白，上调 N-钙粘蛋白和波形蛋白。HAb18G/CD147 的表达受细胞存活 PI3K/Akt/GSK3β 信号通路的控制，并受转录因子 Slug 的直接调控。CD147 的转染也诱导 TGF-β 的表达升高。转染 CD147 的肝细胞具有间充质表型，可加速体内肿瘤形成和肿瘤转移。免疫组织化学分析显示 HAb18G/CD147 与 E-钙粘蛋白表达呈负相关（r(s)=-0.3622，P=0.0105），HAb18G/CD147 与 Slug 表达呈正相关（r(s)=0.3064，P=0.0323）在人 HCC 组织中。本研究揭示了 HAb18G/CD147 在 HCC 进展过程中介导 EMT 的新作用，并表明 CD147 是 TGF-β→PI3K/Akt→GSK3β→Snail→Slug→CD147 信号级联中的 Slug 靶基因。我们的结果表明，CD147 可能是治疗和预防 HCC 的潜在靶点。
