BTB/POZ domain-containing protein 7: Epithelial-mesenchymal transition promoter and prognostic biomarker of hepatocellular carcinoma
BTB/POZ domain-containing protein 7: Epithelial-mesenchymal transition promoter and prognostic biomarker of hepatocellular carcinoma
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含BTB/POZ结构域的蛋白7：上皮间质转化启动子和肝细胞癌的预后生物标志物
DOI：
10.1002/hep.26268
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发表时间：
2013-06-01
期刊：
影响因子：
13.5
通讯作者：
Shen, Hong
中科院分区：
文献类型：
--
作者：
Tao, Yi-Ming;Huang, Jin-Lin;Shen, Hong
上皮间质转化（EMT）是肝细胞癌（HCC）转移的关键步骤。含BTB/POZ结构域的蛋白7（BTBD 7）调节HCC进展中涉及的EMT相关蛋白。然而，BTBD 7在HCC中的作用尚未确定。使用高转移性HCC HCCLM 3细胞、永生化L02肝细胞、转移性HCC动物模型和三个独立的HCC患者样本队列，我们旨在确定BTBD 7在HCC转移中的参与。我们发现BTBD 7信使RNA和蛋白在HCC细胞和肿瘤组织中高度表达，这种表达与细胞运动性增强、静脉浸润和预后不良有关。BTBD 7在体内外均能促进肝癌血管生成和转移，但不影响细胞增殖和集落形成。BTBD 7通过激活RhoC-Rock 2-FAK信号通路增强HCC侵袭和EMT表型，导致基质金属蛋白酶-2/9产生和微血管形成。应用预测风险评分模型，考克斯回归分析显示，BTBD 7高表达结合高微血管密度是HCC临床结局的强有力的独立预测因素。结论：BTBD 7是一个新的肝癌预后因子和潜在的治疗靶点。（肝脏学2013; 57：2326-2337）
Epithelial-mesenchymal transition (EMT) is a critical step in the metastasis of hepatocellular carcinoma (HCC). BTB/POZ domain-containing protein 7 (BTBD7) regulates EMT-associated proteins implicated in HCC progression. However, the role(s) of BTBD7 in HCC have not been identified. Using highly metastatic HCC HCCLM3 cells, immortalized L02 hepatocytes, metastatic HCC animal models, and three independent cohorts of HCC patient specimens, we aimed to determine the involvement of BTBD7 in HCC metastasis. We show that BTBD7 messenger RNA and protein was highly expressed in HCC cells and tumor tissues, with such expression being associated with: enhanced cell motility, venous invasion, and poor prognosis. BTBD7 promoted HCC angiogenesis and metastasis in vitro and in vivo, but did not influence cell proliferation or colony formation. BTBD7 enhancement of HCC invasion and EMT phenotype occurred through activation of a RhoC-Rock2-FAK-signaling pathway, resulting in matrix metalloproteinase-2/9 production and microvessel formation. Applying a predictive risk score model, Cox regression analysis revealed that high BTBD7 expression integrated with high microvessel density was a powerful independent predictive factor of HCC clinical outcome. Conclusion: The present study identifies BTBD7 as a novel candidate prognostic factor and a potential therapeutic target of HCC. (HEPATOLOGY 2013; 57:2326-2337)