Clinicopathological Significance of ZEB1 Protein in Patients with Hepatocellular Carcinoma
Clinicopathological Significance of ZEB1 Protein in Patients with Hepatocellular Carcinoma
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DOI：
10.1245/s10434-011-1772-6
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发表时间：
2012-05-01
影响因子：
3.7
通讯作者：
Yang, Jia-Mei
中科院分区：
文献类型：
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作者：
Zhou, Yan-Ming;Cao, Lu;Yang, Jia-Mei
ZEB1 是 ZFH 蛋白家族（锌指 E 盒结合同源盒）的成员，在癌发生过程中的上皮间质转化 (EMT) 中发挥核心作用。在本研究中，我们研究了肝细胞癌 (HCC) 患者中 ZEB1 的表达及其临床效应及其潜在机制。通过蛋白质印迹法评估了 5 个 HCC 细胞系以及 110 名 HCC 患者的配对癌组织和非癌组织中的 ZEB1 表达水平。在MHCC-97H细胞系中对ZEB1进行短发夹RNA（shRNA）干扰。与非转移性HCC细胞系（Hep3B、PLC和Huh-7）相比，在转移性人HCC细胞系（MHCC-97L和MHCC-97H）中检测到相对较高水平的ZEB1蛋白。 ZEB1 在 110 名 HCC 患者中的 72 名 (65.4%) 中高水平表达，并与晚期 TNM 分期、肿瘤大小 > 5 cm、肝内转移、血管侵犯和频繁的早期复发相关。多变量分析结果显示，ZEB1 高表达是总体生存率和无病生存率较差的重要预后因素。沉默ZEB1导致MHCC-97H细胞系的运动性显着抑制，并伴随上皮标记物E-钙粘蛋白的表达增加以及间质标记物N-钙粘蛋白和波形蛋白的表达减少。此外，沉默ZEB1可防止小鼠原位肿瘤模型中肝内转移的扩散并增加总体生存率。这项研究表明，ZEB1高表达与HCC恶性进展以及随后诱导EMT变化导致的患者生存率低相关。
ZEB1, a member of the ZFH family of proteins (zinc-finger E-box binding homeobox), plays a central role in epithelial-mesenchymal transition (EMT) during carcinogenesis. In this study, we investigated the expression of ZEB1 in patients with hepatocellular carcinoma (HCC) and its clinical effects with underlying mechanisms.Expression levels of ZEB1 were assessed by Western blot in 5 HCC cell lines and in paired cancerous and noncancerous tissues from 110 patients with HCC. Short-hairpin RNA (shRNA) interference for ZEB1 was performed in MHCC-97H cell line.ZEB1 protein was detected at a relatively high level in metastatic human HCC cell lines (MHCC-97L and MHCC-97H) when compared with that in nonmetastatic HCC cell lines (Hep3B, PLC and Huh-7). ZEB1 was expressed at high levels in 72 of 110 HCC patients (65.4%) and correlated with advanced TNM stage, tumor size > 5 cm, intrahepatic metastasis, vascular invasion, and frequent early recurrence. The results of multivariate analysis revealed that ZEB1 high expression was a significant prognostic factor for poor overall and disease-free survivals. Silencing ZEB1 resulted in significant suppression of motility of MHCC-97H cell line, which was accompanied with increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin. Furthermore, silencing ZEB1 prevented the spread of intrahepatic metastasis and increased overall survival in mouse orthotopic tumor models.This study shows that ZEB1 high expression was correlated with HCC malignant progression and subsequent poor patient survival by induction of EMT changes.