Liver Cancer Institute, Zhong Shan Hospital, Fudan University, Shanghai, China.
Clin Cancer Res. 2011 Dec 1;17(23):7294-302. doi: 10.1158/1078-0432.CCR-11-1327. Epub 2011 Oct 5.
To investigate the expression of metadherin (MTDH) for its prognostic value in hepatocellular carcinoma (HCC) and its role in promoting HCC metastasis.
This study employed a tissue microarray containing samples from 323 HCC patients to examine the expression of MTDH and its correlation with other clinicopathologic characteristics. The role of MTDH in the regulation of HCC metastasis was investigated both in vitro and in vivo using short hairpin RNA (shRNA)-mediated downregulation of MTDH in HCC cell lines with various metastatic potentials.
The expression of MTDH was markedly higher in HCC tumors than in normal liver tissue. Particularly high MTDH expression was observed in tumors with microvascular invasion, pathologic satellites, poor differentiation, or tumor-node-metastasis stages II to III. Furthermore, the clinical outcome was consistently poorer for the MTDH(high) group than for the MTDH(low) group in the 1-, 3-, and 5-year overall survival (OS) rates and in the 1-, 3-, 5-year cumulative recurrence rates. In a nude mice model, the shRNA-mediated downregulation of MTDH resulted in a reduced migratory capacity in HCC cell lines, as well as a reduction in pulmonary and abdominal metastasis. Furthermore, we found that the expression level of MTDH correlated with four epithelial-mesenchymal transition (EMT) markers. Knockdown of MTDH expression in HCC cell lines resulted in downregulation of N-cadherin and snail, upregulation of E-cadherin, and translocation of β-catenin.
MTDH may promote HCC metastasis through the induction of EMT process and may be a candidate biomarker for prognosis as well as a target for therapy.
研究 METADHERIN（MTDH）的表达及其在肝细胞癌（HCC）中的预后价值，并探讨其促进 HCC 转移的作用。
本研究采用包含 323 例 HCC 患者样本的组织微阵列，检测 MTDH 的表达及其与其他临床病理特征的相关性。利用短发夹 RNA（shRNA）下调具有不同转移潜能的 HCC 细胞系中 MTDH 的表达，在体外和体内研究 MTDH 在调控 HCC 转移中的作用。
MTDH 在 HCC 肿瘤中的表达明显高于正常肝组织。在具有微血管侵犯、病理卫星灶、低分化或肿瘤-淋巴结-转移分期 II 至 III 的肿瘤中，MTDH 的表达更高。此外，在 1 年、3 年和 5 年总生存率（OS）和 1 年、3 年和 5 年累积复发率方面，MTDH（高）组的临床结果始终比 MTDH（低）组差。在裸鼠模型中，shRNA 介导的 MTDH 下调导致 HCC 细胞系的迁移能力降低，以及肺和腹部转移减少。此外，我们发现 MTDH 的表达水平与四个上皮-间充质转化（EMT）标志物相关。在 HCC 细胞系中下调 MTDH 表达导致 N-钙黏蛋白和 snail 下调，E-钙黏蛋白上调，β-连环蛋白易位。
MTDH 可能通过诱导 EMT 过程促进 HCC 转移，并且可能是预后的候选生物标志物以及治疗的靶点。
