Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the most common liver malignancy and a major health problem globally
MTDH is attracting increasing attention from oncologists because it is overexpressed in a number of malignancies, such as breast cancer, malignant glioma, and neuroblastoma [3, 5, 6], and its overexpression is associated with poor clinical outcome
MTDH promotes metastatic ability of hepatocellular carcinoma (HCC) cells To investigate the role of MTDH in HCC metastasis, we treated LM3 and 97H cells with a lentivirus-targeting MTDH to create LM3-short hairpin RNA (shRNA) and 97H-shRNA cell lines that
Summary
Hepatocellular carcinoma (HCC) is the most common liver malignancy and a major health problem globally. Current standard practices for treatment of HCC, surgical resection, and liver transplantation are less than satisfactory due to high recurrence rates [1]. MTDH plays an important role in the regulation of carcinogenesis and tumor progression [3, 6, 7]. It can interact with NF-kB and promotes NF-kB–induced tumor progression and metastasis [8]; it enhances the chemoresistance of cancer through activation of the aldehyde dehydrogenase 3 family, member A1 (ALDH3A1), and the hepatocyte growth factor receptor [3]
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