Metadherin Promotes Hepatocellular Carcinoma Metastasis through Induction of Epithelial–Mesenchymal Transition

Abstract

Purpose: To investigate the expression of metadherin (MTDH) for its prognostic value in hepatocellular carcinoma (HCC) and its role in promoting HCC metastasis.Experimental Design: 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.Results: 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 shRNAmediated 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 b-catenin. Conclusions: 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. Clin Cancer Res; 17(23); 7294-302. Ó2011 AACR.

Epithelial-mesenchymal transition expression profiles as a prognostic factor for disease-free survival in hepatocellular carcinoma: Clinical significance of transforming growth factor-β signaling

“…However, TGF-β signaling was not activated in one-third of patients with an E-cadherin low / vimentin high expression profile. Although the precise mechanism of EMT induction in these patients remains unclear, it is possible that several transcription factors (such as Snail, Twist and ZEB1) as well as other molecules are also involved in the process of EMT and are therefore associated with a poor prognosis in HCC (5,6,(20)(21)(22)(23)(24)(25)(26)(27). Thus, several mechanisms, including TGF-β signaling, may be involved in the process of EMT in HCC patients.…”

The emerging role of astrocyte-elevated gene-1 in hepatocellular carcinoma (Review)

“…It was further demonstrated that the expression level of AEG-1 was correlated with four epithelialto-mesenchymal transition (EMT) markers. Knockdown of AEG-1 expression in HCC cell lines resulted in downregulation of N-cadherin and Snail, upregulation of E-cadherin and translocation of β-catenin (42). Another study using Huaier polysaccharide also confirmed that downregulation of AEG-1 inhibited the metastatic potential of HCC cells through EMT (52).…”

“…In a study using cell lines and a nude mouse model, downregulation of AEG-1 resulted in the reduced migratory capacity of HCC cell lines, as well as a reduction in pulmonary and abdominal metastases in mice (42). It was further demonstrated that the expression level of AEG-1 was correlated with four epithelialto-mesenchymal transition (EMT) markers.…”

“…In a subsequent study, AEG-1 expression was assessed by immunohistochemistry in tissue microarrays of 323 HCC patients, which demonstrated that the majority of the tumor tissues expressed significantly higher levels of AEG-1 when compared with adjacent non-tumor tissues; with AEG-1 High present in 54.2% (175 of 323) of all the patients (42). In addition, by Pearson χ 2 test, AEG-1 expression was found to be closely associated with microvascular invasion (P<0.001), pathologic satellites (P= 0.007), tumor differentiation (P=0.002) and TNM stage (P= 0.001).…”

Metastasin leads to poor prognosis of hepatocellular carcinoma through partly inducing EMT

“…In preliminary studies (11)(12)(13), EMT was verified to be involved in the cascade of signaling events inducing HCC metastasis (14,15). However, the concrete mechanisms of induction of EMT in HCC remain unclear.…”