Lentiviral-Mediated Short Hairpin RNA Knockdown of MTDH Inhibits Cell Growth and Induces Apoptosis by Regulating the PTEN/AKT Pathway in Hepatocellular Carcinoma.

Wen-Fang Li,Qin Ou,Hang Dai,Chang-An Liu

doi:10.3390/ijms160819419

Abstract

The activation of oncogenes and the loss of tumor suppressor genes are believed to play critical roles in the pathogenesis of human hepatocellular carcinoma (HCC). Metaherin (MTDH), also called astrocyte elevated gene-1 (AEG-1), is frequently amplified in a variety of cancers, but the roles of MTDH with regard to growth and apoptosis in HCC have not yet been studied. In the present study, we first analyzed the expression of MTDH in HCC samples. We found that MTDH protein levels are higher in most HCC cancerous tissues compared with their matched adjacent non-tumor tissues. Additionally, the MTDH mRNA was also higher in HCC tissues compared to their matched adjacent non-tumor tissues. Knockdown of the endogenous MTDH using small interfering RNA further showed that deficiency of MTDH suppressed cell growth and caused apoptosis in HCC cells. Knockdown MTDH promoted PTEN and p53 expression in HCC cells and inhibited AKT phosphorylation. Knockdown MTDH also inhibited tumor growth in vivo. All these results indicated that MTDH protein levels in most HCC tissues are higher than non-tumor tissues, and knockdown of MTDH inhibited growth and induced apoptosis in HCC cells through the activation of PTEN. Therefore, MTDH might be an effective targeted therapy gene for HCC.

Highlights

Hepatocarcinogenesis is a complex multistep process in which many signalling cascades are altered, leading to a heterogeneous molecular profile
The results showed that MTDH was differently expressed in hepatocellular carcinoma (HCC) tissues
Expression level of MTDH was significantly increased in HCC tissues compared to matched non-cancerous liver tissues. These results suggested that MTDH might have important roles in HCC pathogenesis

Summary

Introduction

Hepatocarcinogenesis is a complex multistep process in which many signalling cascades are altered, leading to a heterogeneous molecular profile. Surgery remains the main therapy for HCC, but only 30% had the opportunity to surgically remove the tumor, and the postoperative five-year survival rate was only about 30%–40% for liver cancer patients [2]. Gene therapy has been emerging as a promising intervention against HCC. Due to the complexity of signaling pathways that initiate and maintain the occurrence and progression of HCC, the poor understanding of underlying molecular mechanisms in HCC development impede HCC therapy. The discovery of oncogenes associated with HCC growth and clarifying their mechanism might provide important clues for HCC clinical treatment [4]

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