Hepatitis B virus X protein-induced upregulation of CAT-1 stimulates proliferation and inhibits apoptosis in hepatocellular carcinoma cells.

Rongjuan Dai,Jing Ma,Xinqiang Xiao,Yi Tian,Xing Gong,Mingming Li,Yue Luo,Feng Peng,Yongfang Jiang,Min Zhang,Yun Xu,Guozhong Gong

doi:10.18632/oncotarget.17631

Rongjuan Dai, Jing Ma + Show 10 more

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https://doi.org/10.18632/oncotarget.17631

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Abstract

The HBx protein of hepatitis B virus (HBV) is widely recognized to be a critical oncoprotein contributing to the development of HBV-related hepatocellular carcinoma (HCC). In addition, cationic amino acid transporter 1 (CAT-1) gene is a target of miR-122. In this study, we found that CAT-1 protein levels were higher in HBV-related HCC carcinomatous tissues than in para-cancerous tumor tissues, and that CAT-1 promoted HCC cell growth, proliferation, and metastasis. Moreover, HBx-induced decreases in Gld2 and miR-122 levels that contributed to the upregulation of CAT-1 in HCC. These results indicate that a Gld2/miR-122/CAT-1 pathway regulated by HBx likely participates in HBV-related hepatocellular carcinogenesis.

Highlights

Hepatitis B virus (HBV) infection is widely recognized as a leading cause of hepatocellular carcinoma (HCC) [1,2,3,4], and the hepatitis B virus (HBV) x protein (HBx) is crucial to the induction of HBV-related HCC
cationic amino acid transporter 1 (CAT-1) protein levels were higher in HCC tissues than in para-cancerous or normal tissues (Figure 1C, 1D); CAT-1 mRNA levels did not differ among the different types of tissues (Figure 1B)
IHC array results indicated that Germ Line Development 2 (Gld2) protein levels were reduced and CAT-1 expression was increased in HCC tissues (Figure 1E)

Summary

Introduction

Hepatitis B virus (HBV) infection is widely recognized as a leading cause of hepatocellular carcinoma (HCC) [1,2,3,4], and the HBV x protein (HBx) is crucial to the induction of HBV-related HCC. HBx promotes the formation and development of HCC via many mechanisms, including trans-activation of various host cell genes related to growth and apoptosis, interactions with p53 and the Ras-Raf-MAP kinase pathway, and inhibition of DNA repair [5,6,7]. Levels of miR-122, which is the most enriched microRNA in normal liver tissues, are markedly decreased in HCC, in HBVrelated HCC [8,9,10]. We found that HBx down-regulated miR-122 in hepatocellular tissue by reducing Germ Line Development 2 (Gld2) protein levels [11]. Whether HBx-induced downregulation of miR-122 promotes the formation and development of HBV-related HCC remains unknown. Since arginine is necessary for the survival of human hepatoma cells [15, 17], CAT-1 might contribute to HCC progression

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