Hepatitis B virus X protein induces expression of alpha-fetoprotein and activates PI3K/mTOR signaling pathway in liver cells
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Mingyue Zhu1,2,*, Junli Guo1,3,*, Wei Li1,2, Yan Lu1,2, Shigan Fu1, Xieju Xie4, Hua Xia1,2, Xu Dong1,2, Yi Chen1,2, Ming Quan3, Shaojiang Zheng1,5, Keping Xie3, Mengsen Li1,2
1Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China
2Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China
3Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
4Department of Physiology and Pathophysiology, Hainan Medical College, Haikou, Hainan 571199, P. R. China
5Tumor Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan 570102, P. R. China
*These authors have contributed equally to this work
Mengsen Li, e-mail: [email protected]
Keping Xie, e-mail: [email protected]
Keywords: AFP, HBx, PI3K/mTOR signaling, Liver cells, Hepatocarcinogenesis
Received: October 10, 2014 Accepted: December 11, 2014 Published: January 21, 2015
The hepatitis B virus (HBV)-X protein (HBx) induces malignant transformation of liver cells, and elevated expression of alpha-fetoprotein (AFP) is a significant biomarker of hepatocarcinogenesis. However, the role of AFP in HBV-related hepatocarcinogenesis is unclear. In this study, we investigated the regulatory impact of AFP expression on HBx-mediated malignant transformation of human hepatocytes. We found that HBV induced the expression of AFP before that of oncogenes, e.g., Src, Ras and chemokine (C-X-C motif) receptor 4 (CXCR4), and AFP activated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in HBV-related HCC tissues and in human liver cells transfected with HBx. Cytoplasmic AFP interacted with and inhibited phosphatase and tensin homolog deleted on chromosome 10 (PTEN), activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promoting mTOR-mediated stimulation of the transcription factor hypoxia inducible factor-1α (HIF-1α), and therefore led to the activation of the promoters of Src, CXCR4, and Ras genes. On the contrary, reduced expression of AFP by siRNA resulted in the repression of p-mTOR, pAKT, Src, CXCR4, and Ras in human malignant liver cells. Taken together, for the first time our study indicates that HBx-induced AFP expression critically promote malignant transformation in liver cells through the activation of PI3K/mTOR signaling.
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