Journal
ONCOTARGET
Volume 6, Issue 14, Pages 12196-12208Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2906
Keywords
AFP; HBx; PI3K/mTOR signaling; Liver cells; Hepatocarcinogenesis
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Funding
- National Natural Science Foundation of China [81360307, 81260306, 81160261, 31060164, 30960153]
- Key Program of Science and Technology, Ministry of Education of China [211146]
- Key Projects of Science and Technology, Hainan Province [ZDXM 20110038]
- New Century Excellent Talents in China [NCET-10-0124]
- Natural Science Foundation of Hainan Province [309034, 310044]
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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-1 alpha (HIF-1 alpha), 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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