title: Hepatitis B virus X protein induces expression of alpha-fetoprotein and activates PI3K/mTOR signaling pathway in liver cells.
abstract: 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.
authors: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
authors: Mingyue
authors: M
authors: Zhu
authors: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.|Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Junli
authors: J
authors: Guo
authors: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
authors: Wei
authors: W
authors: Li
authors: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
authors: Yan
authors: Y
authors: Lu
authors: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
authors: Shigan
authors: S
authors: Fu
authors: Department of Physiology and Pathophysiology, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
authors: Xieju
authors: X
authors: Xie
authors: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
authors: Hua
authors: H
authors: Xia
authors: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
authors: Xu
authors: X
authors: Dong
authors: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
authors: Yi
authors: Y
authors: Chen
authors: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Ming
authors: M
authors: Quan
authors: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.|Tumor Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan 570102, P. R. China.
authors: Shaojiang
authors: S
authors: Zheng
authors: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Keping
authors: K
authors: Xie
authors: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China.
authors: Mengsen
authors: M
authors: Li
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D008099:Liver / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins; D000509:alpha-Fetoproteins / Q000378:metabolism*
chemical_list: D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D000509:alpha-Fetoproteins; C057628:hepatitis B virus X protein; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases
keywords: AFP; HBx; PI3K/mTOR signaling; hepatocarcinogenesis; liver cells