title: HBx drives alpha fetoprotein expression to promote initiation of liver cancer stem cells through activating PI3K/AKT signal pathway.
abstract: Hepatitis B virus (HBV)-X protein (HBx) plays critical role in inducing the malignant transformation of liver cells. Alpha fetoprotein (AFP) expression is closely related to hepatocarcinogenesis. We report that Oct4, Klf4, Sox2 and c-myc expression positively associated with AFP(+)/HBV(+) hepatocellular carcinoma(HCC) tissues, and the expression of the stemness markers CD44, CD133 and EpCAM was significantly higher in AFP(+)/HBV(+) HCC tissues compared to normal liver tissues or AFP (-)/HBV(-) HCC tissues. AFP expression turned on prior to expression of Oct4, Klf4, Sox2 and c-myc, and the stemness markers CD44, CD133 and EpCAM in the normal human liver L-02 cell line or CHL cell lines upon transfection with MCV-HBx vectors. Stem-like cells generated more tumour colonies compared to primary cells, and xenografts induced tumourigenesis in nude mice. Expression of reprogramming-related proteins was significantly enhanced in HLE cells while transfected with pcDNA3.1-afp vectors. The specific PI3K inhibitor Ly294002 inhibited the effects of pcDNA3.1-afp vectors. AFP-siRNA vectors were able to inhibit tumour colony formation and reprogramming-related gene expression. Altogether, HBx stimulates AFP expression to induce natural reprogramming of liver cells, and AFP plays a critical role in promoting the initiation of HCC progenitor/stem cells. AFP may be a potential novel biotarget for combating HBV-induced hepatocarcinogenesis.
authors.affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Dong
authors.affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Lin
authors.affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.
authors.forename: Xueer
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.
authors.forename: Junli
authors.initials: J
authors.lastname: Guo
authors.affiliation: Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.|Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.|Hainan Medical College, Institution of Tumour, Haikou, 570102, Hainan Province, People's Republic of China.
authors.forename: Mengsen
authors.initials: M
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D064593:Heterografts; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000821:virology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034622:RNA Interference; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D014410:Tumor Stem Cell Assay; D054334:Viral Regulatory and Accessory Proteins; D000509:alpha-Fetoproteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000090062:Kruppel-Like Factor 4; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D000509:alpha-Fetoproteins; C097353:AFP protein, human; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C057628:hepatitis B virus X protein; C494918:AKT1 protein, human
keywords: alpha fetoprotein; cancer stem cells; hepatitis B virus x protein (HBx); hepatocarcinogenesis; natural reprogramming