Abstract
BackgroundHepatitis B virus (HBV)-X protein(HBx) is a transactivator of host several cellular genes including alpha-fetoprotein(AFP) and AFP receptor(AFPR) which contributes to HBV-associated tumor development. The expression of AFP/AFPR are correlated with hepatocellular carcinoma(HCC)-initial cells. But the role of AFP and AFPR in promoting occurrence of HBV-related HCC were still unclear.MethodsA total of 71 clinical patients’ liver specimens, normal human liver cells L-02 and HCC cell lines, PLC/PRF/5 were selected for analyzing the effects of HBx on expression of AFP, AFPR and Src. The expression of goal proteins were detected by Immunohistochemical stained and Western blotting; HBx-expressed vectors were constructed and transfected into L-02 cells, laser confocal microscopy was applied to observe expression and location of AFP, AFPR and Src in the normal liver cells and HCC cells, soft agar colony formation assay was used to observe colonies formed of the cells.ResultsWe confirmed HBx gives preference to promote the expression of AFP and AFPR; HBx priors to up-regulate the expression of AFPR and AFP in L-02 cells and in normal liver specimens; AFPR signal been able to stimulate Src expression. The results also indicated that phosphatidylinositol 3-kinase(PI3K) inhibitors Ly294002 and GDC0941 effectively suppress AFPR mediated up-regulation expression of Src in AFPR positive HCC lines.ConclusionsHBx priors to drive the expression of AFP and AFPR to promote expression of Src in normal liver cells and hepatoma cells; AFP and AFPR maybe play pivotal role in HBV-related hepatocarcinogenesis; Targeting AFPR is an available therapeutic strategy of HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1384-9) contains supplementary material, which is available to authorized users.
Highlights
Hepatitis B virus (HBV)-X protein(HBx) is a transactivator of host several cellular genes including alpha-fetoprotein(AFP) and AFP receptor(AFPR) which contributes to HBV-associated tumor development
We discovered that HBx priors to induce expression of AFP and AFPR in normal liver tissues and liver cell lines via activating Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (AKT) signal, and AFP promoted expression of Src was mediated by AFPR, AFPR signal possess a character to activate PI3K/AKT
The results indicated that AFP expressed in HBV-infected tissues, HBV positive cirrhosis liver tissues and HBV-related HCC tissues was 42.8%, 70.6% and 86.4% respectively; AFPR expressed in these tissues was 50.0%, 75.5% and 90.9% respectively; Src expressed in these tissues was 28.6%, 52.9% and 63.6% respectively; The levels of AFPR was significantly higher in AFP+/HBV+ liver tissues than in AFP-/HBV+ or AFP-/ HBV- liver tissues (Additional file 1)
Summary
Hepatitis B virus (HBV)-X protein(HBx) is a transactivator of host several cellular genes including alpha-fetoprotein(AFP) and AFP receptor(AFPR) which contributes to HBV-associated tumor development. The role of AFP and AFPR in promoting occurrence of HBV-related HCC were still unclear. Alpha fetoprotein(AFP) is an early biomarker of HCC diagnosis, promote tumor cells proliferation effects of AFP have been reported by several groups [15,16], data indicated that AFP play pivotal role in the hepatocarcinogenesis [17]. Our investigations found that these effects of AFP maybe mediated by AFP receptors(AFPR) [18,19], cytoplasmic AFP activated PI3K/ AKT signal pathway to promote expression of some oncogenes and proliferation of HCC cells [16,20,21]. HBx priors to induce expression of AFP and AFPR to activate PI3K/AKT signal pathway in normal liver tissues and cell lines [22]. Our results supported that AFP and AFPR as potential stimulated factors for HBx inducing hepatocarcinogenesis
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