Hepatitis B x-interacting protein induces HepG2 cell proliferation through activation of the phosphatidylinositol 3-kinase/Akt pathway

Abstract

Hepatitis B x-interacting protein (HBXIP), a co-factor of survivin, was originally identified by its binding with the C-terminus of the hepatitis B virus x protein (HBx). We have recently shown that HBXIP promotes the growth of both normal liver cells and hepatoma cells in vitro, but the molecular mechanisms of this have not been documented. In this study, we investigated the potential effects of HBXIP on the proliferation of HepG2 cells and the intracellular signaling pathway mediating these changes. Over-expression of the HBXIP gene promoted the proliferation of HepG2 cells, as shown by the MTT assay. We also showed that HBXIP induced cellular accumulation in the S phase concomitantly with up-regulation of cyclinD(1) and down-regulation of p21 and p53 levels. Moreover, HBXIP over-expression cells showed activation of the PI3K/Akt pathway; this activation was accompanied by an increase in phosphorylation of glycogen synthase kinase 3β. LY294002, a specific inhibitor of PI3K, blocked HBXIP-stimulated Akt phosphorylation and suppressed the cell cycle promotion induced by HBXIP in HepG2 cells. The increase in cyclinD(1) protein levels induced by HBXIP was inhibited when cells were incubated with LY294002. In conclusion, our data suggest that the proliferation of HepG2 cells promoted by HBXIP is associated with activation of the PI3K/Akt signaling pathway.

The Oncoprotein HBXIP Uses Two Pathways to Up-regulate S100A4 in Promotion of Growth and Migration of Breast Cancer Cells

“…It has been reported that S100A4 expression can be enhanced by AKT kinase in breast cancer cell lines (29) and HBXIP is able to active AKT signaling in hepatoma HepG2 cells (30). Thus, we supposed that PI3K/AKT pathway may be involved in the regulation of S100A4 meditated by HBXIP in breast cancer cells.…”

“…It has been reported that the up-regulation of S100A4 involves PI3K/AKT signaling pathway which promotes the proliferation and growth of cancer cells (29). HBXIP was able to active AKT signaling in HepG2 cells (30). Accordingly, we proposed the possibility that HBXIP might upregulate S100A4 through PI3K/AKT signaling pathway as well.…”

Hepatocellular Carcinoma: Insights from the Centrosome Abnormalities

“…Interestingly, both of PKC and MAPK are required for phosphorylation of HBx, which, in turn, alters its subcellular localization and dysregulation of cell cycle progression, leading to hepatocarcinogenesis in HBV-infected cells. Besides, phosphoinositide 3-kinase (PI3K), a family of enzymes linked to extraordinarily diverse group of cellular functions, are involved in cancer (Lee et al, 2001;Yun et al, 2004, Wang et al, 2011. In HBV-infected cells, PI3K/Akt pathway can be activated through Akt phosphorylation by HBXIP, which also induce up-regulate cyclin D and down-regulate p21 and p53 expression, promoting cell proliferation (Wang, et al, 2011).…”

The role of hepatitis B virus X protein is related to its differential intracellular localization

“…Chung et al [26] also showed that the HBx contributes to the transcriptional regulation of matrix metallopeptidase 9 through the ERK and PI3K-Akt/ PKB pathway, and increases the invasive potential of cells. In addition, the proliferation of HepG2 cells promoted by hepatitis B X-interacting protein (HBXIP) is associated with activation of the PI3K/Akt signaling pathway [27].…”