PTEN modulates insulin-like growth factor II (IGF-II)-mediated signaling; the protein phosphatase activity of PTEN downregulates IGF-II expression in hepatoma cells

Abstract

The PTEN gene (phosphatase and tensin homologous on chromosome 10) is frequently mutated or deleted in a number of malignancies including human hepatocellular carcinoma (HCC). We reported previously that the hepatitis B virus X (HBx) protein, known to be a causative agent in the formation of HCC, activates insulin-like growth factor II (IGF-II) expression through Sp1 phosphorylation by protein kinase C (PKC) or mitogen-activated protein kinase (MAPK) signaling. In this report we demonstrate that the PTEN effect on HBx induced IGF-II activation in a hepatoma cell line. Expression of PTEN and IGF-II was inversely related in different hepatoma cell lines. PTEN expression induced decreased Sp1 DNA binding by dephosphorylating Sp1 and interfered with transcriptional transactivation of IGF-II by HBx in hepatoma cells. The protein phosphatase activity was involved in PTEN downregulation of IGF-II transcription through downregulation of MAPK, MAPK kinase phosphorylation and PKC translocation. Our data suggest that PTEN blocks Sp1 phosphorylation in response to HBx, by inactivating PKC, MAPK and MAPK kinase which eventually downregulate IGF-II expression, during the formation of HCC.