Title

Activation of signal transduction pathways during hepatic oncogenesis.

Publication Date

1-1-2016

Journal

Cancer Letters

DOI

10.1016/j.canlet.2015.09.016

PMID

26433160

PMCID

4684747

PubMedCentral® Posted Date

1-1-2017

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

no

Keywords

signal transduction pathways, hepatocellular carcinoma

Abstract

BACKGROUND AND AIMS: Understanding the molecular pathogenesis of hepatocellular carcinoma (HCC) is essential to identify therapeutic targets. A hepatitis B virus (HBV) related double transgenic murine model was developed. METHODS: Liver specific expression of HBV X protein (HBx) and insulin receptor substrate 1 (IRS1) was achieved and transgenic mice were followed from birth to age 21 months. Liver and tumor tissue were assessed for histologic changes as well as activation of signal transduction pathways by qRT-PCR and multiplex ELISA protein assays. RESULTS: Overexpression of HBx and IRS1 stimulates liver cell proliferation in the double transgenic mice. Only the male mice developed HCC starting at age 15-18 months. The IN/IGF1/IRS1/MAPK/ERK and IN/IGF1/IRS1/PI3K/AKT/GSK3ß cascades were activated early (6-9 months) in the liver followed by WNT/ß-catenin and Notch signaling. Aspartate ß-hydroxylase (ASPH) was found to link these upstream growth factor signaling pathways to downstream Notch activation in tumor tissues. CONCLUSIONS: Sustained overexpression of HBx and IRS1 led to constitutive activation of a tripartite growth factor signal transduction cascade in the liver and was necessary and sufficient to promote HCC development and progression.