SHP2 is induced by the HBx-NF-?B pathway and contributes to fibrosis during human early hepatocellular carcinoma development.

ABSTRACT: The non-receptor tyrosine phosphatase SHP2 has scaffolding functions in signal transduction cascades downstream of growth receptors. A recent study suggested that SHP2 acts as a tumor suppressor during hepatocellular carcinoma (HCC) development. Herein we examined whether SHP2 links the HBx-NF-?B pathway to EGFR signaling during HCC development. The overexpression of HBx or NF-?B led to increased SHP2 expression via NF-?B binding to the Shp2 promoter. EGF treatment induced ERK activation as well as the rapid assembly of SHP2, EGFR, and Gab1. Upon LPS stimulation, NF-?B-SHP2-ERK activation and phosphorylated STAT3 levels exhibited a negative correlation in vitro. By contrast, in patients with HBV-associated HCC, NF-?B-SHP2-ERK and IL-6-JAK-STAT3 pathway activity levels were concomitantly higher in adjacent non-neoplastic tissues than in HCC tissues. The immunohistochemical analysis of 162 tissues of patients with HCC revealed that SHP2 levels were significantly higher in non-neoplastic background tissues than in corresponding HCC tissues and considerably increased in background liver tissues with advanced fibrosis (P < 0.001). SHP2 expression increased gradually from normal liver to chronic hepatitis, cirrhosis, and background liver with a dysplastic nodule, but was decreased or lost in dysplastic nodules and HCC. This is the first report to describe the existence of the HBx-NF-?B-SHP2 pathway, linking HBV infection to the EGFR-RAS-RAF-MAPK pathway in the liver. SHP2 depletion from the negative crosstalk between NF-?B and STAT3 accelerates HCC development.

SUBMITTER: Kang HJ 

PROVIDER: S-EPMC5432333 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature