SHP2 is induced by the HBx-NF-κB pathway and contributes to fibrosis during human early hepatocellular carcinoma development
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Hyo Jeong Kang1,*, Dal-Hee Chung1,2,*, Chang Ohk Sung1, Su Hyun Yoo1, Eunsil Yu1, Nayoung Kim2, Sy-Hye Lee2, Ji-Young Song2, Chong Jai Kim1, Jene Choi1
1Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
2Asan Institute for Life Science, Asan Medical Center, Seoul, Korea
*These authors have contributed equally to this work
Jene Choi, email: firstname.lastname@example.org
Keywords: SHP2, NF-κB, hepatitis B virus, cirrhosis, hepatocellular carcinoma
Received: March 18, 2016 Accepted: February 20, 2017 Published: March 06, 2017
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-κB pathway to EGFR signaling during HCC development. The overexpression of HBx or NF-κB led to increased SHP2 expression via NF-κB 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-κB–SHP2–ERK activation and phosphorylated STAT3 levels exhibited a negative correlation in vitro. By contrast, in patients with HBV-associated HCC, NF-κB–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-κB–SHP2 pathway, linking HBV infection to the EGFR–RAS–RAF–MAPK pathway in the liver. SHP2 depletion from the negative crosstalk between NF-κB and STAT3 accelerates HCC development.
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