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Cancer Lett. 2016 Sep 28;380(1):98-105. doi: 10.1016/j.canlet.2016.06.011. Epub 2016 Jun 21.

The hepatitis B virus X protein promotes pancreatic cancer through modulation of the PI3K/AKT signaling pathway.

Author information

1
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang University; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address: liangtingbo@zju.edu.cn.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer, with poor outcomes. Infection with the hepatitis B virus (HBV) may be associated as a worse prognosis for PDAC patients; however, the mechanisms involved in this process are unclear. We evaluated whether HBV infection leads to PDAC with a more aggressive phenotype, and attempted to elucidate the mechanisms involved. Clinicopathological data and outcomes from 64 patients with PDAC were collected and compared between serum HBsAg+ and HBsAg- patients. Furthermore, we examined the effects of the HBV X protein (HBx) on proliferation and migration of the pancreatic cancer cell lines PANC-1 and SW1990. We investigated expression changes of over 500 proteins by protein array analysis and identified several HBV- and PDAC-related candidates, which were further validated by immunoblotting and enzyme-linked immunosorbent assay. No differences in clinicopathological features were observed between HBsAg+ and HBsAg- patients; however, HBsAg+ patients had a shorter median survival time (8 vs. 13 months), although the differences were not significant. HBV DNA was detected in clinical specimens, even in PDAC patients considered "HBV-free", potentially due to occult infection. HBx expression significantly enhanced cellular proliferation and migration and induced an epithelial-mesenchymal transition phenotype. Expression of ErbB4 and TGF-α was increased in parallel with HBx expression, and several downstream pathways including PI3K/AKT, MAPK, and ERK were upregulated. Inhibition of the PI3K/AKT pathway reversed the effects of HBx in PDAC cell lines. HBx may, therefore, contribute to the progression of PDAC through modulation of these pathways.

KEYWORDS:

HBx; Migration; PI3K/AKT signaling; Risk factor; Survival

PMID:
27339327
DOI:
10.1016/j.canlet.2016.06.011
[Indexed for MEDLINE]

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