title: The hepatitis B virus X protein promotes pancreatic cancer through modulation of the PI3K/AKT signaling pathway.
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.
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Su
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qihan
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Jingying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Tingbo
authors.initials: T
authors.lastname: Liang
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000473:pathology / Q000601:surgery / Q000821:virology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006509:Hepatitis B / Q000150:complications / Q000378:metabolism* / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D053208:Kaplan-Meier Estimate; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery / Q000821:virology; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066247:Receptor, ErbB-4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D006514:Hepatitis B Surface Antigens; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D058539:Phosphatidylinositol 3-Kinase; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: HBx; Migration; PI3K/AKT signaling; Risk factor; Survival