Study On The Influence Of Hepatitis B Virus X Protein On Pancreatic Cancer Cells And Related Mechanisms

Introduction:Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive and lethal cancer, with a poor prognosis. To date, several risk factors of PDAC have been identified. Recently, increasing evidence from epidemiological researches suggest that the well-known oncogenic virus, hepatitis B virus (HBV), may be associated with a special type of PDAC with a worse prognosis; However, the mechanism is unknown. In addition, available studies showed Hepatitis B virus X (HBx) was essential for HBV induced carcinogenesis. The aim of our study is to evaluate whether HBV infection can lead to PDAC with more aggressive phenotype, and try to notify its mechanisms.Methods:Sixty-two patients with pathologically proved PDAC were collected and demographic, clinical, pathological and outcome data were compared between HBV infected patients and HBV-free patients. PCR was used to detect HBV DNA in DNA extractions of clinical specimens. Using PANC-1, SW1990 pancreatic cancer cell lines with or without HBx-plasmid transfection, we evaluated the cell ability of proliferation and migration in vitro. We used protein array to investigate the expression changes of more than 500 proteins, and selected several HBV-and PADC-related candidates, which were further tested and verified by immunoblotting and enzyme-linked immunosorbent assay.Results:No differences in clinicopathological factors were observed between patients with or without serum HBsAg. However, HBsAg (+) PDAC patients tended to have a shorter median survival time (8vs.13 months). HBV DNA could be detected in clinical specimens, even in serum HBV-marker-negtive PDAC patients. Transfection of HBx significantly enhanced cell proliferation and migration, with an epithelial-mesenchymal transition phenotype. ErbB4 and TGF-a were increased in parallel with HBx expression, and several downstream pathways including PI3K/AKT, MAPK, and ERK, were elevated. Furthermore, inhibition of PI3K/AKT pathway could eliminate the effect of HBx on PDAC cell lines.Conclusion:PDAC patients with serum HBsAg+had a potentially worse prognosis, though with insignificant difference. The difference may be more remarkable if we could distinguish real HBV infected patients, including occult HBV infection, from these who were real HBV-free. HBx could increase the malignancy of PDAC by PI3K/AKT and other signaling pathways.Further investigations are needed to develop a direct and better understanding of the underlying mechanism between HBV infection and PDAC.