Original ArticlesThe hepatitis B virus X protein promotes pancreatic cancer through modulation of the PI3K/AKT signaling pathway
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is the cancer with the worst prognosis. Recent advances in diagnostics and therapy have failed to satisfactorily improve the overall survival (OS) of this lethal disease, with a 5-year OS of only 8%, even in the US [1]. Several risk factors have been identified for pancreatic cancer, including cigarette smoking, diabetes mellitus, obesity, heavy alcohol use, and pancreatitis [2].
Viral infection is a common risk factor for multiple types of cancer. It has been estimated that chronic viral infection contributes to 15–20% of cancers, such as hepatitis B virus (HBV)- and hepatitis C virus-related liver cancers, human papilloma virus-related cervical cancer, Epstein–Barr virus-related Burkitt lymphoma and nasopharynx cancer, and human immunodeficiency virus-related Kaposi's sarcoma and non-Hodgkin's lymphoma [3]. Complicated mechanisms including the induction of inflammation and genome disturbance are involved in virus-associated cancers [4], [5]. The role of viral infection in pancreatic cancer has also been explored [6], [7], [8], [9]. Recently, there have been an increasing number of epidemiological studies on the association between the well-known oncogenic virus, HBV, and PDAC, although the relationship between the two remains unclear. The majority of these studies determined that HBV infection was an independent risk factor and prognostic factor for PDAC patients, and suggested a unique subtype of PDAC with a worse prognosis [3], [8], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. However, other studies found no association between HBV infection and PDAC [20], [21], [22], [23], [24]. HBV is a liver-tropic virus, but previous studies have demonstrated its capacity to invade extra-hepatic organs including the pancreas [25], [26], [27]. While the biological significance of this phenomenon is under debate, Lang and colleagues proposed that the harboring of HBV in extra-hepatic tissues serves as an extra-hepatic source of virus without the pathological consequences on the infected extra-hepatic organs [26]. Yoshimura and colleagues, however, found that HBV DNA, HBV surface antigen (HBsAg), replication intermediates and antibodies could be detected in the pancreatic fluid and pancreatic tissue of chronic pancreatitis or PDAC patients with HBV infection [27], suggesting that HBV could replicate in pancreatic cells. In addition, this result also implied that HBV infection in the pancreas is a chronic process and that the pancreas is capable of accommodating HBV replication. This could result in pancreatic damage and provide a mechanism through which HBV infection could result in a worse prognosis for PDAC patients. Given the same origin (endodermal pluripotent stem cells) of the liver and pancreas during the early stages of embryogenesis, it is possible that the two organs share multiple genetic traits and may have similar responses to HBV. Furthermore, previous studies have shown that HBV infection increased the rate of synchronous liver metastasis and was an independent prognostic factor in PDAC [14]. Together these studies indicate that HBV infection could be an aggravating factor for PDAC.
The relation between HBV and liver cancer has been extensively studied. The hepatitis B virus X protein (HBx), a small 17-kDa soluble protein encoded by the HBV X gene, is essential for HBV-related oncogenesis in the liver [28], [29]. Previous studies on hepatic cancer showed that HBx was a general trans-activator and played a significant role in intracellular signal transduction, viral replication, cell cycle progression, cellular proliferation and apoptosis, protein degradation and the genetic stability of liver cells [28], [30], [31]. In this study, we evaluated HBV as a potential aggravating factor for PDAC and identified the mechanisms through which HBx could influence PDAC progression.
Section snippets
Clinical data collection
Samples from sixty-four patients with PDAC confirmed by pathology were collected between 2013 and 2014 at the Second Affiliated Hospital, Zhejiang University School of Medicine. Two patients died of other diseases following surgery and were excluded from the survival analysis. Six patients were lost to follow-up. The demographic, clinical, pathological data and outcomes were collected under the supervision of the institutional ethics committee. HBV infection was evaluated by serum HBsAg,
PDAC patients with serum HBsAg+ appear to show a worse prognosis
No differences are observed with regards to T stage, vascular invasion, lymph node metastasis, and peri-neural invasion between PDAC patients with serum HBsAg− or HBsAg+. Overall survival (OS) is shorter in patients with serum HBsAg+ (median survival time, 8 vs. 13 months, P = 0.310, Fig. 1A). Since overall survival can be affected by postoperative treatments, such as chemotherapy, stratification analysis, according to the frequency of chemotherapy (<12 times, and ≥12 times), was applied to
Discussion
Although several epidemiological studies have suggested a link between HBV and pancreatic cancer, the extent of this relationship is still unknown. HBV infection is a complex process that is incompletely understood. HBV infection can be latent and the virus can exert effects prior to detection. Occult HBV infection is characterized by negative serum HBsAg but positive serum HBV DNA or tissue HBV DNA [37]. Epidemiological studies of HBV infection in China showed that, in patients with occult HBV
Authors' contributions
Tingbo Liang, Xueli Bai and Qi Zhang conceived the idea. Yiwen Chen, Xueli Bai, Liang Wen, Wei Su, Qihan Fu, Xu Sun, Yu Lou, Jiaqi Yang, Jingying Zhang, Qi Chen, and Jianxin Wang performed the experiments. Yiwen Chen and Qi Zhang analyzed the data and wrote the manuscript. All authors approved the manuscript.
Conflict of interest
None.
Acknowledgments
This work was financially supported by the National High Technology Research and Development Program of China (SS2015AA020405), the Training Program of the Major Research Plan of the National Natural Science Foundation of China (91442115), the Key Innovative Team for the Diagnosis and Treatment of Pancreatic Cancer of Zhejiang Province (2013TD06), the National Natural Science Foundation of China (81401954), the Zhejiang Provincial Natural Science Foundation (LY14H160034 and LY13H160012), and
References (43)
- et al.
Hepatitis B and C virus infections as possible risk factor for pancreatic adenocarcinoma
Med. Hypotheses
(2012) - et al.
Chronic hepatitis virus infection increases the risk of pancreatic cancer: a meta-analysis
Hepatobiliary Pancreat. Dis. Int
(2013) - et al.
Association between hepatitis B or hepatitis C virus infection and risk of pancreatic adenocarcinoma development: a systematic review and meta-analysis
Pancreatology
(2013) - et al.
Identification and impact of hepatitis B virus DNA and antigens in pancreatic cancer tissues and adjacent non-cancerous tissues
Cancer Lett
(2013) - et al.
Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis
Adv. Cancer Res
(2009) - et al.
A 2010 update on occult hepatitis B infection
Pathol. Biol. (Paris)
(2010) - et al.
Cancer statistics
CA Cancer J. Clin
(2016) - et al.
Recent progress in pancreatic cancer
CA Cancer J. Clin
(2013) - et al.
Chronic inflammation: a common and important factor in the pathogenesis of neoplasia
CA Cancer J. Clin
(2006) - et al.
Inflammation and cancer: an ancient link with novel potentials
Int. J. Cancer
(2007)
Association between Helicobacter pylori infection and pancreatic cancer. A cumulative meta-analysis
JOP
Association between Helicobacter pylori infection and pancreatic cancer development: a meta-analysis
PLoS ONE
Hepatitis B or C viral infection and risk of pancreatic cancer: a meta-analysis of observational studies
World J. Gastroenterol
HBV- and HCV-related infections and risk of pancreatic cancer
JOP
Hepatitis B virus status and the risk of pancreatic cancer: a meta-analysis
Eur. J. Cancer Prev
HBV infection increases the risk of pancreatic cancer: a meta-analysis
Cancer Causes Control
Association between hepatitis B virus and pancreatic cancer
J. Clin. Oncol
Are risk factors associated with outcomes in pancreatic cancer?
PLoS ONE
The status of HBV infection influences metastatic pattern and survival in Chinese patients with pancreatic cancer
J. Transl. Med
Hepatitis B virus status and risk of pancreatic ductal adenocarcinoma: a case-control study from China
Pancreas
ABO blood group, hepatitis B viral infection and risk of pancreatic cancer
Int. J. Cancer
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Yiwen Chen and Xueli Bai contributed equally to this work.