Detection of serum hepatitis B Virus antigen and hepatitis C virus antibody from prostate cancer patients in Japan

Objective: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection increases hepatocellular carcinogenesis. Some studies suggest that HBV and HCV can activate androgen signaling. We assessed the association between hepatitis virus infection and prostate cancer in the Japanese population. Patients and methods: We retrospectively reviewed 212 patients who received needle biopsy of the prostate between 2013 and 2014. Hepatitis B surface antigen (HBsAg) and anti-HCV antibody in serum were evaluated by chemiluminescent immunoassay. Prostate cancer was detected in 182 (85.8%) patients. Results: Serum HBsAg was positive in one (0.5%) prostate cancer patient and one (3.3%) control patient (p = 0.264). Serum anti-HCV antibody was positive in four (2.2%) prostate cancer patients and one (3.3%) control patient (p = 0.537). Conclusions: Our results suggest that HBV and HCV infection is not associated with prostate cancer development and progression in Japanese patients. Abbreviations: HBV: hepatitis B virus; HCV: hepatitis C virus; HBsAg: hepatitis B surface antigen; HCC: hepatocellular carcinoma; AR: androgen receptor; CLIA: chemiluminescent immune assay; PSA: prostate-specific antigen; HBx: hepatitis B virus X Introduction Bacterial or viral infections may be involved in prostate cancer development and progression [1,2]. In particular, patients with hepatitis C virus (HCV) infection have a higher prevalence and mortality of prostate cancer [3-5]. Hepatitis B virus (HBV) and HCV are wellknown carcinogenic viruses in human hepatocellular carcinoma (HCC), and chronic infection increases HCC risk. In addition to these viruses, androgenic steroids might be responsible for HCC [6,7]. Some studies have shown that HBV/HCV infections promote androgen receptor (AR) signaling in HCC [8-14]. Prevalence of HBV-associated HCC is higher in men than women [15], supporting the association between AR signaling and HBV infection. AR signaling is essential for prostate cancer development and progression, therefore, its association with HBV/HCV infection might play an important role in prostate cancer development or progression. Here, we evaluated the association between HBV/HCV infection and prostate cancer in Japanese patients. Patients and methods Patients A total of 212 biopsy specimens were obtained from Yokohama City University Hospital and related hospitals. Thirty specimens were diagnosed as non-cancer tissues and 182 as prostate cancer. Each patient gave informed consent for the use of clinical information, and the study was approved by Yokohama City University Ethical Committee. Hepatitis B Surface Antigen (HBsAg) and Anti-HCV Antibody Detection To detect HBV and HCV infection, HBsAg and anti-HCV antibody were measured by chemiluminescent immune assay (CLIA), which is routinely used in our hospitals. The results of CLIA and related clinical information of each patient were used to detect HBV and HCV infection. Statistical analysis All statistical analysis was performed using PASW Statistics 18 (IBM Corp., Armonk, NY, USA). Age and prostate-specific antigen (PSA) level were tested for normality by Kolmogolov–Smirnov analysis. Then, the Mann–Whitney U test was used to test the association with cancer and normal samples. To test the association between each virus infection and clinical characteristics, we applied Fisher’s exact test. A value of p < 0.05 indicated statistical significance. Results Patient characteristics are listed in Table 1. Thirty non-cancer and Correspondence to: Hitoshi Ishiguro, Photocatalyst Group, Kanagawa Academy of Science and Technology, 3-25-13, Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, Japan. Tel: +81-44-280-1181, Fax: +81-44-280-1182, E-mail: pg-ishiguro@newkast.or.jp


Introduction
Bacterial or viral infections may be involved in prostate cancer development and progression [1,2].In particular, patients with hepatitis C virus (HCV) infection have a higher prevalence and mortality of prostate cancer [3][4][5].Hepatitis B virus (HBV) and HCV are wellknown carcinogenic viruses in human hepatocellular carcinoma (HCC), and chronic infection increases HCC risk.In addition to these viruses, androgenic steroids might be responsible for HCC [6,7].Some studies have shown that HBV/HCV infections promote androgen receptor (AR) signaling in HCC [8][9][10][11][12][13][14].Prevalence of HBV-associated HCC is higher in men than women [15], supporting the association between AR signaling and HBV infection.AR signaling is essential for prostate cancer development and progression, therefore, its association with HBV/HCV infection might play an important role in prostate cancer development or progression.Here, we evaluated the association between HBV/HCV infection and prostate cancer in Japanese patients.

Patients
A total of 212 biopsy specimens were obtained from Yokohama City University Hospital and related hospitals.Thirty specimens were diagnosed as non-cancer tissues and 182 as prostate cancer.Each patient gave informed consent for the use of clinical information, and the study was approved by Yokohama City University Ethical Committee.

Hepatitis B Surface Antigen (HBsAg) and Anti-HCV Antibody Detection
To detect HBV and HCV infection, HBsAg and anti-HCV antibody were measured by chemiluminescent immune assay (CLIA), which is routinely used in our hospitals.The results of CLIA and related clinical information of each patient were used to detect HBV and HCV infection.

Statistical analysis
All statistical analysis was performed using PASW Statistics 18 (IBM Corp., Armonk, NY, USA).Age and prostate-specific antigen (PSA) level were tested for normality by Kolmogolov-Smirnov analysis.Then, the Mann-Whitney U test was used to test the association with cancer and normal samples.To test the association between each virus infection and clinical characteristics, we applied Fisher's exact test.A value of p < 0.05 indicated statistical significance.

Discussion
In this study, we did not find any association between HBV and HCV infections and prostate cancer.In support of our results, other studies have also failed to show infection of HBV in prostate tissues [2,16].The association between HBV and AR activation in liver tissues or cells is reported.Hepatitis B virus X (HBx) protein regulates AR expression [9].HBx protein also regulates AR activity and androgendependent gene expression [10][11][12].Therefore, HBV might have a role in prostate cancer progression in some cases.Furthermore, some studies suggest the association between HCV infection and prostate cancer.Krystyna et al. [3] reported the association between HCV and prostate cancer in African and African-American individuals.HCV-positive patients have higher cancer prevalence and there is a correlation between HCV infection and prostate cancer progression [4,5].Kanda et al. [13] showed that HCV regulates androgen signaling through activation of signal transducer and activator of transcription 3. Thus, HCV also might be involved in prostate cancer development and progression through androgen signaling.
Although our study showed no significant associations between HBV and HCV and prostate cancer, it was limited by surveillance of clinical history.We did not distinguish patients with active infection from virus carriers.Therefore, further investigation is needed to clarify the importance of HBV and HCV infection in prostate cancer.

Conclusion
We investigated whether HBV and HCV infection is linked to prostate cancer progression.Although HBV and HCV infection could accelerate androgen signaling in HCC, virus infection was not prevalent in prostate cancer patients.Future work is needed to understand the 182 cancer cases were analyzed to detect HBV and HCV infection.Mean age was 67.0 ± 9.3 years in non-cancer patients and 68.3 ± 7.3 years in cancer patients.There was no significant difference between noncancer and cancer patients (p = 0.624).Mean PSA level was 7.5 ± 5.4 ng/ml in non-cancer patients and 42.1 ± 174.1 ng/ml in cancer patients.Thus, PSA level was marginally higher in the cancer group than normal group (p = 0.112).There were no cancer recurrences and cancer-related deaths in this study.Serum obtained from each patient was evaluated using CLIA by our hospital, regardless of whether prostate cancer patients had HBV or HCV infection.Results are summarized in Tables 2 and 3. HBV infection was detected only in one cancer case.This case had Gleason score 6 and clinical staging was T1cN0M0.There was no statistical significance between prostate cancer and HBV infection (p = 0.264).HCV infection was detected in four cancer cases and one noncancer case.All four HCV-infected cancer cases had Gleason score 7. Clinical staging of three cases was T1cN0M0 and one was T2N0M0.There was also no statistical significant between prostate cancer and HCV infection (p = 0.537).As a result of the low infection rate in our samples, we could not perform further statistical analyses to confirm the association between infection and clinical characteristics.

Table 1 .
Clinical characteristics of analyzed patients.

Table 2 .
Association between prostate cancer and HBsAg.

Table 3 .
Association between prostate cancer and HCV.biological mechanisms of prostate cancer progression in patients with HBV or HCV infection.