Novel role of human beta defensin-1 as a tumor suppressor that may be part of the innate immune system involved in tumor immunity

Abstract

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Although it is known that innate immunity is key for protecting the body against foreign agents such as bacteria, little is known about elements of the innate immune system that have anti-tumoral activity. Defensins are small 3-4 kDa peptides clustered on the short arm of chromosome 8 (segment 8p22-8p23) that have been shown to have antimicrobial and antiviral activities. It has been demonstrated that there are chromosomal deletions in the 8pter-p23 regions in a variety of cancers including prostatic carcinoma. Additionally, there is a positive correlation between deletions in 8pter-p23 region and poor prognosis in prostate cancer. Furthermore, it has been postulated that there may be three separate potential tumor suppressor genes located in the 8pter-8p23 region. However, no specific gene has been identified that function in prostate cancer. Human β-defensin-1 (DEFB1) is located at chromosome position 8p23.2. We have previously demonstrated that there is cancer-specific loss of DEFB1 in malignant prostatic clinical samples, while high levels of expression are maintained in benign regions. Overall, 82% of prostate cancers exhibit either complete loss of DEFB1 protein expression or only minimal expression, while the adjacent benign epithelium retained expression in all cases. The high incidence of loss of DEFB1 expression in prostate cancer, along with its chromosomal location of 8p23.2, raised the possibility that it may be a tumor suppressor gene (TSG). To gain insight in its role in prostate cancer, DEFB1 was cloned into an inducible expression system to examine what effect it had on prostate cancer cell lines. In addition, DEFB1 expression levels were measured in prostatic tissue from patients that underwent radical prostatectomy to determine expression levels in benign tissue. The DEFB1 expression system was adjusted to produce DEFB1 protein in prostate cancer cells similar to those found in benign tissue. Induction of DEFB1 expression resulted in rapid morphological changes in both PC3 and DU145. In addition, there was a decrease in cellular growth and an accumulation of apoptotic and necrotic cells. Our findings suggest that DEFB1 may be a TSG and its loss may contribute to tumorigenesis in prostate cancer.