ABSTRACT
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-tumor activity. Human Beta Defensin-1 (hBD-1), an important component of the innate immune response, is lost at high frequencies in malignant prostatic tissue, while high levels of expression are maintained in adjacent benign regions. In prostate carcinoma, frequent genetic alterations occur in the 8p22-23 region and several studies indicate there may be multiple tumor suppressor genes present within this region. The high incidence of loss of hBD-1 expression in prostate cancer, along with its chromosomal location of 8p23.2, raised the possibility that it may play a role in tumor suppression. To gain insight as to its function in prostate cancer, hBD-1 was cloned and ectopically expressed in four prostate cancer cell lines. Induction of hBD-1 expression resulted in a decrease in cellular growth in DU145 and PC3 cells. However, hBD-1 has no effect on the growth of androgen receptor (AR) positive LNCaP prostate cancer cells, but was again growth suppressive to PC3 cells with ectopic AR expression (PC3/AR+). hBD-1 also caused rapid induction of cytolysis and caspase-mediated apoptosis in DU145 and PC3 prostate cancer cells. Although the regulation of hBD-1 was not addressed in this study, our preliminary data demonstrated that the pathways involved may include cMYC and PAX2. Data presented here are the first to provide evidence of its potential role in prostate cancer cell death.
Subject(s)
Apoptosis/immunology , Immunity, Innate , Prostatic Neoplasms/immunology , Tumor Suppressor Proteins/immunology , beta-Defensins/immunology , Apoptosis/genetics , Cell Death/genetics , Cell Death/immunology , Cell Line, Tumor , Chromosome Aberrations , Chromosomes, Human, Pair 8/genetics , Chromosomes, Human, Pair 8/immunology , Cloning, Molecular , Gene Expression , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/immunology , Humans , Immunity, Innate/genetics , Male , PAX2 Transcription Factor/genetics , PAX2 Transcription Factor/immunology , PAX2 Transcription Factor/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/immunology , Proto-Oncogene Proteins c-myc/metabolism , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/genetics , beta-Defensins/biosynthesis , beta-Defensins/geneticsABSTRACT
In a previous large-scale gene expression profiling study of renal epithelial neoplasms, human beta-defensin-1 (DEFB1) was found to be significantly down-regulated in conventional clear cell (renal) carcinoma. We have now completed an expanded expression analysis of this gene. We performed immunohistochemical analysis for the DEFB1 protein in clinical specimens of both renal cell carcinoma and prostate cancer. In a subset of prostate cancers, we performed laser capture microdissection and RT-PCR to correlate mRNA levels with protein levels. Overall, 82% of prostate cancers exhibit either complete loss of protein expression or only minimal expression, whereas the adjacent benign epithelium retained expression in all cases. Similarly, 90% of renal cell carcinomas show cancer-specific loss of DEFB1 protein. In the prostate cancer subset analysis, mRNA levels correlate with protein levels. We have thus demonstrated the cancer-specific down-regulation of DEFB1 in a large sample of prostatic and renal carcinomas and validated one of the key findings of previous cancer gene profiling studies of prostatic and renal neoplasia.
