Role of TMPRSS2-ERG Gene Fusion in Negative Regulation of PSMA Expression

Prostate specific membrane antigen (PSMA) is overexpressed in prostatic adenocarcinoma (CaP), and its expression is negatively regulated by androgen stimulation. However, it is still unclear which factors are involved in this downregulation. TMPRSS2-ERG fusion is the most common known gene rearrangement in prostate carcinoma. Androgen stimulation can increase expression of the TMPRSS2-ERG fusion in fusion positive prostate cancer cells. The purpose of this investigation is to determine whether PSMA expression can be regulated by the TMPRSS2-ERG gene fusion. We employed two PSMA positive cell lines: VCaP cells, which harbor TMPRSS2-ERG fusion, and LNCaP cells, which lack the fusion. After 24 hours of androgen treatment, TMPRSS2-ERG mRNA level was increased in VCaP cells. PSMA mRNA level was dramatically decreased in VCaP cells, while it only has moderate change in LNCaP cells. Treatment with the androgen antagonist flutamide partially restored PSMA expression in androgen-treated VCaP cells. Knocking down ERG by siRNA in VCaP cells enhances PSMA expression both in the presence and absence of synthetic androgen R1881. Overexpressing TMPRSS2-ERG fusions in LNCaP cells downregulated PSMA both in the presence or absence of R1881, while overexpressing wild type ERG did not. Using PSMA-based luciferase reporter assays, we found TMPRSS2-ERG fusion can inhibit PSMA activity at the transcriptional level. Our data indicated that downregulation of PSMA in androgen-treated VCaP cells appears partially mediated by TMPRSS2-ERG gene fusion

Association of Pro/Anti-inflammatory Cytokine Gene Polymorphisms with Benign Prostate Hyperplasia Risk

Benign prostate hyperplasia (BPH) is a common condition in aged men and result from prolong chronic inflammation in prostate gland. Cytokines are important molecules responsible for inflammation. Single nucleotide polymorphisms (SNPs) in promoter region of cytokine genes have been shown to alter the level of cytokines. Hence we evaluated the association of pro-inflammatory and anti-inflammatory cytokine SNPs in a North Indian cohort of BPH patients. We observed that IL-1B −511 CT + TT genotypes conferred protective effect for susceptibility to BPH (OR 0.39, P 0.001). Our results also demonstrated that TNF-A −1031 C allele to be associated with risk for BPH (OR 1.89, P < 0.0001). Moreover, we also observed twofold risk for IL-10 −1082 cytokine gene polymorphism (OR 1.96, P 0.048). No association was observed with risk of BPH for IFN-G +874, IL-1 RN VNTR, IL-6 −174, IL-10 −819 and TGF-B +28. Our findings of IL-1B −511, TNF-A −1031 and IL-10 −1082 suggested that these variants play important role in susceptibility to BPH. Future studies in large cohort of different ethnicity BPH groups are warranted to establish definite associations with other cytokine gene polymorphisms as well