Hae Jong Kim

Expression of resistin in the prostate and its stimulatory effect on prostate cancer cell proliferation

What’s known on the subject? and What does the study add?

Expression of human β-defensin-2 in the prostate

What’s known on the subject? and What does the study add?

Genetic variations in VDR associated with prostate cancer risk and progression in a Korean population

Low levels of vitamin D are implicated as a potential risk factor for prostate cancer, and the vitamin D receptor (VDR) gene may be important in the onset and progression of prostate cancer. In this study, sequence variants in the VDR gene were investigated in a Korean study cohort to determine whether they are associated with prostate cancer risk. We evaluated the association between 47 single nucleotide polymorphisms (SNPs) in the VDR gene and prostate cancer risk as well as clinical characteristics (prostate-specific antigen level, clinical stage, pathological stage and Gleason score) in Korean men (272 prostate cancer patients and 173 benign prostatic hyperplasia patient who underwent a prostate biopsy, which was negative for malignancy) using unconditional logistic regression. The statistical analysis suggested that two VDR sequence variants (rs2408876 and rs2239182) had a significant association with prostate cancer risk (odds ratio [OR]. 1.41; p=0.03; OR, 0.73; p=0.05, respectively). Logistic analyses of the VDR polymorphisms with several prostate cancer related factors showed that several SNPs were significant; nine SNPs to PSA level, three to clinical stage, two to pathological stage, and three SNPs to the Gleason score. The results suggest that some VDR gene polymorphisms in Korean men might not only be associated with prostate cancer risk but also significantly related to prostate cancer-related risk factors such as PSA level, tumor stage, and Gleason score. However, current limitation for small cohort with not-healthy control group might have false positive effects; therefore it should be overcome via further large-scale validating studies.

Single nucleotide polymorphisms in fibroblast growth factor 23 gene, FGF23, are associated with prostate cancer risk

To determine whether sequence variants within the FGF23 gene are associated with the risk of developing prostate cancer in a Korean population.

HNF1B Polymorphism Associated With Development of Prostate Cancer in Korean Patients

OBJECTIVE To identify whether the genetic variations in HNF1B are associated with the development of prostate cancer in Korean patients. Genome-wide association studies have found the HNF1B gene at 17q12 to be a major causal gene for the risk of prostate cancer. METHODS We evaluated the association of 47 single nucleotide polymorphisms (SNPs) in the HNF1B gene with prostate cancer risk and clinical characteristics (Gleason score and tumor stage) in Korean men (240 case subjects and 223 control subjects) using unconditional logistic regression analysis. RESULTS Of the 47 SNPs, 14 were associated with prostate cancer risk (P = .002-.02); 9 SNPs were associated with a lower risk of prostate cancer (odds ratio 0.67-0.71, P = .005-.05), and 5 SNPs were associated with a greater risk of disease (odds ratio 1.49-1.51, P = .002-.02). In an analysis involving only patients with prostate cancer, 1 SNP (rs11868513) in the HNF1B gene was more frequent in patients with tumors with a greater stage than in those with a lower tumor stage. Two SNPs (rs4430796 and rs2074429) and 1 haplotype (Block3_ht1) were more frequent in patients with Gleason score of ≥7 than in those with Gleason score <6. CONCLUSION As in studies from other populations, our findings indicate that HNF1B is also associated with prostate cancer risk in the Korean population.

Single nucleotide polymorphisms in DKK3 gene are associated with prostate cancer risk and progression

ABSTRACT We had investigated whether sequence variants within DKK3 gene are associated with the development of prostate cancer in a Korean study cohort. We evaluated the association between 53 single nucleotide polymorphisms (SNPs) in the DKK3 gene and prostate cancer risk as well as clinical characteristics (PSA, clinical stage, pathological stage and Gleason score) in Korean men (272 prostate cancer subjects and 173 benign prostate hyperplasia subjects) using unconditional logistic regression analysis. Of the 53 SNPs and 25 common haplotypes, 5 SNPs and 4 haplotypes were associated with prostate cancer risk (P=0.02–0.04); 3 SNPs and 2 haplotypes were significantly associated with susceptibility to prostate cancer, however 2 SNPs and 2 haplotypes exhibited a significant protective effect on prostate cancer. Logistic analyses of the DKK3 gene polymorphisms with several prostate cancer related factors showed that several SNPs were significant; three SNPs and two haplotypes to PSA level, three SNPs and two haplotypes to clinical stage, nine SNPs and two haplotype to pathological stage, one SNP and one haplotypes to Gleason score. To the authors knowledge, this is the first report documenting that DKK3 polymorphisms are not only associated with prostate cancer but also related to prostate cancer-related factors.

Association between cytochrome CYP17A1, CYP3A4, and CYP3A43 polymorphisms and prostate cancer risk and aggressiveness in a Korean study population.

In this study, we evaluated genetic variants of the androgen metabolism genes CYP17A1, CYP3A4, and CYP3A43 to determine whether they play a role in the development of prostate cancer (PCa) in Korean men. The study population included 240 pathologically diagnosed cases of PCa and 223 age-matched controls. Among the 789 single-nucleotide polymorphism (SNP) database variants detected, 129 were reported in two Asian groups (Han Chinese and Japanese) in the HapMap database. Only 21 polymorphisms of CYP17A1, CYP3A4, and CYP3A43 were selected based on linkage disequilibrium in Asians (r2 = 1), locations (SNPs in exons were preferred), and amino acid changes and were assessed. In addition, we performed haplotype analysis for the 21 SNPs in CYP17A1, CYP3A4, and CYP3A43 genes. To determine the association between genotype and haplotype distributions of patients and controls, logistic analyses were carried out, controlling for age. Twelve sequence variants and five major haplotypes were identified in CYP17A1. Five sequence variants and two major haplotypes were identified in CYP3A4. Four sequence variants and four major haplotypes were observed in CYP3A43. CYP17A1 haplotype-2 (Ht-2) (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.04-2.18) was associated with PCa susceptibility. CYP3A4 Ht-2 (OR: 1.87; 95% CI: 1.02-3.43) was associated with PCa metastatic potential according to tumor stage. rs17115149 (OR: 1.96; 95% CI: 1.04-3.68) and CYP17A1 Ht-4 (OR: 2.01; 95% CI: 1.07-4.11) showed a significant association with histologic aggressiveness according to Gleason score. Genetic variants of CYP17A1 and CYP3A4 may play a role in the development of PCa in Korean men.

Effect of low concentrations of hydrogen peroxide on the contractile responses of rat detrusor smooth muscle strips.

This study was designed to determine how the contractility of rat detrusor smooth muscle strips changes in the presence of low concentrations of hydrogen peroxide (H(2)O(2)). The strips were dissected from the base of Sprague-Dawley rat bladders and their contractile responses to a cumulative increase in H(2)O(2) concentration (3 x 10(-6)-3 x 10(-2)g%) were measured. How the duration of exposure to the fixed concentration of 3 x 10(-4)g% H(2)O(2) affected contractility was also examined. Moreover, the effect of 3 x 10(-4)g% H(2)O(2) pretreatment on the response to cumulative increases in the concentrations of phenylephrine or acetylcholine (10(-8)-10(-4)M) was assessed. To elucidate the mechanism by which H(2)O(2) induced contraction, we examined the effect of pretreatment with 10nM Y-27632, 10 microM indomethacin, 10 microM SQ29548, 10 microM verapamil, 10 microM vitamin E, or 1 microM Bay-K 8644 on the contractile responses generated by cumulatively increasing the concentration of H(2)O(2). H(2)O(2)-induced contractile responses in Ca(2+)-free physiological solution were also examined. Low concentrations of H(2)O(2) increased the contractile responses of the strips in a dose-dependent manner but increasing treatment duration decreased these responses. H(2)O(2)-pretreatment significantly augmented the contraction induced by phenylephrine (P<0.05) but had no effect on the response to acetylcholine. Pretreatment with Y-27632, indomethacin, vitamin E, verapamil, and Bay-K 8644 significantly inhibited the H(2)O(2)-induced contraction (P<0.05). SQ 29548-pretreatment had no effect. H(2)O(2) could not increase the contractile responses in Ca(2+)-free physiological solution. Thus, low concentrations of H(2)O(2) may directly affect detrusor smooth muscles and thereby induce detrusor overactivity.

Zinc induces LPS-mediated upregulation of HBD-2 via ERK1/2 and p38MAPK signaling pathways in human prostate epithelial cells

ABSTRACT This study aimed to clarify the role of zinc in human prostate epithelial cell defense against bacterial infection. To explore the effect of zinc on lipopolysaccharide (LPS)-mediated induction of human β-defensin-2 (HBD-2), the normal human prostate epithelial cell lines (RWPE-1) were co-treated with zinc/LPS and HBD-2 mRNA expression was quantitated by the reverse transcription polymerase chain reaction (RT-PCR). We also conducted a Western blot analysis to determine whether zinc stimulates p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase-1 and -2 (ERK1/2) signaling pathways. To investigate the involvement of the p38MAPK and ERK1/2 signaling pathways in zinc-mediated upregulation of HBD-2, quantitative real-time PCR and immunocytochemical staining were then used to quantify HBD-2 mRNA expression and protein production, respectively, which was treated with either U0126 (ERK1/2 inhibitor) or SB203580 (p38MAPK inhibitor) prior to each analysis of HBD-2. Cotreatment of RWPE-1 cells with zinc/LPS-upregulated HBD-2 expression to an even greater extent than either LPS alone or zinc alone. Moreover, the treatment of RWPE-1 cells with zinc significantly increased both the total and phosphorylated forms of ERK1/2 and p38MAPK. ERK1/2 and p38MAPK signaling via the inhibitors U0126 and SB203580 pharmacologically inhibited zinc-mediated upregulation of HBD-2. These results strongly suggest that zinc plays an important role in the immune response of the prostate. Furthermore, we demonstrate that zinc-mediated upregulation of HBD-2 expression upon bacterial infection of prostate epithelial cells involves the ERK1/2 and p38MAPK signaling pathways.

Expression of Beta-Defensin 131 Promotes an Innate Immune Response in Human Prostate Epithelial Cells.

Previously, using the Illumina HumanHT-12 microarray we found that β-defensin 131 (DEFB131), an antimicrobial peptide, is upregulated in the human prostate epithelial cell line RWPE-1 upon stimulation with lipoteichoic acid (LTA; a gram-positive bacterial component), than that in the untreated RWPE-1 cells. In the current study, we aimed to investigate the role of DEFB131 in RWPE-1 cells during bacterial infection. We examined the intracellular signaling pathways and nuclear responses in RWPE-1 cells that contribute to DEFB131 gene induction upon stimulation with LTA. Chromatin immunoprecipitation was performed to determine whether NF-κB directly binds to the DEFB131 promoter after LTA stimulation in RWPE-1 cells. We found that DEFB131 expression was induced by LTA stimulation through TLR2 and p38MAPK/NF-κB activation, which was evident in the phosphorylation of both p38MAPK and IκBα. We also found that SB203580 and Bay11-7082, inhibitors of p38MAPK and NF-κB, respectively, suppressed LTA-induced DEFB131 expression. The chromatin immunoprecipitation assay showed that NF-κB directly binds to the DEFB131 promoter, suggesting that NF-κB is a direct regulator, and is necessary for LTA-induced DEFB131 expression in RWPE-1 cells. Interestingly, with DEFB131 overexpression in RWPE-1 cells, the accumulation of mRNA and protein secretion of cytokines (IL-1α, IL-1β, IL-6, and IL-12α) and chemokines (CCL20, CCL22, and CXCL8) were significantly enhanced. In addition, DEFB131-transfected RWPE-1 cells markedly induced chemotactic activity in THP-1 monocytes. We concluded that DEFB131 induces cytokine and chemokine upregulation through the TLR2/NF-κB signaling pathway in RWPE-1 cells during bacterial infection and promotes an innate immune response.