Human β-Defensin-1, a Potential Chromosome 8p Tumor Suppressor: Control of Transcription and Induction of Apoptosis in Renal Cell Carcinoma

Abstract

Human b-defensin-1 (hBD-1) is a candidate tumor suppressor gene located on chromosome 8p23. Previously, we showed that cancer-specific loss of hBD-1 was found in 90% of renal clear cell carcinomas and in 82% of prostate cancers. To investigate the possible mechanisms of decreased gene expression and determine the function of hBD-1 protein in urological cancers, we sequenced hBD-1 gene coding regions in prostatic and renal cancer samples. We then analyzed the frequency distribution of promoter polymorphisms and determined the effect of these base changes on transcriptional activity of the hBD-1 promoter. A polymorphism at À688 bases upstream of the ATG start codon affects hBD-1 promoter activity, leading to a rate of reporter gene transcription that is 40% to 50% lower than the wild-type sequence when tested in either DU145 or TSU-Pr1 cell lines. In addition, a polymorphism at À44 bases was shown to enhance transcription up to 2.3 times more than the wild-type sequence in the same cell lines. In addition, three novel hBD-1 promoter mutations were found in renal and prostate cancer clinical samples. An iso-5-aza-2 ¶-deoxycytidine treatment was effective in transcription up-regulation in DU145, suggesting a possible upstream methylation-dependent effect. Synthetic hBD-1 peptide inhibited bladder cancer cell TSU-Pr1 proliferation. Overexpression of the hBD-1 gene in renal cancer cells SW156 resulted in caspase-3-mediated apoptosis. These data support the hypothesis that hBD-1 is a potential tumor suppressor gene for urological cancers. Promoter point mutations may be responsible for cancer-specific loss of hDB-1 expression.

Genomic variations within DEFB1 are associated with the susceptibility to and the fatal outcome of severe sepsis in Chinese Han population

“…30 The À44C/G variation, which was located in the 5 0 -UTR of DEFB1, has been implicated in the pathogenesis of infections with HIV and Candida. 24,28 In this study, it is noteworthy that, even with a standard Bonferroni correction for multiple tests on the five SNPs and three haplotypes, the P-values for the association of À44G/C and haplotype À20G/À44G/À52G as well as haplotype À20A/À44C/À52G with related phenotypes are still significant.…”

“…This strongly supports the significance of the present findings. Using reporter gene constructs analysis, a very recent study demonstrated that the À44G/ C polymorphism did influence the promoter activity of DEFB1, 30 which may lead to a variation in transcription or translation of DEFB1, or in stability of DEFB1 mRNA. Therefore, individuals carrying different alleles at À44 loci of DEFB1 may show different host immune response to infection and ultimately influence the pathophysiological course of sepsis.…”

Rat recombinant β-defensin 22 is a heparin-binding protein with antimicrobial activity

“…Various peptides of the b-defensin family are involved in and mediate various biological processes based on their pleiotropic activities. [2][3][4][5][6][7][8][9] A number of these processes are beyond immune-related events; these include cell differentiation, tumour development, tissue remodelling 10 and sperm maturation. 11 Nonetheless, the roles of most of the b-defensins that are prevalently expressed in the epididymis are still unclear.…”

Expresión diferencial en placenta de beta-defensinas humanas y detección de variantes alélicas en el gen DEFB1 de madres positivas para VIH-1

“…Because the A allele in the A692G SNP has been previously associated with a reduction in the HBD-1 expression compared to the G allele (71), it is likely that the presence of A1836G G/G and not the A692G A/G SNP explains the upregulation of the HBD-1 expression. The functional effect of the DEFB1 SNPs is still controversial (71,72) and requires more comprehensive studies. The G1654A SNP is adjacent to the first of six conserved cysteine residues and potentially has an effect on the folding of the peptide, thereby affecting peptide function (43).…”