Interleukin-6 (IL-6), a pro-inflammatory cytokine, is involved in prostate cancer progression, including androgen independence. Serum IL-6 levels also correlate with prostate tumor burden, prostate-specific antigen levels and metastasis. Since circulating cytokine levels vary considerably inter-individually, such variation could be linked to genetic factors, including genetic polymorphism. The -174G>C/rs1800795 polymorphism in the IL-6 promoter is functionally relevant in terms of transcriptional regulation and disease association. We investigated a possible association of the -174G/C polymorphism with prostate cancer. Since significant racial disparities exist in prostate cancer incidence, we also investigated this association between the -174G/C polymorphism and prostate cancer in Caucasians and African-Americans, separately. Direct sequencing of the PCR amplicon from genomic DNA was used for genotyping rs1800795 in all subjects [age-matched controls (N = 140) and prostate cancer patients (N = 164)]. Sample size and power was calculated using the PGA software. We found the GG genotype to be associated with increased risk of prostate cancer in Caucasian subjects, whereas the CC genotype was associated with increased risk in the African-American sample set. Such a dimorphic genotypic association with cancer and race is unique and suggests a complex gene-gene and gene-environment interaction.

Background 2′ -5′ –oligoadenylate synthetase (2-5 OAS1), an antiviral, pro-apoptotic and anti-proliferative gene converts ATP to a series of 2′ -5′ –oligoadenylates (2-5A). 2-5A in turn activates RNaseL, a candidate hereditary prostate cancer gene. OAS1 polymorphism (rs2660) has been associated with increased susceptibility to infections and various diseases. In general, the low enzyme activity AA genotype promotes susceptibility whereas high enzyme activity GG genotype confers protection. In this study we investigated the association of this functional polymorphism (rs2660) in OAS1 with prostate cancer. Methods Sample size and power was calculated using the PGA software. Genomic DNA from a controls (n=140) and prostate cancer patients (n=164) were used for genotyping SNPs rs2660, rs1131454 and rs34137742 on all samples. Statistical analysis was performed using logistic regression model. Results Significant association was observed between rs2660 genotype (A/G) and prostate cancer. Genotype AA increased the risk whereas GG genotype decreased the risk of prostate cancer. The GG genotype was not observed in the African American samples. The AA genotype also increased the risk of prostate cancer with age. Conclusions OAS1 SNP rs2660 AA genotype is significantly associated with prostate cancer whereas GG genotype protects against prostate cancer. OAS1 rs2660 could be a prostate cancer susceptibility polymorphism, a significant observation especially in a context of the OAS1-RNaseL pathway. Thus a functional defect in OAS1 due to rs2660 SNP can not only attenuate RNaseL function, but can also alter cell growth and apoptosis independent of RNaseL.

Epidemiological studies show that the incidence and mortality rates of prostate cancer (PCa) are significantly higher in African-American (AA) men when compared with Caucasian (CA) men in the United States. Transforming growth factor β (TGFβ) signaling pathway is linked to health disparities in AAs. Recent studies suggest a role of TGFβ3 in cancer metastases and its effect on the migratory and invasive behavior; however, its role in PCa in AA men has not been studied. We determined the circulating levels of TGFβ3 in AA and CA men diagnosed with PCa using ELISA. We analyzed serum samples from both AA and CA men diagnosed with and without PCa. We show that AA PCa patients had higher levels of TGFβ3 protein compared with AA controls and CA patients. In fact, TGFβ3 protein levels in serum were higher in AA men without PCa compared with the CA population, which may correlate with more aggressive disease seen in AA men. Studies on AA-derived PCa cell lines revealed that TGFβ3 protein levels were also higher in these cells compared with CA-derived PCa cell lines. Our studies also reveal that TGFβ does not inhibit cell proliferation in AA-derived PCa cell lines, but it does induce migration and invasion through activation of PI3K pathway. We suggest that increased TGFβ3 levels are responsible for development of aggressive PCa in AA patients as a consequence of development of resistance to inhibitory effects of TGFβ on cell proliferation and induction of invasive metastatic behavior.

RNAs have been shown to exhibit differential enrichment between nuclear, cytoplasmic, and exosome fractions. A current fundamental question asks why non-coding RNA partition into different spatial compartments. We report on the analysis of cellular compartment models with miRNA data sources for spatial-mechanistic modeling to address the broad area of multi-scalar cellular communication by miRNAs. We show that spatial partitioning of miRNAs is related to sequence similarity to the overall transcriptome. This has broad implications in biological informatics for gene regulation and provides a deeper understanding of nucleotide sequence structure and RNA language meaning for human pathologies resulting from changes in gene expression.