Functional analysis implicating the SNP rs61552325 in ERBB2 as an effector for androgen-insensitive prostate cancer cell invasion.

BACKGROUND: As one of the most common cancers in men, the pathogenesis of prostate cancer has been widely researched. Aberrant activation of the erb-b2 receptor tyrosine kinase 2 (ERBB2) has been found to play a critical role in metastatic prostate cancer. In our previous study, we demonstrated that rs61552325 (Pro1140Ala) located in ERBB2 is strongly correlated to prostate cancer. Therefore, we initially studied the effect of rs61552325 on androgen-independent prostate cancer cell metastasis. RESULTS: Bioinformatic results demonstrated that the mutant Pro1140Ala likely decrease the stability of the ERBB2 protein and its interactions. The mean migration rate after 6 h for PC3 minor variant cells which carried the G allele was 1.28-fold higher than major variant PC3 cells that carried the C allele (P = 0.016). The mean invasion rate of DU145 putative minor variant cells was 0.40 reducer than negative control cells (P = 5.9E-04). METHODS: rs61552325 major variant (C allele) and minor variant (G allele) were produced by site directed mutagenesis and transfected into DU145 and PC3 cells. A wound healing assay was performed to compare migration abilities between alleles. After knocking down endogenous ERBB2 and then expressing the rs61552325 minor variant, invasion abilities were evaluated with a transwell assay using DU145 and PC3 cells. CONCLUSIONS: Our data showed that the rs61552325 major variant decreases PC3 cell migration and its minor variant depresses DU145 cell invasion, suggesting that rs61552325 is likely an important change during prostate cancer invasion.

Immunization associated with erectile dysfunction based on cross-sectional and genetic analyses.

Erectile dysfunction (ED) is a global disease affecting a large number of people. Some studies have found a relationship between low-grade inflammation and ED. We hypothesized that the immune system might play a key role in the outcome of ED. Five immune agents (C3, C4, IgA, IgM, and IgG) were collected based on the Fangchenggang Area Male Health and Examination Survey (FAMHES), using methods of a traditional cross-sectional analysis. Our results repeated the significant association between ED and metabolic syndrome, obesity, and so forth. However, there seemed to be no positive relation between the tested indexes and ED risk in the baseline analysis (C3: P = 0.737; C4: P = 0.274; IgA: P = 0.943; IgG: P = 0.069; IgM: P = 0.985). Then, after adjusting for age and multivariate covariates, a potentially significant association between ED and IgG was discovered (P = 0.025 and P = 0.034, respectively). Meanwhile, in order to describe the development of ED on a gene level, SNP-set kernel-machine association test (SKAT) was applied with the known humoral immune genes involved. The outcomes suggested that PTAFR (binary P value: 0.0096; continuous P value: 0.00869), IL27 (0.0029; 0.1954), CD37 (0.0248; 0.5196), CD40 (0.7146; 0.0413), IL7R (0.1223; 0.0222), PSMB9 (0.1237; 0.0212), and CXCR3 (0.0849; 0.0478) might be key genes in ED, especially IL27, when we restricted the family-wise error rate (FWER) to 0.5. Our study shows that IgG and seven genes (PTAFR, CD37, CD40, IL7R, PSMB9, CXCR3, and especially IL27) might be key factors in the pathogenesis of ED, which could pave the way for future gene and immune therapies.

RTK/ERK pathway under natural selection associated with prostate cancer.

Prostate cancer (PCa) is a global disease causing large numbers of deaths every year. Recent studies have indicated the RTK/ERK pathway might be a key pathway in the development of PCa. However, the exact association and evolution-based mechanism remain unclear. This study was conducted by combining genotypic and phenotypic data from the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa) with related databases such as the HapMap Project and Genevar. In this analysis, expression of quantitative trait loci (eQTLs) analysis, natural selection and gene-based pathway analysis were involved. The pathway analysis confirmed the positive relationship between PCa risk and several key genes. In addition, combined with the natural selection, it seems that 4 genes (EGFR, ERBB2, PTK2, and RAF1) with five SNPs (rs11238349, rs17172438, rs984654, rs11773818, and rs17172432) especially rs17172432, might be pivotal factors in the development of PCa. The results indicate that the RTK/ERK pathway under natural selection is a key link in PCa risk. The joint effect of the genes and loci with positive selection might be one reason for the development of PCa. Dealing with all the factors simultaneously might give insight into prevention and aid in predicting the success of potential therapies for PCa.