The survivin molecule as a double-edged sword in cellular physiologic and pathologic conditions and its role as a potential biomarker and therapeutic target in cancer.

Survivin is a member of the family of apoptosis inhibitory proteins with increased expression level in most cancerous tissues. Evidence shows that survivin plays regulatory roles in proliferation or survival of normal adult cells, principally vascular endothelial cells, T lymphocytes, primitive hematopoietic cells, and polymorphonuclear neutrophils. Survivin antiapoptotic role is, directly and indirectly, related to caspase proteins and shows its role in cell division through the chromosomal passenger complex. Survivin contains many genetic polymorphisms that the role of some variations has been proven in several cancers. The -31G/C polymorphism is one of the most important survivin mutations which is located in the promoter region on a CDE/CHR motif. This polymorphism can upregulate the survivin messenger RNA. In addition, its allele C can increase the risk of cancers in 1.27-fold than allele G. Considering the fundamental role of survivin in different cancers, this protein could be considered as a new therapeutic target in cancer treatment. For this purpose, various strategies have been designed including the prevention of survivin expression through inhibition of mRNA translation using antagonistic molecules, inhibition of survivin gene function through small inhibitory molecules, gene therapy, and immunotherapy. In this study, we describe the structure, played roles in physiological and pathological states and genetic polymorphisms of survivin. Finally, the role of survivin as a potential target in cancer therapy given challenges ahead has been discussed.

Protective effect of oestrogen receptor α-PvuII transition against idiopathic male infertility: a case-control study and meta-analysis.

RESEARCH QUESTION: Is there any genetic association between oestrogen receptor alpha [ERα]-PvuII polymorphism and idiopathic male infertility? DESIGN: A total of 226 infertile and 213 fertile men participated in the present case-control study. ERα-PvuII genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism [PCR-RFLP] method. Meta-analysis was also performed by pooling data collected from seven other eligible studies identified by searches of PubMed, Embase, Google Scholar, and Science Direct databases. Summary odds ratios were estimated by fixed- or random-effects models. The molecular effects of ERα-PvuII polymorphism were evaluated by bioinformatics tools. RESULTS: A significant protective association was reported between ERα-PvuII and male infertility in the homozygote model [OR=0.54, 95%CI=0.3-0.98, p=0.042]. Also, a similar association was observed in asthenozoospermia subgroup [OR=0.4, 95%CI=0.18-0.9, p=0.025]. Meta-analysis also revealed that the ER-PvuII polymorphism was significantly associated with the decreased risk of male infertility in the heterozygote co-dominant model [OR=0.80, 95%CI=0.64-0.99, p=0.042]. Moreover, similar protective results were reported in stratified analyses in Caucasian subgroup in the dominant genetic model [OR=0.66, 95%CI=0.45-0.96, p=0.029] and in the heterozygote co-dominant model [OR=0.62, 95%CI=0.41-0.93, p=0.021]. A significant association was also found in studies with sample size of less than 400 subjects in heterozygote co-dominant model [OR=0.69, 95%CI=0.50-0.95, p=0.023]. The bioinformatics data indicated that ER-PvuII polymorphism could significantly affect RNA structure of ERα [p=0.004]. CONCLUSION: The ERα-PvuII polymorphism could be considered as a possible protective factor against male infertility.

Arg399Gln substitution in XRCC1 as a prognostic and predictive biomarker for prostate cancer: Evidence from 8662 subjects and a structural analysis.

BACKGROUND: The Arg399Gln polymorphism in the X-ray repair cross-complementing group 1 gene (XRCC1) may alter the risk of prostate cancer (PCa). The present study aimed to investigate the association of the XRCC1-Arg399Gln polymorphism with PCa risk in an Iranian population, as followed by a meta-analysis and an in silico analysis. METHODS: In a case-control study, 360 subjects were included (180 men with PCa and 180 healthy controls). XRCC1-Arg399Gln genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. In the meta-analysis, 14 eligible studies were included to which our case-control data were added to estimate the pooled odds ratios. Some bioinformatics tools were employed to evaluate the effects of Arg399Gln substitution on molecular aspects of the XRCC1 protein. RESULTS: Our case-control study revealed a significant association between the XRCC1-Arg399Gln polymorphism and PCa risk. The data from overall meta-analysis showed significant associations between the mentioned polymorphism and PCa risk in allelic and recessive genetic models. In addition, we observed statistically significant associations in stratified analyses by ethnicity, sample size and source of controls. Our in silico analysis showed that Arg399Gln substitution could be damaging with respect to the function and structure of the XRCC1 protein. CONCLUSIONS: Based on these results, the XRCC1-Arg399Gln polymorphism might be a risk factor for PCa and it could be considered as a prognostic and predictive biomarker for susceptible men.

Androgen receptor (AR)-CAG trinucleotide repeat length and idiopathic male infertility: a case-control trial and a meta-analysis.

CAG trinucleotide repeats in androgen receptor (AR) gene encode a polyglutamine tract in AR N-terminal transactivation domain. Studies have been conducted to evaluate the effect of CAG repeat length on male infertility, which have yielded contradictory results. This study aimed to explore the number of AR-CAG repeats in 150 fertile controls and 150 idiopathic infertile men, divided into four azoospermia, oligozoospermia, asthenozoospermia, and teratozoospermia subgroups. In addition, a meta-analysis was conducted based on previous studies to assess the association of the mentioned variation with male infertility in recent years. Polymerase chain reaction (PCR) targeting followed by an electrophoresis on polyacrylamide gel was used for AR-CAG genotype detecting. Moreover, a systematic search was performed in PubMed, Web of Science, Science Direct, and Google Scholar databases to collect eligible studies for meta-analysis purpose. According to the results, a significant association was observed between increased length of AR-CAG polymorphism and male infertility (p< 0.0001). Furthermore, there were similar significant associations in the azoospermia (p= 0.048), asthenozoospermia (p= 0.013) and teratozoospermia (p= 0.002) subgroups. In addition, meta-analysis on forty studies showed a significant association between AR-CAG polymorphism in the overall analysis (SMD= 0.199, 95 % CI= 0.112-0.287, p<0.001) and the Caucasian subgroup (SMD= 0.151, 95 % CI= 0.040-0.263, p= 0.008). Our results elucidated that long stretches of CAG repeat might lead to AR dysfunction, contributing to male infertility especially in the Caucasian population.