The hypoxia-inducible factor-1α（HIF-1α） plays an important role in regulating angiogenesis, which is essential for tumor growth and metastasis. Genetic variations of HIFIA （coding HIF-1α） have been shown to inf...The hypoxia-inducible factor-1α（HIF-1α） plays an important role in regulating angiogenesis, which is essential for tumor growth and metastasis. Genetic variations of HIFIA （coding HIF-1α） have been shown to influence an individual＇s susceptibility to many human tumors; however, evidence on associations between HIFIA single-nucleotide polymorphisms （SNPs） and prostate cancer （PCa） risk is conflicting. We genotyped three potentially functional polymorphisms in HIFIA （rs11549465, rs11549467 and rs2057482） using the TaqMan method and assessed their associations with PCa risk in a case-control study of 662 PCa patients and 716 controls in a Chinese Hart population. Compared with rs 11549467 GG genotype, the variant genotypes GA ＋AA had a significantly increased PCa risk （adjusted odds ratio （OR）= 1.70; 95% confidence interval （C1）= 1.06-2.72）, particularly among older patients （0R=2.01; 95%C1 = 1.05-3.86）, smokers （0R=2.06; 95%C1 = 1.07-3.99）, never drinkers （OR=2.16; 95%C1 = 1.20-3.86） and patients without a family history of cancer （OR= 1.71; 95%C1= 1.02-2.89）. Furthermore, patients with rs11549467 variant genotypes were associated with a higher Gleason score （OR=2.14; 95%CI = 1.22-3.75）. No altered PCa risk was associated with the rs 11549465 and rs2057482 polymorphism. However, the combined variant genotypes of rs2057482 and rs 11549467 were associated with increased PCa risk （0R=2.10; 95%C1= 1.23-3.57 among subjects carrying three or more risk alleles）. These results suggest that HIFIA polymorphisms may impact PCa susceptibility and progression in the Chinese Han population.展开更多
Prostate-associated gene 4 （PAGE4） is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is a...Prostate-associated gene 4 （PAGE4） is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein （IDP） that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun, c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer （PCa）. Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCa, especially patients with low-risk disease.展开更多
文摘The hypoxia-inducible factor-1α（HIF-1α） plays an important role in regulating angiogenesis, which is essential for tumor growth and metastasis. Genetic variations of HIFIA （coding HIF-1α） have been shown to influence an individual＇s susceptibility to many human tumors; however, evidence on associations between HIFIA single-nucleotide polymorphisms （SNPs） and prostate cancer （PCa） risk is conflicting. We genotyped three potentially functional polymorphisms in HIFIA （rs11549465, rs11549467 and rs2057482） using the TaqMan method and assessed their associations with PCa risk in a case-control study of 662 PCa patients and 716 controls in a Chinese Hart population. Compared with rs 11549467 GG genotype, the variant genotypes GA ＋AA had a significantly increased PCa risk （adjusted odds ratio （OR）= 1.70; 95% confidence interval （C1）= 1.06-2.72）, particularly among older patients （0R=2.01; 95%C1 = 1.05-3.86）, smokers （0R=2.06; 95%C1 = 1.07-3.99）, never drinkers （OR=2.16; 95%C1 = 1.20-3.86） and patients without a family history of cancer （OR= 1.71; 95%C1= 1.02-2.89）. Furthermore, patients with rs11549467 variant genotypes were associated with a higher Gleason score （OR=2.14; 95%CI = 1.22-3.75）. No altered PCa risk was associated with the rs 11549465 and rs2057482 polymorphism. However, the combined variant genotypes of rs2057482 and rs 11549467 were associated with increased PCa risk （0R=2.10; 95%C1= 1.23-3.57 among subjects carrying three or more risk alleles）. These results suggest that HIFIA polymorphisms may impact PCa susceptibility and progression in the Chinese Han population.
文摘Prostate-associated gene 4 （PAGE4） is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein （IDP） that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun, c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer （PCa）. Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCa, especially patients with low-risk disease.
