Journal
CANCER BIOLOGY & THERAPY
Volume 13, Issue 9, Pages 720-726Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.20554
Keywords
hypoxia-inducible factor-1 alpha; prostate; cancer; polymorphism; mRNA; C1772T
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Funding
- Israel Cancer Association
- Dr Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF)
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Hypoxia-inducible factor 1 alpha (HIF-1 alpha) gene polymorphisms have been investigated for a possible role in mediating genetic predisposition to cancer. Our previous data show that men homozygous to C1772T polymorphism had 4-fold risk to develop prostate cancer. Therefore, we studied the effects of C1772T polymorphism on HIF-1 alpha expression. HIF-1 alpha mRNA expression levels were significantly higher in peripheral blood leukocytes of prostate cancer patients with the TT genotype compared with the CC genotype. Expression of C1772T HIF-1 alpha in HIF-1 alpha knockout cancer cells showed higher expression levels and stabilization of HIF-1 alpha mRNA compared with the wild-type. Mutated HIF-1 alpha protein half-life was similar to that of the wild-type. Hence, our data provide evidence that C1772T polymorphism causes activation of HIF-1 alpha as a gain-of-function mechanism driven by stabilization of HIF-1 alpha mRNA. These findings may also explain the increased risk of men homozygous to this mutation to develop prostate cancer.
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