Research Paper

HIF1A C1772T polymorphism leads to HIF-1α mRNA overexpression in prostate cancer patients

Volume 13, Issue 9   July 2012
Pages 720 - 726
http://dx.doi.org/10.4161/cbt.20554
Keywords: C1772T, cancer, hypoxia-inducible factor-1α, mRNA, polymorphism, prostate
Authors: Michael Vainrib, Maya Golan, Sharon Amir, Duyen T. Dang, Long H. Dang, Anat Bar-Shira, Avi Orr-Urtreger, Haim Matzkin and Nicola J. Mabjeesh

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Abstract:
Hypoxia-inducible factor 1α (HIF-1α) 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-1α expression. HIF-1α 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-1α in HIF-1α knockout cancer cells showed higher expression levels and stabilization of HIF-1α mRNA compared with the wild-type. Mutated HIF-1α protein half-life was similar to that of the wild-type. Hence, our data provide evidence that C1772T polymorphism causes activation of HIF-1α as a gain-of-function mechanism driven by stabilization of HIF-1α mRNA. These findings may also explain the increased risk of men homozygous to this mutation to develop prostate cancer.

Received: November 23, 2011; Accepted: April 29, 2012; Published Online: May 31, 2012

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