Department of Urology, Meir Medical Center; Kfar Saba, Israel.
Cancer Biol Ther. 2012 Jul;13(9):720-6. doi: 10.4161/cbt.20554. Epub 2012 May 31.
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.
缺氧诱导因子 1α（HIF-1α）基因多态性被研究用于介导癌症遗传易感性的可能作用。我们之前的数据表明，C1772T 多态性纯合子的男性患前列腺癌的风险增加了 4 倍。因此，我们研究了 C1772T 多态性对 HIF-1α表达的影响。与 CC 基因型相比，TT 基因型的前列腺癌患者外周血白细胞中 HIF-1α mRNA 表达水平显著升高。与野生型相比，在 HIF-1α 敲除癌细胞中，C1772T HIF-1α 的表达水平更高，HIF-1α mRNA 的稳定性也更高。突变型 HIF-1α 蛋白半衰期与野生型相似。因此，我们的数据提供了证据表明，C1772T 多态性导致 HIF-1α的激活，作为由 HIF-1α mRNA 稳定驱动的功能获得机制。这些发现也可能解释了携带这种突变的男性患前列腺癌风险增加的原因。
