The C1772T genetic polymorphism in human HIF-1α gene associates with expression of HIF-1α protein in breast cancer
The C1772T genetic polymorphism in human HIF-1α gene associates with expression of HIF-1α protein in breast cancer
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DOI：
10.3892/or_00000127
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发表时间：
2008-11-01
期刊：
影响因子：
4.2
通讯作者：
Yoon, Kyung-Sik
中科院分区：
文献类型：
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作者：
Kim, Hye Ok;Jo, Yong Hwa;Yoon, Kyung-Sik
低氧诱导因子-1(HIF-1)是参与细胞对低氧反应的重要遗传成分。HIF-1也与调节肿瘤的发展和生长有关。在以往的研究中，HIF-1α基因的C1772T(P582S)或G1790A(A588T)多态性已在肾细胞癌、头颈部和食管鳞癌以及结直肠癌和前列腺癌中被发现。在我们的研究中，我们研究了HIF-1α基因的多态性是否可以解释HIF-1α蛋白的表达模式以及对乳腺癌临床进展的影响。我们还检测了HIF-1α对预后的影响。基因多态和蛋白表达在预测生物行为中的作用。我们用聚合酶链式反应和直接测序的方法检测了90名乳腺癌患者和102名健康对照的HIF-1α基因外显子12的多态性。采用免疫组织化学方法检测石蜡包埋标本中HIF-1α的表达。我们将其表达与已知的预后因素联系起来。乳腺癌患者和健康对照组C1772T的T等位基因频率分别为5.6和4.4%，而G1790A的A等位基因频率分别为1.7和4.4%。HIF-1α在56.7%(51/90)的患者中过表达。其过表达与T1772多态等位基因相关(p=0.04)。有淋巴结转移(P=0.041)、组织学分级高(P=0.001)、Ki-67指数增高(P=0.031)的乳腺癌组织中HIF-1α蛋白水平升高。这些结果提示，C1772T(P582S)基因多态性和表达分析可能为乳腺癌患者的治疗提供一个新的预后因素，并可能有助于临床决策。
Hypoxia-inducible factor 1 (HIF-1) is an important genetic component involved in the cellular response to hypoxia. HIF-1 is also linked to the regulation of tumor development and growth. In previous studies, the C1772T (P582S) or the G1790A (A588T) polymorphisms of the HIF-1 alpha gene have been identified in renal cell carcinoma, head and neck and esophageal squamous cell carcinomas as well as colorectal and prostate cancers. In our study, we investigated whether polymorphisms of the HIF-1 alpha gene may account for the expression patterns of HIF-1 alpha, protein and impact of clinical progression in breast cancer. We also examined the impact of prognosis of HIF-1 alpha. gene polymorphism and protein expression in the prediction of biological behavior. We performed polymerase chain reaction and direct sequencing to detect polymorphisms in exon 12 of HIF-1 alpha from 90 breast cancer patients and 102 healthy controls. The expression of HIF-1 alpha was measured in paraffin-embedded specimens from patients by immunohistochemistry. We associated its expression with known prognostic factors. The frequency of the T allele for C1772T in breast cancer patients and healthy controls was 5.6 vs. 4.4%, whereas, the frequency of the A allele for G1790A was 1.7 vs. 4.4%. HIF-1 alpha was overexpressed in 56.7% (51 of 90) of the patients. Its overexpression associated with the T1772 polymorphic allele (p=0.04). Elevated levels of HIF-1 alpha protein were found in cases of breast cancer with lymph node metastasis (p=0.041), high histological grade (p=0.001) and increased Ki-67 index (p=0.031). These results suggest the potential use of C1772T (P582S) polymorphism and expression analysis in providing a new prognostic factor for unfavorable disease outcomes and may help for clinical decision-making in the treatment of breast cancer patients.