Polymorphisms in the hypoxia-inducible factor-1α gene confer susceptibility to pancreatic cancer
Polymorphisms in the hypoxia-inducible factor-1α gene confer susceptibility to pancreatic cancer
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DOI：
10.4161/cbt.12.5.15982
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发表时间：
2011-09-01
影响因子：
3.6
通讯作者：
Hao, Jihui
中科院分区：
文献类型：
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作者：
Wang, Xiuchao;Liu, Yingwei;Hao, Jihui
转录因子缺氧诱导因子-1(HIF-1)由α和β亚基组成。最近的研究表明，HIF-1α基因可能存在C1772T和G1790A单核苷酸多态(SNPs)。这些SNP可能增加HIF-1α的稳定性和活性。在本研究中，我们通过对263例胰腺导管腺癌(PDAC)患者的循环单个核细胞进行基因分型来寻找这些SNPs，并以271名健康志愿者为对照。其结果是，PDAC患者的C1772T和G1790A两个SNP的频率均高于健康志愿者(C1772T：21vs.11%，p<；0.01；G1790A：25vs.8%，p<；0.01)。此外，C1772T：OR=2.156，95%CI：1.324-3.511；G1790A：OR=3.716，95%CI：2.213-6.238。采用免疫组织化学方法检测68例PDAC肿瘤组织中HIF-1α的表达水平。为此，我们设计了一种基于HIF-1α阳性细胞染色强度和频率的半定量方法。因此，G1790A SNP与HIF-1α表达增加有关，而C1772T SNP与HIF-1α表达增加无关。我们还将基因分型数据与患者的生存时间、血清CA19-9和肿瘤的体积、分级、分期和有无淋巴结转移相关联。C1772T SNP与这些参数中的任何一个都没有关联。相反，G1790A SNP与血清CA19-9和肿瘤体积的增加相关。结论：HIF-1α基因中的C1772T和G1790A SNPs增加了胰腺癌的易感性。此外，G1790A SNP与肿瘤产生的HIF-1α的增加和癌症的进展有关。
The transcription factor hypoxia-inducible factor-1 (HIF-1) has alpha and beta subunits. Recent studies have shown that the HIF-1 alpha gene may have C1772T and G1790A single nucleotide polymorphisms (SNPs). These SNPs may increase the stability and activity of HIF-1 alpha. In the present study, we looked for these SNPs by genotyping circulating mononuclear cells from 263 patients with pancreatic ductal adenocarcinoma (PDAC), using 271 healthy volunteers as controls. As a result, both SNPs were more frequent in PDAC patients than in healthy volunteers (C1772T: 21 vs. 11%, p < 0.01; G1790A: 25 vs. 8%, p < 0.01). Further, both SNPs were associated with higher risks for PDAC (C1772T: OR = 2.156, 95% CI: 1.324-3.511, p < 0.05; G1790A: OR = 3.716, 95% CI: 2.213-6.238, p < 0.01). We also stained HIF-1 alpha by immunohistochemistry in 68 PDAC tumors to examine their HIF-1 alpha expression levels. To this end, we designed a semi-quantitative method that was based on the staining intensity and frequency of HIF-1 alpha-positive cells. As a result, the G1790A SNP, but not C1772T SNP, was associated with an increased HIF-1 alpha expression. We also related genotyping data to patient's survival times, serum CA19-9 and tumor's volumes, grades, stages and lymph-node metastasis. The C1772T SNP was not associated with any of these parameters. In contrast, the G1790A SNP was associated with increases in serum CA19-9 and in tumor volumes. In conclusion, the C1772T and G1790A SNPs in the HIF-1 alpha gene increase the susceptibility to pancreatic cancer. In addition, the G1790A SNP is associated with increases in tumor-produced HIF-1 alpha and in the progression of the cancer.