Single nucleotide polymorphism in the microRNA-199a binding site of HIF1A gene is associated with pancreatic ductal adenocarcinoma risk and worse clinical outcomes.
Single nucleotide polymorphism in the microRNA-199a binding site of HIF1A gene is associated with pancreatic ductal adenocarcinoma risk and worse clinical outcomes.
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HIF1A 基因 microRNA-199a 结合位点的单核苷酸多态性与胰腺导管腺癌风险和较差的临床结果相关
DOI：
10.18632/oncotarget.7263
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发表时间：
2016-03-22
期刊：
影响因子：
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通讯作者：
Hao J
中科院分区：
文献类型：
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作者：
Wang X;Ren H;Zhao T;Ma W;Dong J;Zhang S;Xin W;Yang S;Jia L;Hao J
缺氧诱导因子-1 α（HIF-1α）在包括胰腺导管腺癌（PDAC）在内的多种肿瘤中过度表达，与不良预后相关。我们的目的是确定生殖系遗传变异对HIF 1A基因中miRNA基因调控环的稳态调节和PDAC风险的影响。对410例PDAC患者和490例健康对照者进行HIF 1A rs 2057482单核苷酸多态性（SNP）基因分型。与CT/TT等位基因组相比，CC基因型SNP HIF 1A与PDAC风险（OR = 1.719，95% CI：1.293-2.286）和较短的总生存期（OS，P<0.0001）显著相关。rs 2057482的C/T变体（位于HIF 1A中miR-199 a结合位点附近的SNP）可能导致miR-199 a对HIF 1A的差异调节。具体而言，rs 2057482的C等位基因在mRNA和蛋白水平上减弱了miR-199 a诱导的HIF-1α表达抑制。在PDAC组织中，rs 2057482-CC基因型的HIF-1α蛋白表达水平显著高于rs 2057482-CT/TT基因型（P<0.0001）。HIF 1A基因CC型和HIF-1α表达增加均与PDAC患者的OS缩短显著相关。经TNM分期、肿瘤分化程度和CA 19 -9水平校正后，HIF-1 α和HIF-1A的表达与总生存期的关系仍有显著性差异（P<0.0001）。综上所述，我们的研究表明，宿主遗传变异可能会干扰miR-199 a/HIF 1A调控环的调节，并改变PDAC风险和不良预后。总之，rs 2057482-CC基因型增加了对PDAC的易感性，并与癌症进展相关。
Hypoxia-inducible factor-1 alpha (HIF-1α) is over-expressed in many cancers including pancreatic ductal adenocarcinoma (PDAC) and correlated with poor prognosis. We aim to determine the effect of germline genetic variants on the regulation of the homeostasis of the miRNA-gene regulatory loop in HIF1A gene and PDAC risk. HIF1A rs2057482 single nucleotide polymorphism (SNP) was genotyped in 410 PDAC cases and 490 healthy controls. The CC genotype SNP HIF1A is significantly correlated with PDAC risk (OR = 1.719, 95% CI: 1.293–2.286) and shorter overall survival (OS, P<0.0001) compared with the CT/TT alleles group. The C/T variants of rs2057482, a SNP located near the miR-199a binding site in HIF1A, could lead to differential regulation of HIF1A by miR-199a. Specifically, the C allele of rs2057482 weakened miR-199a–induced repression of HIF-1α expression on both mRNA and protein levels. In the PDAC tissue, individuals with the rs2057482-CC genotype expressed significantly higher levels of HIF-1α protein than those with the rs2057482-CT/TT genotype (P<0.0001). Both the CC genotype of SNP HIF1A and increased HIF-1α expression are significantly associated with shorter OS of patients with PDAC. After adjusted by TNM staging, differentiation grade, and the levels of CA19-9, both SNP HIF1A and HIF-1α expression retained highly significance on OS (P<0.0001). Taken together, our study demonstrates that host genetic variants could disturb the regulation of the miR-199a/HIF1A regulatory loop and alter PDAC risk and poor prognosis. In conclusion, the rs2057482-CC genotype increases the susceptibility to PDAC and associated with cancer progression.