微小RNA基因变异和幽门螺杆菌感染相关性胃癌发生、发展和预后关系的研究

miRNAs are dysregulated by H.pylori infection and played an integral role at multiple steps in gastric carcinogenesis,including immune response,cell cycle progression, proliferation, apoptosis, migration,invasion and metastasis. We will determine miRNA expression profiles of gastric tumors and gastric normal tissues using miRNA microarrays to identify significantly dysregulated miRNAs,and will genotype the relevant genetic variants in these dysregulated miRNAs, then investigate genetic variants and miRNAs expression levels are associated with the initiation of gastric cancer (GC) and TNM stages. Here, the another objective is to explore the potential interaction among miRNA genes using a established prospective cohort study on GC patients, therefore, to predict tumor recurrence more timely and survival rate more accurately. Moreover, functional analysis on the identified SNPs and downstream target genes will be conducted to elucidate the effects of miRNA polymorphisms on the development, metastasis, and recurrence of GC. Based on the results of this study, we believe many markers responsible for early diagnosis of GC and treatment response may show up. Thus, this study will provide insight on successful identification of patients at higher risks of tumor recurrence and on more subject-specific prescription of treatments and health cares.

Hp感染后引起胃黏膜组织miRNAs异常表达, 参与免疫应答、细胞增殖、凋亡、血管形成等重要的生物学过程，影响胃癌的发生、发展和转移进程。本研究利用miRNA芯片筛选与胃癌发生相关的差异表达miRNAs，利用测序法确定差异表达miRNAs上的基因变异位点，质谱法检测变异位点的基因型并测定miRNAs表达水平，比较miRNAs的不同基因型、mRNA表达水平与肿瘤发生和临床分期的关系。并利用已建立的前瞻性胃癌随访队列,深入探讨不同miRNA变异位点间的交互作用及miRNA表达水平在预测肿瘤的复发和转移及生存期评估中的作用。对强关联的基因变异位点进行体内外功能性分析，确定功能性miRNAs，预测其下游靶基因，检测下游靶基因的mRNA和蛋白质表达水平变化，以阐明miRNAs在胃癌进展、转移和复发中的作用机制，寻找早期诊断和预后评估标记物，筛选转移复发高危患者,给予个性化的随访和治疗。

幽门螺杆菌感染后引起胃黏膜组织miRNAs异常表达，参与免疫应答、细胞增殖、凋亡、血管形成等重要的生物学过程，影响胃癌的发生、发展和预后。本研究探索了miRNAs相关基因变异与幽门螺杆菌感染相关胃癌的易感性、进展和预后的关系及可能的作用机制。结果显示，幽门螺杆菌感染与胃癌的发生相关（感染率，胃癌组67.6% vs 对照组49.1%），而与胃癌患者的预后无关（log-rank P=0.360）。对19个miRNAs区域的SNP分析后显示，pri-miR-219-1上rs213210位点C/C基因型不仅与幽门螺杆菌感染风险降低相关(OR 0.66, 95%CI: 0.46–0.95)，还与胃癌易感性降低相关（OR 0.76, 95% CI：0.62–0.93）。携带pre-miR-146a rs2910164位点G/G 基因型的个体，胃癌易感性降低（OR 0.76，95%CI：0.60-0.97）；但携带G/G基因型的胃癌患者术后死亡风险升高（HR: 1.30; 95% CI: 1.01–1.68)，且在TNM分期各层内显示出相同的趋势。携带pri-miR-218 rs11134527位点G等位基因型的胃癌患者预后相对较好（HR=0.73, 95% CI: 0.58–0.93, P = 0.01）。此外，对miRNA靶位点区域13个SNP分析显示，LIN28A 3’UTR区域的rs3811463位点，CD133的rs2240688位点，CD44的rs187116位点与胃癌的易感性相关，但未观察到各位点基因型与相应蛋白表达水平相关。调整TNM分期等其他因素的影响后，胃癌患者每多携带一个IL23R rs10889677 C等位基因型，死亡风险就升高28%（HR 1.28, 95% CI: 1.07-1.53）。对于未接受化疗的胃癌患者，携带PD-L1 rs2297136 GG患者的死亡风险是AG+GG基因型患者的2.87倍（95%CI：1.03-7.99）。我们进一步分析了rs2297136所在的PD-L1及免疫检查点通路的PD-L2、PD1的表达与胃癌进展和预后的关系；发现PD-L1表达在TNM分期较早者阳性率较高，但PD-L2和PD1与胃癌病理指标无关。预后分析显示，PD-L1与PD1同时表达的胃癌患者预后相对较好（HR 0.48, 95%CI=0.27-0.84）。

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