PGC靶标相关miRNA多态与胃癌发病风险的关系及机制研究

Recent years, scholars paid more and more attention to the microRNA polymorphisms as a disease diagnostic molecular marker. Our colleagues recently found that the expression of pepsinogen C (PGC) significantly decreased from the controls to atrophic gastritis and to gastric cancer, which was a good biomarker of the diagnosis of gastric cancer and precancerous disease. Then, whether miRNA targeted PGC is involved in the dynamic process of gastric cancer and/or precancerous disease? Whether polymorphisms related miRNA targeted PGC can be used as a marker diagnosing high-risk individuals for gastric carcer and precancerous disease? These questions all need to be explored. This study aims to carry out a case-control study based on Northern Chinese population, to detect 5 polymorphisms related miRNA targeted PGC in the controls, atrophic gastritis and gastric cancer groups, analyzing the association of these polymorphisms and the risk of gastric cancer and precancerous disease, in the same time, according to detect the corresponding organ samples and serum samples, to explore the polymorphisms effect on the mature miRNA and PGC gene expression, furthermore its possible pathogenic mechanisms. It provides theoretical basis and experimental basis for the diagnosis of gastric cancer and to explore the polymorphism related miRNA targeted PGC as a biomarker of gastric cancer high-risk individuals.

miRNA多态做为疾病诊断的分子标志物近年越发受到学者重视。本室前期研究发现，胃蛋白酶原C（PGC）的表达从正常对照→萎缩性胃炎→胃癌依次显著下降，是胃癌及癌前疾病诊断的良好标志物。那么，以PGC为靶标的miRNA是否参与了胃癌及癌前疾病的动态变化过程？PGC靶标相关miRNA多态是否可以做为胃癌及癌前疾病高风险个体的识别标志？这些均尚未可知。本研究拟开展以中国北方人群为基础的病例-对照研究，检测对照组、萎缩性胃炎组及胃癌组PGC靶标相关的5种miRNA多态，分析其与胃癌及萎缩性胃炎（癌前疾病）发病风险的关系，并通过检测对应组织及血清标本成熟miRNA及靶标PGC基因的表达，探讨miRNA多态与成熟miRNA、及靶标蛋白PGC基因表达之间的关系，进而探讨其可能的致病机制。为胃癌的诊断及探讨PGC靶标相关miRNA多态作为胃癌高风险个体识别的标志及其机制提供理论依据和实验基础。

本项目的研究内容为探讨以PGC基因为靶标的miRNA多态是否可以作为胃癌及萎缩性胃炎发病风险的预警标志物，以及多态对成熟miRNA及靶标PGC基因表达的影响，进而探讨其可能的致病机制；同时研究miRNA与其靶标的相互作用关系。本项目在中国北方大样本人群中，首次发现了5种miRNA多态（包括let-7a1 rs10739971、let-7a2 rs629367、let-7e rs8111742、 miR-365b rs121224、miR-4795 rs1002765），与胃癌及萎缩性胃炎的发病风险相关，且首次发现四种miRNA多态与其靶标PGC基因多态在胃癌及萎缩性胃炎发生发展过程中存在交互作用。其中与胃癌发病风险相关的let-7a2 rs629367多态对其成熟体let-7a的表达有影响。这些miRNA多态均具有作为预警胃癌及癌前疾病发病风险的分子标志物的潜能。我们进一步通过生物信息学筛选及荧光素酶验证的方法，证实7种miRNA(分别为let-7c、let-7f、miR-98、miR-365、miR-520a-5p、miR-4725和miR-4795)与PGC互为靶标，该结果为阐明PGC基因与胃癌发生发展关系的作用机制提供了实验依据。另外，我们还发现PGC基因多态可能与PTPN11/IL1B基因多态存在交互作用，且PGC 基因多态是具有功能的，能够上调PGC的蛋白表达和与转录因子结合的能力。这为更好的阐述以PGC为中心的调控网络，以及系统的探讨PGC与miRNA，PGC与其他基因之间的交叉网络调控机制提供了线索。本项目经费按计划支出无结余，共计产出11篇标注该项目资助的英文论文，总影响因子达28.983分。