血浆分泌型miRNA作为非小细胞肺癌分子标志物及参与肿瘤微环境调节的机制研究

非小细胞肺癌（NSCLC）早期诊断困难，预后差， 但无理想的分子诊断标志物。分泌型miRNA是一类具备生理功能的新型细胞间信号交流分子，与肿瘤密切相关。我们前期研究发现，一些miRNA在NSCLC血浆和癌细胞培液外泌体（exosome）中均高表达；肺癌细胞分泌的exosome可携带特定miRNA进入相关成纤维细胞和巨噬细胞；生物信息学预测它们参与这两种细胞表型和功能变化。据此提出假说：血浆分泌型miRNA是NSCLC潜在的分子标志物，它们以exosome为载体进入肿瘤微环境相关成纤维细胞和巨噬细胞，改变其表型和功能，参与NSCLC发生发展。为验证假说，我们拟通过临床标本、细胞及动物研究，筛选对NSCLC有诊断价值的分泌型miRNA；探明其调节肿瘤微环境相关成纤维细胞和巨噬细胞的作用机制；构建其与下游靶基因间的调控网络。为NSCLC的诊断、发病机制、分子靶向治疗提供新思路和新途径。

NSCLC is difficulty in early detection and has a poor prognosis; however, no specific diagnostic marker has been discovered. Secreted miRNAs are a class of novel intercellular communication signal molecules that have physiologic functions. Our previous studies found that several miRNAs were significantly upregulated in exosomes from plasma from NSCLC patients and also from supernatant of NSCLC cell lines; NSCLC-secreted exosome was able to carry specific miRNAs into fibroblasts and macrophage; Bioinformatics analysis suggested that these miRNAs might be involved in the alteration in phenotype and function of these two kinds of cells. Thus, we hypothesize that plasma secreted miRNAs are potential molecular biomarkers of NSCLC and they may enter into tumor microenvironment-associated fibroblasts and macrophage, change their phenotype and function and be involved in the development and progression of NSCLC. In order to verify this hypothesis, we will adopted clinical samples, cell lines and tumor-bearing mouse model, to select secreted miRNAs that have clinical value in the diagnosis of NSCLC; to explore the role and mechanism of secreted miRNAs in regulating tumor microenvironment related fibroblasts and macrophage; and to construct the regulatory network between miRNAs and their downstream target genes. The purpose of our study is to open up a new idea and new ways for the diagnosis, mechanism and molecular targeting treatment of NSCLC.