慢性炎症促胰腺癌发生。申请人发现炎症细胞主要群体—巨噬细胞，能够抑制胰腺导管上皮细胞（PDEC）中DNA损伤修复关键基因BRCA1、BRCA2表达。基于前期研究提出科研假说：巨噬细胞一方面通过TGF-β通路，上调PDEC中miR-1224-3p、miR-526b-5p等靶向BRCA1/2 mRNA的miRNA；另一方面通过外泌体，向PDEC输送5'核酸外切酶XRN1。XRN1能够降解结合了miRNA的mRNA。两方面协作，降解BRCA1/2 mRNA，下调其表达，进而抑制DNA同源重组修复，导致基因组不稳定，从而增加恶变几率。基于前期建立的多种体内体外模型，我们将研究巨噬细胞/外泌体/XRN1，和巨噬细胞/TGF-β/miRNA信号通路，对PDEC中BRCA1/2表达的调控；以及BRCA1/2缺陷对DNA损伤修复和基因组稳定性的影响。从而为揭示胰腺“炎癌转化”的分子机制奠定一定的理论基础。

Chronic inflammation is a risk factor of pancreatic cancer. However, the mechanisms involved are still unclear. Previous studies have shown that inflammation can inhibit the expression of BRCA1. Deficiencies of BRCA1 and BRCA2 increase the incidence of pancreatic cancer. Since BRCA1 and BRCA2 participate in the homologous recombination (HR) repair of DNA double-strand break (DSB), and play an important role in maintaining genomic stability, it is possible that inflammation might promote the occurrence of pancreatic cancer through repressing expressions of BRCA1 and BRCA2. Based on our serial studies, which were supported by previous NSFC grants, we found out that marcrophages, the dominant population of inflammatory cells, could repress expressions of BRCA1 and BRCA2 in pancreatic ductal epithelial cells (PDECs). We hypothesize that marcrophages could up-regulate several miRNAs in PDECs through TGF-β pathway. These miRNAs include miR-1224-3p and miR-526b-5p et. al., which could target BRCA1 and BRCA2 mRNAs. Binding of miRNAs could stimulate 5' decapping of BRCA1 and BRCA2 mRNAs. Moreover, macrophages might deliver XRN1, the key 5' exoribonuclease, into PDECs through exosome manner. XRN1 can recognize and degrade 5' decapped mRNAs. These two mechanisms may synergistically result in the selective degradation of BRCA1 and BRCA2 mRNAs. Down-regulations of BRCA1 and BRCA2 inhibit homologous recombination (HR)-mediating DNA double-strand break (DSB) repair, leading to genomic instability and mutation accumulation, which will increase the risk of tumorigenesis. In the present study, we will verify the mechanisms involved in the regulation of BRCA1 and BRCA2 expressions through macrophage/TGF-β/miRNA, and macrophage/exosome/XRN1 pathways. Moreover, by using several well-established animal models, we will investigate the participation of BRCA1 and BRCA2 deficiencies in the genomic instability. Our study will not only establish a new paradigm that significantly affects our views on how chronic inflammation leads to the occurrence of pancreatic cancer, but will also lay groundwork for discovering new markers for the early diagnosis of deadly pancreatic cancer.