幽门螺杆菌感染是导致胃上皮细胞癌变最强的危险因素，环状RNA是目前RNA领域的最新研究热点，申请者首次发现环状RNAhsa_circ_0002669在胃癌组织中表达显著降低并发挥重要的生物学功能，幽门螺杆菌感染可显著抑制其表达。本课题拟在此基础上：①探讨幽门螺杆菌通过NF-κB及β-catenin依赖的途径调节RNA编辑酶ADAR1表达，并从ADAR1介导的RNA编辑视角解析幽门螺杆菌抑制该环状RNA表达的分子机制；②确定该环状RNA作为miRNA“海绵”所吸附的miRNA并剖析miRNA所靶向的下游分子，明确该环状RNA抑制胃粘膜细胞恶性转化的分子机制，阐明幽门螺杆菌通过调控该环状RNA及其下游分子网络促进细胞恶性转化的机理。③从动物及临床组织标本中验证该环状RNA及其分子网络在幽门螺杆菌感染促进胃粘膜细胞恶性转化中的作用。为基于circ_0002669为靶点的胃癌早期干预提供理论依据。

Infection with helicobacter pylori (H. pylori) is regarded as the strongest risk factor for gastric carcinogenesis and progression. CircRNA is considered as the new research hotspots in the field of RNA. Our previous study results showed that the level of hsa_circ_0002669 was down-regulated significantly in human gastric cancer tissues compared with the corresponding noncancerous tissues by RNA sequencing analysis and qRT-PCR validation. Furthermore, we found that the level of hsa_circ_0002669 can be significantly inhibited with helicobacter pylori infection in gastric epithelial cells. Overexpression of hsa_circ_0002669 can inhibited cell proliferation and migration significantly. But the molecular mechanism has not yet been clarified. Based on the recent research progress and our previous studies, the aim of this project is to explore the molecular mechanism of gastric mucosa tissues malignant transformation induced helicobacter pylori by regulating hsa_circ_0002669 from molecules and cells level, experimental animal level and the clinical gastric tissue sample level. The main contents of this project are as follows： (1) To investigate whether helicobacter pylori can up-regulate RNA editing enzymes ADAR1 expression through NF-κB andβ-catenin signal pathway. To make clear the molecular mechanism of helicobacter pylori inhibiting hsa_circ_0002669 expression from RNA editing angle mediated by ADAR1；(2) To make clear the molecular mechanisms of hsa_circ_0002669 inhibiting the malignant transformation of gastric epithelial cells. To investigate whether hsa_circ_0002669 can act as miRNA molecule "sponge" and identify the miRNA that can bind with hsa_circ_0002669 and explore the downstream target molecules of the miRNA. To elucidate the mechanism of helicobacter pylori promoting the malignant transformation by regulating hsa_circ_0002669 and its downstream target molecules network.(3) To verify that helicobacter pylori promotes the malignant transformation of gastric mucosa tissues by regulating hsa_circ_0002669 and its downstream target molecules network from the animal level and human pathological tissue levels. This study aims to provide the theory evidence for the hypothesis that hsa_circ_0002669 can be used as a key point and therapeutic target in the early intervention of gastric cancer .