具核梭杆菌(Fn)对我国高发地区食管鳞癌发生发展的影响及机制研究

食管鳞癌是我国特色的高发癌种，有家族和地域聚集性，且诱因不明。在高发地区，不良饮食习惯、家族病史、口腔卫生差可使患病风险增加2-5倍，这些因素均会影响食管微生态健康。申请人分析了155例我国食管鳞癌患者的微生态特征，发现病灶中含多种致病微生物，其中具核梭杆菌（Fn）是高丰度致病菌之一，与预后差显著相关。为了深入阐明Fn对食管鳞癌发生发展的影响和作用，本项目利用663例我国高发区患者样本开展以下研究：临床数据分析：①基于患者全基因组数据分析Fn丰度、检出率；②基于病理和随访资料建立Fn与病情发展、预后的关系。表型检验：利用细胞系、食管鳞癌原发模型鼠，检验Fn感染对病情发生发展的影响。机制研究：①基于患全基因组、转录组数据，筛选与Fn富集有关的基因/通路，并在细胞/动物层面验证；②利用基因编辑技术或药物开展细胞实验，检验上述基因/通路的作用。最终阐明Fn对我国食管鳞癌发生发展的影响和作用机制。

Abstract: Esophageal squamous cell carcinoma (ESCC) is a type of cancer with high incidence in China, with family and regional clustering characteristics, but the causes are unclear. In the high risk areas, poor diet, family history of ESCC, and poor oral hygiene are associated with an increased risk for ESCC by 2-5 times, all those risk factors can disturb the health of the "esophageal microbiota ecosystem". The applicant completed the microbiological analysis of 155 ESCC patients in China, and found that ESCC contains a variety of pathogenic microbes, among which the Fusobacterium nucleatum (Fn) is one of the high abundance pathogenic bacteria, which is significantly correlated with poor prognosis. In order to further clarify the effects and mechanisms of Fn on the tumorigenesis and progression of ESCC in China, series of studies will be carried out on the basic of 663 Chinese ESCC patients from the high-incidence areas. Firstly, Clinical data analysis: a). Fn abundance and positive rate will be analyzed based on patients’ whole genome sequence data. b) The relationship between Fn and disease progression and prognosis will be established based on the pathological information and follow-up data. Secondly, Phenotypic study: Cell lines, cell line transplantation model and primary ESCC mice model will be employed to explore the influence of Fn infection on the development and progression of ESCC. Thirdly, Mechanism study: a). Based on patients’ omics data, the genes/pathways that are related to Fn enrichment will be screened, and then validated at the cellular/animal level. b) To confrim the critical function of genes/pathways above, cell experiments will be conducted with gene editing technology or small molecule drugs. The final aims of the study are to clarify the influence and mechanism of Fn on the progression of ESCC patients in China, and provide theoretical basis for developing mirobiological therapy for ESCC.