RNA m5C甲基化修饰调控胆囊癌发生发展的机制研究

5-methylcytosine (m5C) has been identified as the most prevalent epitranscriptomic modification on eukaryotic RNAs. Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis because of the metastasis after surgery. It is not yet clear of the comprehensive analysis of mRNA m5C methylomes in human GBC and how RNA m5C modification modulates GBC tumorigenesis and progression. In our pioneering studies, RNA m5C methyltransferase NSUN2 was up-regulated in human GBC tissues and cell lines. Functionally, we identified that NSUN2 can inhibit GBC cell migration and invision, promote colony formation in vitro. By integrating multiple platforms and technologies ranging from RNA-seq, m5C-BS-seq and bioinformatics to cell biology, molecular cell biology, biochemistry and animal models, we aim to plot m5C distribution along the GBC mRNA, identify the differentially expressed genes (DEGs) and m5C differentially modified genes (DMGs) between GBC and normal gallbladder tissue and explore molecular mechanisms how RNA m5C regulates GBC tumorigenesis and progression, by then illustrate theoretical reasons of GBC diagnosis and treatments.

5-甲基胞嘧啶（m5C）是一种在RNA中广泛存在的甲基化修饰。胆囊癌是一种常见的胆道系统恶性肿瘤，易转移，病人预后非常差。迄今对RNA m5C在胆囊癌中的甲基化图谱及其与肿瘤的侵袭转移关系仍不清楚。我们前期研究发现m5C甲基转移酶NSUN2在胆囊癌组织和胆囊癌细胞亚群中高表达；NSUN2能够抑制胆囊癌细胞的迁移和侵袭；促进胆囊癌细胞形成克隆。本项目拟结合胆囊癌临床标本转录组和甲基化组高通量测序、生物信息学、细胞生物学、分子生物学、生物化学、动物模型等平台，在国内外首次从不同角度全面深入的研究RNA m5C甲基化在胆囊癌中的分布规律；鉴定癌和癌旁组织中的差异表达基因、RNA m5C差异修饰基因及其功能；阐明RNA m5C修饰协同差异基因调控胆囊癌发生发展的机制，为胆囊癌的诊断和治疗提供新的理论依据。

5-甲基胞嘧啶（m5C）是一种在RNA中广泛存在的甲基化修饰。胆囊癌是一种常见的胆道系统恶性肿瘤，易转移，病人预后非常差。迄今对RNA m5C在胆囊癌中的甲基化图谱及其与肿瘤的侵袭转移关系仍不清楚。本项目研究发现RNA m5C甲基转移酶NSUN2在胆囊癌组织和胆囊癌细胞亚群中高表达；NSUN2能够抑制胆囊癌细胞的迁移、侵袭和划痕愈合；促进胆囊癌细胞生长和形成克隆；且在裸鼠瘤中也得到证实，NSUN2促进裸鼠皮下成瘤，抑制裸鼠肺转移瘤的形成。NSUN2的互作蛋白RPL6能够调控其促进胆囊癌的生长。RNA m5C甲基化在胆囊癌比癌旁组织中丰度高。HuR 是NSUN2 影响胆囊癌进程的潜在的下游靶基因。我们的研究有望为胆囊癌的诊断和治疗提供新的理论依据。