转运RNA衍生片段在子宫内膜癌中的作用机制与临床意义

tRFs是一类新型的转运RNA衍生的小RNA片段。近年来针对tRFs的功能解析迅猛发展，但其具体作用方式和参与的信号通路仍知之甚少。我们前期研究发现，在子宫内膜癌肿瘤组织存在大量异常表达tRFs，来源于血浆外泌体的若干5ʹ-tRFs可以准确区分健康人和子宫内膜癌病人，并初步鉴定了子宫内膜癌中的tRF ArgTCT-20在肿瘤中异常高表达且与病人预后显著负相关。为此，我们提出了tRFs失调促进了子宫内膜癌发生发展进程的研究假说。本项目将利用小RNA测序数据鉴定子宫内膜癌的驱动tRFs，建立能有效地早期诊断并预测早期子宫内膜癌病人临床结果的tRF表达谱，阐明tRFs在子宫内膜癌发生发展和转移复发中的作用及机制。本项目有望发现作为癌症药物新靶点的tRFs及其调控的下游因子。同时，预期发现的tRFs有潜力作为临床诊断和预后的分子标记物，从而为将来子宫内膜癌病人个性化治疗打下坚实基础。

Transfer RNA-derived RNA fragments (tRFs), a novel class of small non-coding RNAs, have received much attention in the past few years, yet their mechanistic role in cancer remains largely unexplored. Our preliminary data analysis has revealed that both 5ʹ-tRFs and 3ʹ-tRFs were globally dysregulated in endometrial tumor tissues. We also performed small RNA sequencing in 29 plasma samples from healthy volunteers and endometrial carcinoma patients, and identified several candidate exosomal tRFs as diagnosis biomarkers for non-invasive screening endometrial carcinoma patients. We further identified a candidate cancer driver tRF ArgTCT-20 which was highly expressed in endometrial carcinoma and was significantly associated with worse prognosis of endometrial carcinoma patients. Based on our strong and extensive preliminary data, we hypothesized that dysregulations of tRFs promote tumorigenesis and progression in the endometrium. To test our hypothesis, we proposed to develop an innovative bioinformatics tool to identify cancer driver tRFs, identify a tRF signature which can distinguish tumor patients from health women and tumor precursors, and investigate their mechanistic roles in endometrial tumorigenesis and progression. At the successful completion of this project, we will identify tRF-regulated downstream elements and determine their mechanistic roles in endometrial cancer. Such results are highly likely to provide novel biomarkers for diagnosis and prognosis and anti-cancer therapy in addition to fundamentally advancing the knowledge of endometrial tumorigenesis and progression.