NOTCH1与STAT3互为ceRNA调控口腔鳞癌肿瘤干细胞的机制研究

CeRNA(competing endogenous RNA) is a kind of endogenous RNAs that regulate their targets in a miRNA competing based mechanism through hare multiple MicroRNA response elements. In this project ,we hypothesize that NOTCH1 and STAT3 may have the potential interaction serve as ceRNA, which regulate cancer stem cells of OSCC by competing a panel of shared miRNAs. This project including 3 parts:Firstly,we screen the shared miRNA by bioinformatic analysis and data mining.Then the expression pattern of NOTCH1 and STAT3 as well as their shared miRNA in human OSCC cell line, C57BL/6 mice model and human samples were detected and biological validation were performed using functional NOTCH1 and STAT3 3'UTR transfection and DICER knock down assay to confirm the ceRNA interaction of NOTCH1 and STAT3. Secondly,we explore the molecular mechanism of NOTCH1 and STAT3 shared miRNA’s influence on cancer stem cells and chemotherapeutic resistence.Knockdown or overpression of shared miRNA were performed in OSCC cell lines and mice model. Thirdly, we will further design combined exogenous competing miRNA sponges based on our data, exploring experimental therapeutics of OSCC by inhibiting NOTCH1 and STAT3 shared miRNA in vitro and in vivo, even clinical trials if possible,investigating their role in oral cancer carcinogenesis and treatment. Achievments of this project will better understand the multiple layer interpretation of key tumor suppressor gene in cancer stem cells of OSCC and develop new stratege for OSCC therapeutics.

CeRNA(competing endogenous RNA) 是能够通过miRNA应答元件竞争结合相同miRNA进而调控靶基因的内源性RNA。通过前期研究,我们提出如下假说：“口腔鳞癌中NOTCH1和STAT3互为ceRNA，通过竞争共享miRNA调控对方的表达，进而调控肿瘤干细胞的功能，影响口腔鳞癌患者的生存及预后”。本项目拟从以下方面开展工作：1.利用生物信息学分析及口腔鳞癌细胞系、小鼠模型和人类标本分析和验证NOTCH1 及STAT3 共享miRNA，并通过转染彼此 3'UTR 及敲减DICER 策略验证NOTCH1 及STAT3 的ceRNA关系；2.明确共享miRNA对口腔癌肿瘤干细胞的调控机制及其对口腔癌化疗耐受的影响；3.设计外源竞争性miRNA海绵，探索体外及小鼠舌癌模型的实验性治疗。研究结果将加深对口腔癌肿瘤干细胞分子网络调控机制的理解，为口腔癌的治疗提供新的靶点及策略