MiR-375 对HPV16/18癌基因E6/E7的调控作用及其机制

高危人乳头瘤病毒（HR-HPV）癌基因E6/E7持续过度表达是宫颈癌发病与进展的关键环节，但迄今对E6/E7高表达的原因及机制仍不确定。miRNA在基因调控中的重要作用为我们探索E6/E7调控机制带来新的启迪。我们初步研究发现，在宫颈癌及其前期病变中miR-375与HPV 16/18 E6/E7表达呈负相关，过表达宫颈癌细胞中miR-375可引起E6/E7表达下调，表明miR-375可能参与E6/E7的表达调控。本课题拟从miRNA调控病毒关键基因表达的全新视角，从分子、细胞、组织标本及动物实验多个层次验证，并寻找miR-375调控这一生物学行为的关键靶体，探讨miR-375在HPV持续感染，HPV整合及致病过程中的重要作用，旨在揭示宫颈癌高危HPV病毒癌基因表达的分子调控机制及机体的防御机制，为寻找阻断宫颈癌发生的新靶点提供证据。

High risk human papillomavirus (HR-HPV) oncogenes E6/E7 constant overexpression is the key step to initiation and progression of cervical cancer. However, the mechanism of E6/E7 high expression is still unclear. The important role of microRNAs (miRNAs) in regulation of genes provides us a new idea in exploring the regulation mechanism of E6/E7. Our current experiment have showed miR-375 expression levels were inversely correlated with HPV16/18 E6 and E7 levels in both precancerous lesions and cervical cancer tissues, and overexpression of miR-375 could inhibited the expression of E6 and E7 in cervical cancerl cell lines. Thus, in this study, we explored the significance and molecular mechnisms of miR-375 in regulating the expression of HR-HPV oncogenes E6/E7 from different levels of molecules, cells, sufficient series of well-defined clinical specimens, and animal models, designed to rich HPV carcinogenic theory and reveal body's defense mechanism, and suggest miR-375 might be an anticancer therapeutic target for cervical cancer patients.