miR-375/JunD信号通路介导的细胞分化在HPV持续感染中的作用及机制

Human papillomaviruses (HPV) infect stratified epithelia and link their productive life cycles tothe differentiation state of the host cell.The factors. In HPV-infected epithelia, cells remain active in the cell cycle upon differentiation to allow productive HPV genome，This process is regulated in part by multiple factors which reduces the proliferative capacity of differentiating epithelial cells replication in suprabasal cells. So differential situation of suprabasal cells is very important for infection model.Any factors blocking the progression of host cell differentiation will changes the infection model and lead to persistent infection. The activity of early gene promoter p97 of HR-HPV is closely related to differentiation of infected host cells.So, HR-HPV may infect the host cell persistent depend on the change of differentiation state induced by itself. miR-375 is an important miRNA related to the progression of malignant cells of cervical cancer, and it is closely related to the expression of E6/E7, but the exact mechanism is still unknown. JunD is a potential target gene targeted by miRNA TargetScan software online, and it is also an important transcript factor of many downstream genes, including the early promoter p97 of HPV 16. And JunD has been proposed to regulate the balance between epithelial proliferation and differentiation. In our previous studies, forced expression of miR-375 in Siha cell line induced decrease of JunD protein expression. It suggest miR-375 may regulate the transcriptional activity of p97 by targeting transcript factor JunD, and on the other hand, miR-375 influence the differentiation of the cervical epithelial cells to benefit the productive life cycle. This research project is try to find out the mechanism of miR-375 regulate the differentiation function by targetting JunD, and influence the activity of promoter p97 and infecion model.

宿主细胞分化是病毒完成完整生命周期所依赖的必备条件，任何阻断或影响细胞分化的因素都使得病毒的感染模式发生改变，而发生持续感染。HR-HPV早期基因E6/E7共同启动子p97的转录活性与受感染宿主细胞的分化密切相关，因此，HR-HPV可能通过自身基因组介导宿主细胞分化改变，导致病毒持续感染。MiR-375作为一个肿瘤抑制性miRNA,在宫颈癌组织中表达下调，并且在此基础上发现miR-375的表达与病毒E6/E7表达密切相关，同时在miR-375过表达时，宿主细胞JunD的表达水平明显下降。因此本研究拟从多个角度探讨miR-375通过靶向JunD介导调控了细胞的分化过程，调节p97转录活性影响病毒癌基因的表达，从而影响病毒的感染模式。为完善病毒致癌理论提供依据，为探寻新的靶向治疗提供研究基础。

高危型HPV是宫颈癌发生的主要病因，病毒癌基因的持续异常表达是发生病变的主要机制，HR-HPV早期基因E6/E7共同启动子p97的转录活性与宿主细胞的参与密不可分。已有的研究发现MiR-375作为一个肿瘤抑制性miRNA,在宫颈癌组织中表达下调，在宫颈癌的发生和进展中起重要作用。本研究围绕JunD分子展开，深入的探讨miR-375通过靶向调控JunD分子调控病毒癌基因的表达异常，参与病毒致癌的过程，并且进一步通过对JunD分子的功能研究，探寻JunD分子作为转录调控因子在宫颈癌中的重要作用。通过这项研究发现，miR-375可以直接调节JunD的表达，一方面miR-375的过表达抑制了JunD的水平，进而抑制了细胞增殖、促进细胞发生凋亡、抑制了细胞的侵袭能力，影响细胞的生物学行为。另一方面，JunD作为宿主细胞的重要转录调控因子，通过与p97启动子区的特异性结合活化病毒癌基因的转录表达，miR-375的过表达削弱了JunD的促进转录的功能，遏制了病毒癌基因启动子的转录活化，抑制病毒癌基因的表达，并进一步影响下游效应分子的蛋白水平而发挥功能。该项研究不仅充分的探讨了JunD在宫颈癌的中作用及机制，并且从miRNA、转录调控等方面深入探讨了HPV病毒癌基因表达失调控的机制，进一步完善了宫颈癌的致病机理，为寻找预防和寻找新的治疗靶点提供了理论和基础。