高危型人乳头瘤病毒（HR-HPV）慢性持续性感染致细胞恶性转化经历了潜伏、分泌、转化三个阶段，后两者分别导致低级别和高级别上皮内病变（即LSIL、HSIL），且p16INK4a的弥漫表达是鉴别诊断HSIL的核心分子标识。如何遏制LSIL向HSIL转化依然是目前精准治疗的难题。我们采用激光捕获显微切割技术获得HSIL及LSIL微量组织进行lncRNA测序，发现HSIL组织中强效致癌基因MIR17HG显著升高；并研究发现，MIR17HG的表达不仅被E6、E7调控，还启动了p16INK4a的表达；推测HR-HPV转化感染阶段MIR17HG的升高驱动了细胞转化。本课题拟解析HPV16感染过程中MIR17HG表达上调并调控p16表达启动细胞恶性转化的分子机理；利用小鼠肿瘤模型探讨纳米材料包裹的MIR17HGsiRNAs阻断并逆转细胞转化的抗肿瘤形成作用；旨在为子宫颈癌及癌前病变的防治提供新思路。

The malignant transformation of cervical epithelial cells caused by chronic persistent HR-HPV infection experiences three phases of latent, productive, and transforming infection, and the latter two phases can result in LSIL and HSIL, respectively. The diffuse expression of p16INK4a is a crucial molecular marker for identification and diagnosis of HSIL. How to inhibit the transformation of LSIL to HSIL is a challenge for precise treatment of the disease. We have sequenced the lncRNA expression profiles with microtissues from HSIL and LSIL by laser capture microdissection and found that the expression of a powerful cancer gene MIR17HG has been significantly increased. Furthermore, MIR17HG is regulated by E6 and E7, and can initiate the expression of p16INK4a. We speculate that MIR17HG induces cell malignant transformation during HR-HPV transforming infection phase. We plan to explore the molecular mechanisms of malignant transformation of cervical epithelial cells due to HPV16 infection; particularly, how the expression levels of MIR17HG are upregulated, and then how MIR17HG contributes to the induced expression of p16. We will explore the anti-tumorigenesis effects by MIR17HG siRNAs coated with nanoparticles on tumor xerographs in nude mice. We hope to provide novel insights in the prevention and therapy of cervical cancer and precancerous lesions.