TLRs/NO途径在高危型HPV感染宫颈局部免疫调节中的作用

Persistent high-risk Human Papilloma Virus (HPV) infection is an essential condition to cause cervical cancer, but the factors determining the prognosis of HPV infection remain unknown. The preliminary researches indicated that Toll-like receptors(TLRs)/ nitric oxide(NO) pathway might be involved in the local immunoregulation of cervical high-risk HPV infection. In this project we further presumed that the destruction of the high-concentration HPV E2 gene function by high-concentration NO might be an initiation factor in high-risk HPV-induced cervical carcinogenesis, while TLRs/NO pathway might be downregulated by HPV E6 and E7 in epithelial tissue of cervical cancer so as to avoid the cytotoxicity of high-concentration NO. In order to prove the foregoing points, this project will further conduct both in vivo and in vitro researches, which mainly focus on: (1) the relationship between TLRs/NO pathway expression and HPV infection status in various grade cervical lesions; (2) the effect of high-concentration NO on HPV E2 gene and its related signaling molecules; (3) the downregulation of TLRs/NO pathway by HPV E6 and E7. The results of this project will contribute to further understanding the role of TLRs/NO pathway in the immunoregulation of cervical high-risk HPV infection, so as to establish a research basis for early prevention and treatment of HPV infection and cervical cancer.

高危型人乳头瘤病毒(HPV)持续性感染是引起宫颈癌的必要条件，但决定HPV转归的因素尚不明确。前期研究提示，Toll 样受体（TLRs）/一氧化氮(NO)途径可能参与宫颈高危型HPV感染的局部免疫调节。本项目进一步推测：高浓度NO对HPV E2基因调控功能的破坏可能在高危型HPV感染致癌机制中起始动作用；而宫颈癌上皮组织可通过HPV E6、E7降调节TLRs/NO途径以实现逃避高浓度NO细胞毒性的目的。为了验证以上观点，本项目拟分别从体内及体外两个方面进行研究，主要包括：（1）体内宫颈上皮TLRs/NO途径表达情况与HPV感染及宫颈病变程度的关系；（2）高浓度NO对E2基因及其相关信号分子的影响；（3）E6、E7对TLRs/NO途径的降调节机制。本项目研究成果将有助于深入了解TLRs/NO途径在宫颈局部免疫调节高危型HPV感染中的作用，从而为HPV感染及宫颈癌的早期防治工作提供研究基础。

高危型人乳头瘤病毒(HPV)持续性感染是引起宫颈癌的必要条件，但决定HPV转归的因素尚不明确。以往研究提示，Toll 样受体（TLRs）/一氧化氮(NO)途径可能参与宫.颈高危型HPV 感染的局部免疫调节。本项目进一步通过体内和体外研究探讨了TLRs/NO 途径在宫颈局部免疫调节高危型HPV 感染中的作用，发现：在hrHPV感染导致的宫颈鳞癌组织中NO的含量以及TLRs/iNOS信号通路的表达水平显著高于hrHPV感染的正常组织；在LPS刺激下，hela、Caski 等hrHPV阳性的宫颈癌细胞株TLR4水平高于hrHPV阴性的宫颈癌细胞株，并且细胞增殖能力增强，抗凋亡能力有所提高，hrHPV阳性宫颈癌细胞株Hela、Caski在12小时上清液NO含量显著高于rhHPV阴性宫颈癌细胞株C-33a。上述研究阐明了TLRs/iNOS信号通路（尤其是TLR4/iNOS信号通路）在免疫调节HPV感染转归及宫颈癌发生机制中的可能作用,从而为HPV 感染及宫颈癌的早期防治工作提供研究基础。