HMGB1对Treg介导宫颈癌免疫逃逸的影响及机制研究

Persistent infection with HPV caused cervical cancer is a serious threat to women's health. At present，the research about the role of the immune escape of tumor cells in cervical cancer is rare. Our researchs show that Foxp3 expression significantly increased accompanied with the higher levels of cervical lesions and the lower degree of cell differentiation and Langer's cells were significantly reduced. That initially confirmed that Treg was related to the local cervical immune. We also found that the higher levels of cervical lesions the more expression of HMGB1 protein, which suggest HMGB1 play an important role in this process that chronic inflammation caused by HPV infections progress to cervical cancer. EP and anti-RAGE can inhibit tumor growth in tumor-bearing mouse model. Combined with the latest international research foundation and previous study, we guess that HMGB1 with RAGE ligand binding, through the regulation of p38MAPK signaling pathway, affect the escape Treg-mediated immune response, promot cervical cells evade the immune system "kill" to promote the process development of HPV infection to cervical intraepithelial neoplasia to cervical cancer, and ultimately lead to cervical cancer. The project intends to proceed from a new vision, a comprehensive understanding of HMGB1 on the effect and mechanism of Treg-mediated cervical cancer immune escape in order to provide a new immunization strategy for cancer prevention and treatment.

宫颈癌是严重威胁女性健康的一种高发病。目前针对肿瘤细胞免疫逃逸在宫颈癌发病中作用的研究很少。申请者前期研究表明随宫颈病变级别增高及细胞分化程度降低Treg特异性表达因子Foxp3表达水平明显增多，Langer's细胞明显减少，初步证实Treg与宫颈局部免疫调节相关。同时发现随宫颈病变进展HMGB1表达水平明显增加，提示在HPV感染进展为宫颈癌这一过程中HMGB1发挥重要作用。HMGB1抑制剂及RAGE受体封闭剂能够明显抑制宫颈癌荷瘤鼠模型肿瘤生长。结合国际研究进展及前期工作基础，推测HMGB1与RAGE结合，通过调控p38MAPK信号通路，影响Treg介导的免疫逃逸反应，促进宫颈细胞逃避免疫系统"杀伤"，推动"HPV感染-CIN-宫颈癌"这一进程发展，最终导致宫颈癌发生。本项目拟从一个新的视觉出发，全面了解HMGB1对Treg介导宫颈癌免疫逃逸的影响及作用机制，为宫颈癌免疫防治提供新策略。

宫颈癌是严重威胁女性健康的一种高发病。目前针对肿瘤细胞免疫逃逸在宫颈癌发病中作用的研究很少。本项目拟从一个新的视觉出发，全面了解HMGB1对Treg介导宫颈癌免疫逃逸的影响及作用机制，为宫颈癌免疫防治提供新策略。本研究通过对不同宫颈病变组织中HMGB1表达进行检测，提示HMGB1在宫颈癌中表达较高，与宫颈癌的FIGO分期、淋巴结转移及预后生存时间密切相关；研究同时表明HMGB1的表达与NF-KB和N-cadherin呈正相关；与E-cadherin呈负相关，HMGB1可能激活NF-KB活性引起宫颈癌的发生发展。在体外研究表明HMGB1的刺激可改变Hela细胞的生物学行为，增强Hela细胞的增殖及侵袭能力；同时，HMGB1的刺激可增加NF-KB及N-cadherin的表达水平；降低E-cadherin的表达；抑制NF-KB及拮抗RAGE受体后HMGB1的刺激作用明显减低，HMGB1可能是通过NF-KB通路引起宫颈癌的发生发展。通过本项目研究结果，提示HMGB1可能成为宫颈癌诊断、治疗及评估预后的重要指标。