PER1介导昼夜节律紊乱重塑免疫微环境促进口腔鳞状细胞癌进展的作用机制研究

昼夜节律紊乱与多种癌症类型的罹癌风险上调相关。我们前期研究发现，节律抑制臂基因PER1等在口腔鳞状细胞癌（OSCC）中表达下调；OSCC癌组织及唾液外泌体miR-24-3p表达上调，外泌体miR-24-3p通过靶向抑制受体细胞PER1的表达发挥其促增殖作用；PER1与免疫系统存在双向调控网络，肿瘤微环境中免疫细胞及炎症因子重编程，IL-6通过招募骨髓来源的抑制细胞促进OSCC发生发展。因此，我们提出昼夜节律紊乱-PER1-IL-6-外泌体miR-24-3p-PER1环路传递节律失衡信号，进而塑造促癌免疫微环境参与OSCC发生发展。本项目拟通过临床病例、节律紊乱模式动物多层面探讨PER1重塑OSCC免疫微环境的机制及作用；同时分析以PER1为靶点的“时间生物化学疗法”对传统顺铂防治疗效的提升作用。旨在为阐明昼夜节律紊乱在OSCC癌变进展中的作用提供证据支持和防治新策略。

Circadian clock disruption increases the risk of many types of cancer. In our previous study, we found that the expression of PER1 and other genes that constitute the repressive arm of circadian clock were down-regulated in oral squamous cell carcinoma (OSCC). We also found that miR-24-3p expressed a higher level in OSCC neoplastic tissues and salivary exosome, exosomal miR-24-3p could promote the proliferation of recipient OSCC cells through targeting PER1; There is a complex bidirectional interaction between components of the circadian clock and components of the immune system, the infiltrate density and composition of immune cells and inflammatory cytokines in the tumor microenvironment are reprogrammed; and IL-6 facilitate the recruitment of myeloid derived suppressor cells to mediate initiation and progression of OSCC. Therefore, we proposed that circadian rhythm disruption-PER-IL-6-exosomal miR-24-3P-PER1 loop may act as a messenger for the dislocation of circadian rhythm with adjacent or distant cells，and accelerate OSCC progression by generating a cancer-promoting immune microenvironment. Our present study intends to use clinical cases and animal model with disrupted circadian rhythmicity to clarify the mechanism of the circadian clock disruption and PER1 modulates the tumor immune microenvironment; and to explore whether the application of optimal circadian timing of drug delivery determined by clock gene PER1 can improve the efficacy of conventional cisplatin therapy. Our results would be helpful to elucidate the role of circadian rhythm disorders in the carcinogenesis of OSCC, and provide references for the use of circadian clock to guide OSCC prevetion and treatment.