舌鳞癌细胞通过SASP调控EZH2进行衰老相关重编程的作用机制

Cellular senescence is widely regarded as irreversible cell cycle arrest and protection against cancer. However, recent studies suggested that the senescent cancer cells could escape from senescence and re-enter cell cycle. Moreover, senescence-associated reprogramming contributed to more aggressive behavior of tumor. The mechanism is yet to be understood. Senescent cells remain viable and typically release senescence-associated secretory phenotype (SASP) to remodel the micro-environment. Moreover, SASP facilitates reprogramming. Our previous study suggested that tongue squamous cell carcinoma (TSCC) cells could undergo senescence escape, along with changes of histone modification and upregulation of EZH2. The expression of EZH2 in TSCC cells was correlated with recurrence. The key cytokines of SASP could regulate the expression of EZH2. Based on these results, we propose that senescent TSCC cells secrete SASP to regulate EZH2, which further promotes senescence-associated reprogramming and results in the cancer evolution. At first，we work to identify the role of EZH2 during senescence-associated reprogramming. Next, we study the effect of SASP in regulating EZH2. Then we will detect the remodeling of the epigenetic modifications, chromatin accessibility, signaling pathways and malignant behaviors in the process of senescence-associated reprogramming. We hope this study can reveal a new mechanism of cancer evolution through senescence, then to raise a new promising target for TSCC biotherapeutics.

细胞衰老构筑的不可逆性细胞周期阻滞，曾被认为是人体对抗肿瘤的保护机制。然而，新近研究发现，肿瘤细胞能发生衰老逃逸，并通过衰老相关重编程发生恶性功能进化，但机制不明。衰老细胞仍保持新陈代谢，通过衰老相关分泌表型（SASP）调控微环境。SASP能促进细胞重编程。我们前期研究发现，舌鳞癌细胞能发生衰老逃逸，过程中伴随组蛋白修饰改变，表观遗传调控因子EZH2上调；舌鳞癌原发灶EZH2表达与患者复发相关；并且证明，SASP的关键细胞因子可以调控EZH2表达。据此，本课题组率先提出：舌鳞癌细胞通过SASP调控EZH2进行衰老相关重编程，实现肿瘤进化。拟探讨EZH2调控衰老相关重编程的机制，分析衰老细胞自分泌SASP对EZH2的调控作用，进而从表观遗传修饰、染色质开放性、信号通路、恶性生物学表型等方面研究衰老相关重编程的动态重塑，阐明通过衰老相关重编程促进肿瘤进化的机制，为肿瘤生物治疗提供理论依据。

细胞衰老构筑的不可逆性细胞周期阻滞，曾被认为是人体对抗肿瘤的保护机制。然而，新近研究发现，肿瘤细胞能发生衰老逃逸，并通过衰老相关重编程发生恶性功能进化，但机制不明。衰老细胞仍保持新陈代谢，通过衰老相关分泌表型（SASP）调控微环境。SASP能促进细胞重编程。本课题组提出：舌鳞癌细胞通过SASP调控EZH2进行衰老相关重编程，实现肿瘤进化。拟探讨EZH2调控衰老相关重编程的机制，分析衰老细胞自分泌SASP对EZH2的调控作用，进而从表观遗传修饰、染色质开放性、信号通路、恶性生物学表型等方面研究衰老相关重编程的动态重塑，阐明通过衰老相关重编程促进肿瘤进化的机制，为肿瘤生物治疗提供理论依据。本项目根据以上研究目标，构建舌鳞癌细胞衰老的体外模型，系统性评价可用于检测肿瘤细胞衰老相关指标，评估各种不同指标的特异性、敏感性及适用范围；构建工具细胞P16INK4a-tdTOMATO自荧光报告衰老细胞模型，为纯化衰老细胞并进一步探究衰老逃逸的机制夯实了基础；并在研究中发现，EZH1、EZH2相互竞争PRC2复合物催化亚基结构在调控口腔鳞癌细胞重编中的作用机制；通过体外实验我们发现舌鳞癌细胞系中存在衰老逃逸的现象。此外，我们发现在口腔癌前病损存在大量衰老细胞，同时早期癌变的肿瘤组织兼具衰老和干性特征，提示衰老相关重编程可能是癌前病损恶变的重要途径。包括dNTP代谢的代谢重编程是推动衰老逃逸的重要机制，Hippo通路在其中发挥了重要作用。