新近发现，上皮细胞自我更新受表观遗传机制调控，其异常与口腔黏膜癌变密切相关。KDM4A作为关键的组蛋白去甲基化酶，在其中作用受到关注。申请人前期研究提示：该酶高表达促进癌细胞侵袭、与患者预后负相关，但其在黏膜癌变早期有何功能？是否通过影响上皮自我更新促进黏膜癌变，都有待阐明。为此，拟：①通过口腔白斑组织芯片，从临床队列证实KDM4A通过影响上皮细胞自我更新参与口腔黏膜癌变；②通过KDM4A与自我更新相关分子指标、细胞表型相关性研究，从细胞水平进一步印证上述结果；③通过mRNA表达谱芯片和染色质免疫共沉淀芯片，探寻KDM4A调控上皮细胞自我更新的信息网络和关键调控因子，并通过刺激、阻断实验进行功能验证。结果不仅有助于阐明KDM4A在口腔黏膜癌变中的作用机制，更重要的是，利用口腔黏膜癌变过程作为观测模型，进一步探索表观遗传调控上皮自我更新的机制，为寻找相关疾病的防治新靶点提供依据。

It has been discovered that self-renew of epithelial cells is regulated by epigenetics. KDM4A is a critical histone demethylase involved in this process. Previous research has revealed that KDM4A had a significantly high expression in OSCC tissues. Moreover, it was correlated with disease-free survival of OSCC patients. There is significant correlation between KDM4A expression and survival probability of the patients. However, the function of KDM4A on the early stage of oral carcinogenesis remains to be elucidated. So tissue microarrays of oral leukoplakia will be used in order to verify that self-renew of epithelial cells in oral carcinogenesis is regulated by KDM4A. Furthermore, cell lines were used to explore the biomarkers and phenotype related to self-renew. Moreover, bioinformatics approach, gene expression profiling and Co-Immunoprecipitation would be employed to identify its related signaling pathways and key molecules. That might be helpful to enucleate the role and the molecular mechanism of KDM4A in carcinogenesis of oral mucosa or other tissue so as to provide a new strategy for precancerous lesion prevention and treatment.