甲基化调控OSR1在口腔癌发生发展中的作用及机制

早期防治是提高口腔癌患者生存率的重要途径。基因表达谱改变是肿瘤的显著特征，转录因子在基因表达起始调控中扮演着关键角色；在口腔癌发生早期即可见基因的异常甲基化，然而目前转录因子在口腔癌中的异常甲基化情况尚不清楚。本项目前期研究显示：①OSR1在口腔癌组织中的甲基化水平显著高于白斑组织；②低表达OSR1的白斑患者无口腔癌生存时间较短；③OSR1在口腔癌中因高甲基化而低表达，且高甲基化的患者预后较差；④过表达OSR1显著抑制口腔癌细胞的增殖。提示OSR1高甲基化可能是白斑癌变的早期事件；OSR1抑制口腔癌的进展，然而其作用机制尚未可知。本项目拟在此基础上①明确OSR1在白斑恶性演变中的作用，阐明其在口腔癌中的功能机制；②扩大样本量证实OSR1在口腔黏膜白斑和口腔癌患者临床转归中的预后价值。以此鉴别出口腔癌发生的早期分子事件，为口腔癌的早期防治提供预后指标和治疗靶点，最终提高口腔癌患者的生存率。

Gene expression alteration is a hallmark of cancer. Transcription factors play vital roles in gene expression initiation. Genes abnormally methylated could be seen in the early stage of oral squamous cell carcinoma (OSCC). However, the roles of transcription factors aberrantly methylated in OSCC are unclear. In our previously study, we found that OSR1 was significantly hypermethylated in the OSCC tissues compared with the oral leukoplakia tissues. Leukoplakia patients with lower OSR1 expression had shorter OSCC-free survival. Furthermore, In contrast to the adjacent normal tissues, OSR1 was downregulated in the OSCC tissues due to its promoter hypermethylation. OSCC patients with high methylation levels of OSR1 showed worse clinical outcomes. Moreover, restoring OSR1 could significantly suppressed OSCC cells proliferation. Thus, these findings suggest that the OSR1 hypermethylation may be an early event during the malignant transformation from leukoplakia to OSCC. OSR1 acts as a tumor suppressor in OSCC, however, the molecular mechanism is unknown. In this project, we will identify the roles and mechanisms of OSR1 in leukoplakia malignant transformation and OSCC progression. We will evaluate the prognostic values of OSR1 in leukoplakia and OSCC patients in larger sample sizes. Through this project, we will clarify the important roles of OSR1 in OSCC progression, which may provide a potential prognostic biomarker and therapeutic target for OSCC patients, and eventually improve the survival rate of OSCC patients.