C4.4A介导的EMT在口腔鳞癌肿瘤干细胞形成过程中的调控作用及机制研究

Previous studies have revealed the essential roles of cancer stem cells (CSCs) in malignant tumors, however the precise mechanisms underlying CSC formation remain poorly understood. Recent studies reported that epithelial-mesenchymal transition (EMT) may be an important mechanism for CSC formation. Currently, we found that the expression of C4.4A was significantly correlated with the biomarkers of EMT and CSCs in oral squamous cell carcinoma (OSCC) CSCs. The aims of this project is to explore the precise role of C4.4A-mediated EMT in the formation of OSCC CSCs, which includes: (1) To evaluate the expression and activation levels of C4.4A-related signals, EMT- and CSCs-related proteins, as well as their relationships in OSCC tissues; (2) To determine the roles of EMT in the formation of OSCC CSCs, and to reveal the mediating effect of C4.4A in this process; (3) To explore the effects of inhibiting C4.4A-mediated EMT in the treatment of OSCC on animal models. Our research may further unmask the mechanisms underlying the malignant progression of OSCC, and may also help to develop novel therapeutics.

研究已证实肿瘤干细胞（CSCs）在恶性肿瘤早期转移过程中起重要作用，但口腔鳞癌CSCs的形成机制尚不明确。最新研究表明上皮-间质转化（EMT）可能是CSCs形成的一条重要途径。我们前期研究结果表明C4.4A与EMT以及CSCs标志物的表达具有高度相关性。本项目旨在研究C4.4A介导的EMT在CSCs形成过程中的调控作用及分子机制，主要内容包括：（1）明确口腔鳞癌中C4.4A信号通路、EMT及CSCs相关基因和蛋白的表达和相关性；（2）明确EMT在口腔鳞癌CSCs形成过程中的调控作用，阐明C4.4A 信号通路在该过程中的介导作用及分子机制；（3）以小鼠原位舌癌模型为实验对象，探索特异性抑制C4.4A介导的EMT过程在治疗口腔鳞状细胞癌中的作用。该项研究将进一步加深对口腔鳞状细胞癌浸润和转移机制的认识，并可能为临床上控制恶性肿瘤的早期转移提供新思路。

转移是恶性肿瘤的主要特征之一，是导致患者死亡的首要因素。肿瘤干细胞（CSCs）在恶性肿瘤早期转移过程中起重要作用，但口腔鳞癌中CSCs的形成机制尚不明确。已有研究表明上皮-间质转化（EMT）可能是CSCs形成的一条重要途径。我们前期研究结果提示C4.4A与EMT标志物的表达具有高度相关性。本项目根据已有理论及本课题组前期研究结果，围绕“C4.4A介导的EMT在口腔鳞癌肿瘤干细胞形成过程中的调控作用及机制研究”这一科学问题开展研究，得到以下结论：①口腔鳞癌原发灶中高表达C4.4A及其结合蛋白AGR2；②C4.4A与AGR2在口腔鳞癌的高表达与不良预后相关；③C4.4A，AGR2的表达与EMT相关分子及CSCs标记分子密切相关；④通过基因敲减C4.4A及AGR2可以抑制口腔鳞癌细胞系的转移侵袭能力及肿瘤细胞干性。截止结题时已发表SCI论文22篇。