本课题组先前建立了口腔黏膜上皮细胞体外癌变模型，再用比较蛋白质组学的方法发现Annexin A1随着细胞癌变而表达下降，获得体内外细胞和组织水平的验证；并发现其表达高低与口腔鳞癌的分化程度相关，分化程度越差，Annexin A1表达越低；经Annexin A1过表达干预可降低癌细胞的增殖和成瘤能力，癌细胞分化变好，并使ERK磷酸化升高；Annexin A1的磷酸化也受到EGFR干预的影响。但经文献复习，发现Annexin A1在肿瘤EGF/ERK/MAPK信号通路中有许多未知之处，具有深入研究的价值。本研究旨在采用分子干预和体内外实验相结合的手段，以EGF相关的ERK/MAPK信号通路为切入点，探索Annexin A1在头颈鳞癌发展中可能抑制EGF/ERK/MAPK信号通路的作用机制，并评价Annexin A1在头颈鳞癌中的预后预警作用及作为药物靶标的潜能，为头颈鳞癌的个体化治疗提供依据。

Head and neck squamous cell carcinoma represents the 6th common cancer worldwide, with a poor prognosis of 5-year survival rate about 50%-60%. Annexin A1 is originally identified and involved for a long time to function as a cellular mediator of the anti-inflammatory effects. However, since its discovery as a major cellular substrate for tyrosine phosphorylation by the epidermal growth factor receptor (EGFR), Annexin A1 is implicated in various pathways known to be involved in cancer through the modulation of mitogen-activated protein kinase (MAPK) signaling, calcium ion mobilization, apoptosis, cell proliferation, and inhibition of cell growth. Our previous studies have established an in vitro cellular carcinogenesis model from normal oral mucosal epithelia to cancerous squamous cells, and comparative proteomic technique has been used to screen the differential proteomic profiles between the cells at different stages of carcinogenesis. Annexin A1 is one of the proteins, which is expressed in a low level accompanying with the carcinogenesis. Further validation confirms in the cellular level and tissue level. Significant correlation is also found between the Annexin A1 expression level and pathological differentiation grade of cancerous tissues, a poorer differentiation grade indicating a lower level of Annexin A1 expression. When the Annexin A1 expression is overexpressed in the cancerous cells by gene transferring with the total Annexin A1 gene, decreased cellular proliferative ability and tumorigenesis ability is found in vitro and in vivo, and the differentiation grade of cancerous tissue becomes better from moderately differentiation grade to well differentiation grade. In the cancerous cells with Annexin A1 overexpression, the phosphoration level of extracellular signal-regulated kinase (ERK) is higher than those without Annexin A1 overexpression. The phosphoration level of Annexin A1 is also affected by adding EGFR into the cell culture media. From the literatures, decreased expression of Annexin A1 has been found in many kinds of cancers, and the molecular intervention with Annexin A1 overexpression could increase the phosphoration level of ERK, suggesting the Annexin A1 might function as a suppressor gene and inhibit the ERK/MAPK signal pathway; however, there are several unknown issues on the molecular mechanism how Annexin A1 plays a role in the EGF/ERK/MAPK signal pathway, which needs deeper studies. Based on our previous results, the aim of this project is to study the potential inhibition role of Annexin A1 in the EGF/ERK/MAPK signal pathway using the molecular intervention, in vitro and in vivo methods in the head and neck squamous cell carcinoma, and also the clinical usefulness of Annexin A1 detection for prognostic prewarning and as potential treatment target, which will provide scientific evidence for personalized treatment in head and neck squamous cell carcinoma.