BPIFB1基因通过CXCL12/CXCR4调节轴参与鼻咽癌发生发展的分子机制

项目名称： BPIFB1基因通过CXCL12/CXCR4调节轴参与鼻咽癌发生发展的分子机制

项目编号： No.81472531

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 曾朝阳

作者单位： 中南大学

项目金额： 80万元

中文摘要： 我们发现BPIFB1基因低表达是鼻咽癌不良预后因素，且与癌组织中巨噬细胞浸润及IL-6等因子分泌负相关，重表达BPIFB1可通过STAT3、MAPK等通路阻滞鼻咽癌细胞增殖诱导凋亡。但分泌性蛋白BPIFB1如何调控细胞内的信号通路，及它对肿瘤微环境的影响还有待深入研究。经酵母双杂交我们发现BPIFB1可与趋化因子CXCL12结合，而CXCL12的受体CXCR4在鼻咽癌中高表达已有报道，但CXCL12/CXCR4调节轴在鼻咽癌发病过程中的机制值得进一步探讨。本项目拟研究BPIFB1与CXCL12及CXCR4的相互作用，并通过CXCL12/CXCR4调节轴对鼻咽癌细胞内信号通路及恶性生物学表型的影响，以及对鼻咽癌细胞微环境的调控，初步明晰BPIFB1在鼻咽癌发生发展过程中的作用机制；通过探讨BPIFB1在鼻咽癌中的表达调控机制，考察小分子药物诱导BPIFB1重表达的可行性及潜在的临床应用前景。

中文关键词： C03_鼻咽肿瘤；BPIFB1基因；趋化因子CXCL12；趋化因子受体CXCR4；基因表达调控

英文摘要： In our previous projects, we have found that the downregualtion of BPIFB1 gene in nasopharyngeal carcinoma (NPC) was a poor NPC prognosis factor, and was negatively associated with the degrees of tumor associated marcrophage (TAM) infiltration and the expression levels of IL-6 in NPC tissues. Re-expression of BPIFB1 could inhibit NPC cell proliferation, induce NPC cell arrest and promote NPC cell apoptosis through STAT3 and MAPK pathways. But as a secreted protein, how BPIFB1 regulates intracellular signaling pathways and its impact on the tumor microenvironment of NPC has not been studied in depth. Using a yeast two-hybrid strategy, we have found that BPIFB1 may interact with cytokine CXCL12. Whereas it was reported that CXCR4, the receptor of CXCL12, was highly expressed in NPC, the mechanisms of the CXCL12/CXCR4 axis in the pathogenesis of nasopharyngeal carcinoma is worthy of further investigation. In the proposed project, we intend to elucidate, in detail, the interaction between BPIFB1 and CXCL12/CXCR4 axis, the impact on their downstream signaling pathways, the malignant phenotype of NPC, and on the regulation of the NPC microenvironment. We are intending to preliminarily clarify the function of BPIFB1 in the carcinogenesis and progression of NPC. We will also investigate the mechanisms of the regulation of BPIFB1 in NPC and study the feasibility of small molecule components to induce BPIFB1 re-expression and its potential clinical applications in NPC.

英文关键词： nasopharyngeal carcinoma;BPIFB1 gene;chemokine CXCL12;chemokine receptor CXCR4;Gene express regulation