成纤维细胞生长因子2型受体选择性剪切体在乳腺癌细胞上皮间质转变中的分子机制研究

Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor of the FGFR family and plays an important role in the progression of breast cancer. Our preliminary studies found that polymorphisms in FGFR2 are associated with the susceptibility of breast cancer in Chinese population; the isoforms (FGFR2 IIIb and FGFR2 IIIc) of FGFR2 are also closely associated with metastasis of breast cancer, which may through epithelial-to-mesenchymal transition (EMT). On the basis of the previous studies, the present research focuses on: 1)FGFR2ome (a complete data set of SNP, Copy number variation, missense mutation, gene amplification and predominant isoform) analyses in Chinese breast cancer patients and cell lines. 2)The effect of SNP, aberrant CpG island hypermethylation, and histone-acetylation on the alternative splicing of FGFR2 IIIb and FGFR2 IIIc mRNA expression. 3)The effect of the alternative splicing of FGFR2 on the downstream of FGF/FGFR2 signal pathway, and the breast cancer cell epithelial-to- mesenchymal transition through overexpression and treatment with FGFR2 IIIb and FGFR2 IIIc monoclonal antibody. Through the study of the mechanism of alternative splicing of FGFR2 in the carcinogenesis, metastasis, and recurrence of breast cancer, provide experimental and theoretical basis for new therapeutic targets discovery, and personalized medicine of breast cancer based on FGFR2.

FGFR2是FGF高亲和力受体，也是乳腺癌的重要易感基因,但其作用机制尚不清楚。我们前期发现FGFR2选择性剪切体FGFR2IIIb和FGFR2IIIc可能通过上皮间质转变（Epithelial-to-mesenchymal transition, EMT）与乳腺癌的转移密切相关。拟在此基础上开展下列研究：1）绘制乳腺癌FGFR2组学图谱；2）发现FGFR2单核苷酸多态性、启动子异常甲基化和组蛋白乙酰化调控FGFR2IIIb和FGFR2IIIc mRNA表达机制；3）联合超表达上调FGFR2IIIb、FGFR2IIIc和单抗抑制下调FGFR2IIIb、FGFR2IIIc对FGFR2下游信号通路激活及乳腺癌细胞EMT的影响，发现FGFR2IIIb和FGFR2IIIc调控乳腺癌细胞EMT的分子机制,为以FGFR2为靶点的乳腺癌靶向治疗及基于分子分型的个体化治疗提供实验和理论依据。

FGFR2是FGF高亲和力受体，也是乳腺癌的重要易感基因,但其作用机制尚不清楚。我们前期发现FGFR2选择性剪切体FGFR2IIIb和FGFR2IIIc可能通过上皮间质转变（Epithelial-to-mesenchymal transition, EMT）与乳腺癌的转移密切相关。在此基础上开展下列研究：1）通过对乳腺癌组织和细胞株中FGFR2选择性剪切体，第二内含子SNP,拷贝数变异，突变，基因扩增，mRNA和蛋白表达，以及FGF/FGFR2信号通路关键基因突变的综合研究，绘制乳腺癌FGFR2组学图谱； 2）发现FGFR2单核苷酸多态性和信号通路关键基因突变、而不是突变和启动子异常甲基化、组蛋白乙酰化调控FGFR2IIIb和FGFR2IIIc mRNA表达是FGFR2发挥作用的主要形式；3）通过对FGFR2下游信号通路激活情况及细胞EMT标志物的测定，发现超表达上调FGFR2IIIb、FGFR2IIIc的细胞株间质化程度较低，而通过单抗抑制下调FGFR2IIIb、FGFR2IIIc后发现细胞间质化程度明显升高，但FGFR2IIIb细胞株更明显。FGFR2IIIb和FGFR2IIIc可能主要通过STAT和AKT信号通路调控乳腺癌细胞EMT过程。本研究为以FGFR2为靶点的乳腺癌靶向治疗及基于分子分型的个体化治疗提供初步理论依据。在获得上述研究结果的基础上，本项目迄今为止已发表SCI论文6篇，获软件著作权1项。培养学术骨干1人，硕士研究生2人。