小细胞肺癌分子靶向治疗新靶点EphA7作用机制研究

The whole genome sequencing of small cell lung cancer in 2012 revealed that EphA7 gene mutation is associated with highly invasive characteristics,which makes it possibly one of the key driver genes in small cell lung cancer. The research team immediately conducted preliminary studies of EphA7 gene and protein in small cell lung cancer,found that compared with normal tissues,the expression of EphA7 in human small cell lung cancer tissues was significantly elevated and patients with higher expression have poor prognosis. Additionally, the EphA7 gene silencing in vitro suppress cell proliferation and migration,simultaneously promote cell apoptosis in small cell lung cancer cell line.Therefore,we hypothesized that EphA7 which is expected to become a new molecular target of small cell lung cancer is involved in proliferation, invasion and other malignant biological process in small cell lung cancer , but its mechanism is under exploring.We propose to study the effect of EphA7 on proliferation, invasion and other malignant biological characteristics in small cell lung cancer in vivo and vitro，verify the mechanism of EphA7,demonstrate the feasibility of EphA7 gene as a molecular target of small cell lung cancer, lay the theoretical foundation of molecular targeted therapy of small cell lung cancer.

2012年针对小细胞肺癌的全基因组测序研究取得重要发现：EphA7基因突变与小细胞肺癌高度侵袭特性相关，可能是小细胞肺癌的关键驱动基因之一。本课题组随即针对小细胞肺癌中EphA7基因及蛋白开展前期研究，发现与正常组织相比，EphA7蛋白在人小细胞肺癌组织中显著高表达，且高表达EphA7蛋白的患者预后差；同时细胞水平的EphA7基因沉默可显著抑制小细胞肺癌细胞增殖及迁移，促进细胞凋亡。因此，我们推测EphA7参与小细胞肺癌的生长、侵袭及转移等恶性生物学进程，有望成为小细胞肺癌靶向治疗的新靶点，但其作用机制尚不清楚，急需进一步探讨。本课题组拟在前期工作基础之上，在细胞水平及活体动物水平开展EphA7基因对小细胞肺癌细胞增殖及侵袭等恶性生物学行为影响的深入研究，并阐明其作用机制，论证EphA7作为小细胞肺癌分子靶向治疗靶点的可行性，以期为小细胞肺癌的靶向治疗奠定理论基础及依据。

小细胞肺癌的全基因组测序研究取得重要发现：EphA7基因突变与小细胞肺癌高度侵袭特性相关，可能是小细胞肺癌的关键驱动基因之一。本课题组随即针对小细胞肺癌中EphA7基因及蛋白开展前期研究，发现与正常组织相比，EphA7蛋白在人小细胞肺癌组织中显著高表达，且高表达EphA7蛋白的患者预后差；同时在细胞水平沉默EphA7基因可显著抑制小细胞肺癌细胞增殖及迁移，促进细胞凋亡，随后我们深入探讨了其作用机制，通过分别筛选PI3K/Akt通路及MAPK信号通路发现EphA7通过Raf/Mek/Erk信号通路抑制细胞增殖，在进一步研究中发现MAPK信号通路与c-myc存在相关性，后证实EphA7基因通过MAPK/c-myc通路发挥作用。随后我们建立裸鼠移植瘤模型，同样验证了敲除EphA7基因可通过抑制MAPK/c-myc通路从而减缓肿瘤生长，论证了EphA7作为小细胞肺癌分子靶向治疗靶点的可行性，为小细胞肺癌的靶向治疗奠定理论基础及依据。