肺癌是严重危害人类健康的恶性肿瘤之一，也是全世界目前发病率和死亡率最高的癌症之一。非小细胞肺癌是肺癌的主要类型，五年生存率仅为15%。因此，研究肺癌的意义十分重大。Eph激酶作为最大的受体酪氨酸激酶家族，在早期发育和成年期中都发挥着重要的作用。近年来Eph家族成员在肿瘤发生发展过程中的作用也得到了广泛的关注，人们发现Eph受体在多种类型的肿瘤中都有异常表达，如乳腺癌，前列腺癌，神经胶质瘤等，其具体作用与肿瘤的类型有关。然而目前关于Eph家族在肺癌中的报道还很少，其成员之一EphB3在非小细胞肺癌中的作用及其分子机制尚不清楚。
2月1日，国际学术期刊Cancer Research发表了上海生科院营养所谢东研究组的最新研究进展：发现受体酪氨酸激酶EphB3在非小细胞肺癌发生发展过程中的作用及其相关机制。这项工作主要由博士生季小丹和李果等完成的。他们研究发现 EphB3 在非小细胞肺癌临床样本和肿瘤细胞株中都呈现高表达的趋势，并且其表达水平和临床病理参数密切相关，包括肿瘤大小，分化程度以及转移。 在非小细胞肺癌细胞系 H520中过表达 EphB3能够促进细胞的生长和迁移，并且显著增强细胞在裸鼠体内的成瘤能力，而由 RNA干扰介导的对EphB3的沉默则显著抑制了肿瘤细胞的生长，迁移以及在体内的成瘤和转移能力。进一步的研究发现干扰 EphB3 引起的生长抑制是由于DNA 合成降低和caspase-8介导的凋亡途径所共同作用的结果。另一方面，干扰 EphB3 引起 FAK（pY397）和Paxillin（pY118）水平的上升、粘着斑（Focal adhesion）数目的增加以及周转速度的减慢，导致细胞迁移能力的下降。总之，这些工作揭示了EphB3作为非小细胞肺癌中的一个生存因子， 通过刺激细胞的增殖和迁移以及提高细胞的存活能力，促进了肿瘤的生长和转移，为非小细胞肺癌的治疗提供了潜在的药物靶点。
该研究课题得到了国家科技部、国家自然科学基金委、中国科学院和上海市科委的资助。（生物谷Bioon.com）
生物谷推荐原文出处：
Cancer Research doi: 10.1158/0008-5472.CAN-10-0717
EphB3 Is Overexpressed in Non–Small-Cell Lung Cancer and Promotes Tumor Metastasis by Enhancing Cell Survival and Migration
Xiao-Dan Ji1, Guo Li1, Yu-Xiong Feng1, Jiang-Sha Zhao1, Jing-Jing Li1, Zhi-Jian Sun1, Shuo Shi1, Yue-Zhen Deng1, Jun-Feng Xu1, Yin-Qiu Zhu1, H. Phillip Koeffler3,4, Xiang-Jun Tong2, and Dong Xie1
Abstract
Eph receptors, the largest subfamily of transmembrane tyrosine kinase receptors, have been increasingly implicated in various physiologic and pathologic processes, and the roles of the Eph family members during tumorigenesis have recently attracted growing attention. Until now, research on EphB3 function in cancer is limited to focusing on tumor suppression by EphB receptors in colorectal cancer. However, its function in other types of cancer remains poorly investigated. In this study, we explored the function of EphB3 in non–small-cell lung cancer (NSCLC). We found that the expression of EphB3 was significantly upregulated in clinical samples and cell lines, and the expression level correlated with the patient pathologic characteristics, including tumor size, differentiation, and metastasis. Overexpression of EphB3 in NSCLC cell lines accelerated cell growth and migration and promoted tumorigenicity in xenografts in a kinase-independent manner. In contrast, downregulation of EphB3 inhibited cell proliferation and migration and suppressed in vivo tumor growth and metastasis. Furthermore, we showed that silencing of EphB3 inhibited cell growth by reducing DNA synthesis and caspase-8–mediated apoptosis and suppressed cell migration by increasing accumulation of focal adhesion formation. Taken together, our findings suggest that EphB3 provides critical support to the development and progression of NSCLC by stimulating cell growth, migration, and survival, thereby implicating EphB3 as a potential therapeutic target in NSCLC.
