肺癌是嚴(yán)重危害人類健康的惡性腫瘤之一,，也是全世界目前發(fā)病率和死亡率最高的癌癥之一。非小細(xì)胞肺癌是肺癌的主要類型,，五年生存率僅為15%,。因此，研究肺癌的意義十分重大,。Eph激酶作為最大的受體酪氨酸激酶家族,，在早期發(fā)育和成年期中都發(fā)揮著重要的作用。近年來Eph家族成員在腫瘤發(fā)生發(fā)展過程中的作用也得到了廣泛的關(guān)注,，人們發(fā)現(xiàn)Eph受體在多種類型的腫瘤中都有異常表達(dá),，如乳腺癌，前列腺癌,，神經(jīng)膠質(zhì)瘤等,，其具體作用與腫瘤的類型有關(guān)。然而目前關(guān)于Eph家族在肺癌中的報道還很少,，其成員之一EphB3在非小細(xì)胞肺癌中的作用及其分子機制尚不清楚,。
2月1日，國際學(xué)術(shù)期刊Cancer Research發(fā)表了上海生科院營養(yǎng)所謝東研究組的最新研究進展：發(fā)現(xiàn)受體酪氨酸激酶EphB3在非小細(xì)胞肺癌發(fā)生發(fā)展過程中的作用及其相關(guān)機制,。這項工作主要由博士生季小丹和李果等完成的,。他們研究發(fā)現(xiàn) EphB3 在非小細(xì)胞肺癌臨床樣本和腫瘤細(xì)胞株中都呈現(xiàn)高表達(dá)的趨勢，并且其表達(dá)水平和臨床病理參數(shù)密切相關(guān),，包括腫瘤大小,，分化程度以及轉(zhuǎn)移。 在非小細(xì)胞肺癌細(xì)胞系 H520中過表達(dá) EphB3能夠促進細(xì)胞的生長和遷移，并且顯著增強細(xì)胞在裸鼠體內(nèi)的成瘤能力,，而由 RNA干擾介導(dǎo)的對EphB3的沉默則顯著抑制了腫瘤細(xì)胞的生長,，遷移以及在體內(nèi)的成瘤和轉(zhuǎn)移能力。進一步的研究發(fā)現(xiàn)干擾 EphB3 引起的生長抑制是由于DNA 合成降低和caspase-8介導(dǎo)的凋亡途徑所共同作用的結(jié)果,。另一方面,，干擾 EphB3 引起 FAK（pY397）和Paxillin（pY118）水平的上升、粘著斑（Focal adhesion）數(shù)目的增加以及周轉(zhuǎn)速度的減慢,，導(dǎo)致細(xì)胞遷移能力的下降,。總之,，這些工作揭示了EphB3作為非小細(xì)胞肺癌中的一個生存因子,， 通過刺激細(xì)胞的增殖和遷移以及提高細(xì)胞的存活能力，促進了腫瘤的生長和轉(zhuǎn)移,，為非小細(xì)胞肺癌的治療提供了潛在的藥物靶點,。
該研究課題得到了國家科技部、國家自然科學(xué)基金委,、中國科學(xué)院和上海市科委的資助,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
