發(fā)布時(shí)間：2018-10-18 08:50

【摘要】：小細(xì)胞肺癌是一種預(yù)后極差的惡性腫瘤�？沟蛲龅鞍譈cl-2的過(guò)表達(dá)經(jīng)常在小細(xì)胞肺癌中發(fā)生,這使其成為潛在的治療靶點(diǎn)。以前的研究表明,靶向Bcl-2的抑制劑ABT-263對(duì)小細(xì)胞肺癌的抑制作用有限。在本研究中,我們首次發(fā)現(xiàn)共抑制N-Myc和Bcl-2在MYCN擴(kuò)增的小細(xì)胞肺癌中具有很強(qiáng)的協(xié)同抗腫瘤作用。我們發(fā)現(xiàn)BET抑制劑JQ1能抑制MYCN擴(kuò)增的小細(xì)胞肺癌N-Myc蛋白的表達(dá)。JQ1對(duì)N-Myc的抑制作用誘導(dǎo)MYCN擴(kuò)增的小細(xì)胞肺癌凋亡蛋白Bim的表達(dá)。此外,JQ1誘導(dǎo)Bim上調(diào)使MYCN擴(kuò)增的小細(xì)胞肺癌對(duì)ABT-263更加敏感,同時(shí)我們通過(guò)siRNA敲低Bim的實(shí)驗(yàn)證明了 JQ1/ABT-263的協(xié)同抑制是通過(guò)Bim蛋白上調(diào)發(fā)揮的。在MYCN擴(kuò)增的小細(xì)胞肺癌中,JQ1/ABT-263共同處理可以顯著降低Bim/Bcl-2的相互作用并抑制Bim與Mcl-1的相互作用。重要的是,JQ1/ABT-263可以協(xié)同抑制MYCN擴(kuò)增的小細(xì)胞肺癌異種移植模型中腫瘤的生長(zhǎng)。我們的研究表明JQ1/ABT-263是一種新型針對(duì)MYCN擴(kuò)增小細(xì)胞肺癌的有效靶向治療策略。
[Abstract]:Small cell lung cancer is a malignant tumor with poor prognosis. Overexpression of anti-apoptotic protein Bcl-2 often occurs in small cell lung cancer, which makes it a potential therapeutic target. Previous studies have shown that ABT-263, an inhibitor of Bcl-2, has limited inhibitory effects on small cell lung cancer. In this study, we found for the first time that co-inhibition of N-Myc and Bcl-2 had strong synergistic antitumor effects in MYCN amplified small cell lung cancer. We found that JQ1, a BET inhibitor, could inhibit the expression of N-Myc protein in small cell lung cancer amplified by MYCN, and the inhibitory effect of JQ1 on N-Myc induced the expression of Bim protein in MYCN amplified small cell lung cancer. In addition, the up-regulation of Bim induced by JQ1 makes MYCN amplified small cell lung cancer more sensitive to ABT-263. We also demonstrated that the synergistic inhibition of JQ1/ABT-263 was mediated by the up-regulation of Bim protein through siRNA knockdown of Bim. In MYCN amplified small cell lung cancer, JQ1/ABT-263 co-treatment could significantly reduce the interaction of Bim/Bcl-2 and inhibit the interaction between Bim and Mcl-1. Importantly, JQ1/ABT-263 synergistically inhibits tumor growth in xenotransplantation models of small cell lung cancer amplified by MYCN. Our results suggest that JQ1/ABT-263 is a novel and effective targeting strategy for MYCN amplified small cell lung cancer.
【學(xué)位授予單位】：中國(guó)科學(xué)技術(shù)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R734.2
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本文編號(hào)：2278620