【摘要】：小細胞肺癌是一種預(yù)后極差的惡性腫瘤�？沟蛲龅鞍譈cl-2的過表達經(jīng)常在小細胞肺癌中發(fā)生,這使其成為潛在的治療靶點。以前的研究表明,靶向Bcl-2的抑制劑ABT-263對小細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擴增的小細胞肺癌中具有很強的協(xié)同抗腫瘤作用。我們發(fā)現(xiàn)BET抑制劑JQ1能抑制MYCN擴增的小細胞肺癌N-Myc蛋白的表達。JQ1對N-Myc的抑制作用誘導(dǎo)MYCN擴增的小細胞肺癌凋亡蛋白Bim的表達。此外,JQ1誘導(dǎo)Bim上調(diào)使MYCN擴增的小細胞肺癌對ABT-263更加敏感,同時我們通過siRNA敲低Bim的實驗證明了 JQ1/ABT-263的協(xié)同抑制是通過Bim蛋白上調(diào)發(fā)揮的。在MYCN擴增的小細胞肺癌中,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擴增的小細胞肺癌異種移植模型中腫瘤的生長。我們的研究表明JQ1/ABT-263是一種新型針對MYCN擴增小細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】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R734.2
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本文編號：2278619