Integration of bioinformatics and experiments to identify TP53 as a potential target in Emodin inhibiting diffuse large B cell lymphoma
Integration of bioinformatics and experiments to identify TP53 as a potential target in Emodin inhibiting diffuse large B cell lymphoma
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整合生物信息学和实验确定TP53作为大黄素抑制弥漫性大B细胞淋巴瘤的潜在靶点
DOI：
10.1016/j.biopha.2018.07.168
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发表时间：
2018-11-01
影响因子：
7.5
通讯作者：
Hu, Jianda
中科院分区：
文献类型：
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作者：
Chen, Yanxin;Mei, Xuqiao;Hu, Jianda
非霍奇金淋巴瘤(NHL)是包括弥漫性大B细胞淋巴瘤(DLBCL)在内的一些侵袭性亚型治疗效果不佳的淋巴系统恶性肿瘤。大黄素是一种具有很强抗癌活性的蒽醌类化合物。然而，大黄素抑制侵袭性非霍奇金淋巴瘤的分子机制尚不清楚。本研究通过生物信息学分析和体外实验研究大黄素对侵袭性非霍奇金淋巴瘤的作用机制。确定了大黄素的主要直接蛋白靶点(DPT)，并预测了与DPTS相关的蛋白/基因。对大黄素相关蛋白/基因进行了大黄素相关途径的研究，从中精炼出3条与非霍奇金淋巴瘤相关的信号通路。先进的综合分析表明，大黄素在非霍奇金淋巴瘤中发挥作用的重要分子和途径是TP53和PI3K。为了验证这些生物信息学结果，我们研究了大黄素及其新的衍生物E35对DLBCL细胞株SU-DHL4的作用。大黄素和E35以时间和剂量依赖的方式抑制SU-DHL4细胞的增殖和诱导其凋亡。大黄素和E35以剂量依赖方式抑制TP53蛋白表达和PI3K/AKT蛋白磷酸化。说明生物信息学分析与实验相结合为揭示大黄素的作用机制提供了一种方便、完整的新途径。
Non-Hodgkin's Lymphoma (NHL) is a group of lymphoid malignancies with unsatisfactory treatment effect in some aggressive subtypes, including diffuse large B cell lymphoma (DLBCL). Emodin is an anthraquinone with potent anti-cancer activities. However, the molecular mechanism of Emodin repressing aggressive NHL remains to be revealed in detail. This study delineated the active mechanism of Emodin action in aggressive NHL by using bioinformatics analysis and in vitro assay. 4 Emodin's primary direct protein targets (DPT) were identified and the DPTs-associated proteins/genes were predicted. Those Emodin-related proteins/genes were subject to enrich Emodin-associated pathways, from which 3 significantly NHL-related signal pathways were refined identified. Advanced integrated analysis exhibited TP53 and PI3K as the significant molecule and pathway by which Emodin may function in NHL. To verify those bioinformatics findings, effects of Emodin and E35, a novel derivative of emodin were investigated on DLBCL cell lines SU-DHL4. Emodin and E35 suppressed proliferation and induced apoptosis of SU-DHL4 cells in a time-and dose-dependent manner. Emodin and E35 declined TP53 protein expression and decreased phosphorylation of PI3K/AKT protein in a dose-dependent manner. All of above showed that combined bioinformatics analysis with experiments offered a novel approach for outlining the mechanisms of Emodin action in DLBCL with convenience and integrity.