CN111840562A - 一种usp7抑制剂在治疗abc-dlbcl药物中的应用 - Google Patents
一种usp7抑制剂在治疗abc-dlbcl药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种USP7抑制剂在治疗ABC‑DLBCL药物中的应用，研究USP7在DLBCL细胞系中的表达情况，然后通过数据库分析显示，用USP7小分子抑制剂抑制USP7活性，CCK‑8法观察ABC型DLBCL细胞增殖、PI染色和流式细胞术检测细胞凋亡的影响及其对ABC型DLBCL BCR信号通路的影响，USP7是目前研究最为广泛的一个泛素特异性蛋白酶，研究表明USP7参与调节细胞多种蛋白底物的活性和功能，USP7表达异常或者活性改变对疾病及肿瘤的发生发展均有重要作用，将会具有良好的应用前景和市场竞争力，对改善我国民生和社会具有良好的促进作用。
Description
技术领域
本发明属于医药领域，具体涉及一种USP7抑制剂在治疗ABC-DLBCL药物中的应用。
背景技术
淋巴瘤是一类起源于淋巴造血***的单克隆增殖性疾病，分为霍奇金淋巴瘤(Hodgkin's lymphoma，HL) 和非霍奇金淋巴瘤 (non-Hodgkin' s lymphoma，NHL),我国每年约有 8.4 万人被诊断为淋巴瘤。非霍奇金淋巴瘤（NHL）是一类异质性明显的恶性血液病，按组织病理类型分为Ｂ细胞NHL和 T／NK细 胞 NHL。在B-NHL中，最常见的亚型为弥漫性大Ｂ细胞淋巴瘤（diffuse large B-cell lymphoma，DLBCL）, 发病率占 NHL的45.8%。随着以美罗华为主的免疫化疗方案（R-CHOP）广泛应用于DLBCL的治疗，半数以上的患者得以治愈，但仍有超过30%的患者面临复发的风险，且对R-CHOP化疗不敏感的患者终将死于DLBCL疾病进展，对于高危 DLBCL 病例，3 年生存率仍低于 60%，有待进一步提高。
进年来基因表达谱及 DNA 测序加深了我们对 DLBCL生物学特性的认识。DLBCL可以区分为生发中心来源（germinal center B-cell–like,GCB）DLBCL和活化B细胞来源（activated B-cell–like, ABC）DLBCL两种亚型，其细胞信号活化转导通路不同，经标准治疗后预后也不同。GCB 型 DLBCL 来源于淋巴滤泡生发中心，表达 CD10、LMO2、BCL6。30%~40%的 GCB 型 DLBCL 存在 t（14，18），30%有c-rel基因扩增，20%可发生组蛋白甲基转移酶EZH2 基因突变，10% PTEN 基因缺失；EZH2与 BCL6 基因协同介导 GCB 型DLBCL 的发生。ABC 型DLBCL 来源于B 细胞的浆母细胞阶段，基因病理学特征是 NF⁃κB 通路的持续激活，从而导致肿瘤细胞增殖活跃和抗凋亡。多数ABC型DLBCL依赖慢性激活B细胞受体（BCR）信号通路，慢性活化的BCR信号由B细胞受体及下游激酶介导。这些激酶包括SYK、PI3K、BTK及PKCβ。大约20%病例存在 CD79A/CD79B 的突变；10%ABC型DLBCL存在CARD11分子突变，这种突变不依赖上游信号便可以激活NF⁃κB通路；24%的ABC型DLBCL可发生编码NF⁃κB的负性调节因子A20的失调。除此之外，TLRs 信号通路中最关键的基因MYD88突变可发生于30%的ABC型DLBCL中。但诱导BCR信号通路活化的具体机制还有待阐明。从目前已知的资料来看，GCB型DLBCL恶性程度较低，主要依赖PI3K/AKT/MTOR通路，而ABC型DLBCL侵袭性强，依赖多条生长信号途径，如BCR/NF⁃κB和JAK-STAT信号通路等。目前多数学者认为 GCB 型 DLBCL 预后要明显好于 ABC型GCB ，是一个独立的预后因素。
近年来，针对信号通路中某些分子的靶向药物陆续开发或已经进入前期临床试验，为DLBCL的治疗带来了新的希望。如BCR通路中BTK的抑制剂Ibrutinib在复发难治的ABC型DLBCL中获得了满意的疗效，Ⅰ/Ⅱ期临床研究显示有效率可以达到40%。但BTK抑制剂因其只抑制BCR信号下游的BTK分子，而DLBCL特别是以NF⁃κB持续活化的ABC型DLBCL涉及到广泛的信号分子的表达异常，故而BTK抑制剂只针对一小部分病人有疗效，且易发生耐药。考虑到分子通路网络的复杂性，单一的靶向药物治疗未必能发挥长期和全面的抗肿瘤作用。全面抑制BCR信号通路活化的药物依然有待开发。
泛素特异性蛋白酶7（ubiquitin-specific protease 7，USP7 ）是目前研究最为广泛的一个泛素特异性蛋白酶，最初是从单纯疱疹病毒 (HSV) 蛋白 ICP0 相互作用蛋白中鉴定出的，因此又称为疱疹病毒相关的泛素特异性蛋白酶( Hausp)。USP7能特异性地水解泛素 C-末端与靶蛋白之间形成的酯键、肽键或异肽键，使泛素脱离靶蛋白，从而影响靶蛋白的稳定性、细胞定位和活性。其作用在于调控细胞周期进程、蛋白质降解、基因表达、DNA 修复及细胞凋亡。研究发现 USP7 通过与癌蛋白、抑癌蛋白相互作用进而参与在肿瘤的发生和进展。大量的文献报道USP7 促肿瘤发生，这体现在它与癌蛋白的相互作用，去泛素化而稳定它们，或通过与抑癌蛋白相互作用抑制抑癌蛋白的功能产生的促癌效应; 也有少量文献表明 USP7 有抑制肿瘤的作用，主要体现在它与抑癌蛋白的相互作用稳定抑癌蛋白或者是 USP7 发挥对基因稳定性的功能。USP7与包括肺癌、结肠癌、乳腺癌、神经胶质瘤、***癌在内的多种肿瘤相关且其在肿瘤中作用受到密切关注。然而，USP7在不同的肿瘤中的底物及调控肿瘤的通路存在较大差异。
表观遗传学调控是一种涉及DNA甲基化及组蛋白修饰（甲基化、乙酰化和磷酸化）的精确调控过程。研究表明USP7可通过调控DNMT1的活性来激活DNA甲基化。USP7通过调节组蛋白去甲基化酶PHF8的稳定促进乳腺癌的发生与发展。这些研究表明USP7在组蛋白修饰中的潜在调控作用，但其机制尚未阐明。目前很少有报导涉及USP7蛋白在淋巴瘤的研究。我们研究结果表明ABC-DLBCL亚型中USP7及BCR信号通路关键蛋白高表达。应用USP7小分子抑制剂抑制USP7，可以下调所有关键的BCR信号通路分子的RNA水平，从而显著诱导ABC-DLBCL细胞死亡。本发明不仅为理解ABC-DLBCL亚型的发病机制提供了新的视角，而且有望为ABC-DLBCL亚型的治疗提供有效的策略。
弥漫性大Ｂ细胞淋巴瘤是最常见的非霍奇金淋巴瘤，发病率高，有超过30%的患者面临复发的风险，且对R-CHOP化疗不敏感的患者终将死于DLBCL疾病进展，对于高危 DLBCL病例，3 年生存率仍低于 60%，有待进一步提高。其中ABC型DLBCL侵袭性及恶性程度较其他类型更高。持续的BCR信号通路慢性活化是ABC型弥漫性大Ｂ细胞淋巴瘤（ABC-DLBCL）的始动因素，同时又是ABC-DLBCL的重要治疗靶点。近年来，针对信号通路中某些分子的靶向药物陆续开发或已经进入前期临床试验，为DLBCL的治疗带来了新的希望。如BCR通路中BTK的抑制剂Ibrutinib在复发难治的ABC型DLBCL中获得了满意的疗效，Ⅰ/Ⅱ期临床研究显示有效率可以达到40%。但BTK抑制剂因其只抑制BCR信号下游的BTK分子，而DLBCL特别是以NF⁃κB持续活化的ABC型DLBCL涉及到广泛的信号分子的表达异常，故而BTK抑制剂只针对一小部分病人有疗效，且易发生耐药。考虑到分子通路网络的复杂性，单一的靶向药物治疗未必能发挥长期和全面的抗肿瘤作用。全面抑制BCR信号通路活化的药物依然有待开发。USP7是目前研究最为广泛的一个泛素特异性蛋白酶，研究表明USP7参与调节细胞多种蛋白底物的活性和功能，USP7 表达异常或者活性改变对疾病及肿瘤的发生发展均有重要作用。目前很少有报导涉及USP7蛋白在淋巴瘤的研究。我们的前期研究提示：和GCB-DLBCL亚型相比USP7在ABC型DLBCL中高表达，这种表达差异提示我们USP7 可能参与ABC-DLBCL的发生。我们的研究以USP7为切入点，应用USP7小分子抑制剂抑制USP7活性，研究其对ABC型DLBCL细胞的杀伤力，明确USP7在ABC-DLBCL中的作用及确定其是否可作为治疗DLBCL的靶点。
发明内容
解决的技术问题：针对上述在面临复发的风险和生存率低等技术问题，本发明目的之一为提供一种USP7抑制剂在治疗ABC-DLBCL药物中的应用。
技术方案：
一种USP7抑制剂在治疗ABC-DLBCL药物中的应用。
进一步的，步骤为：
第一步，USP7表达与ABC型DLBCL的关系：确定USP7是否与ABC型DLBCL相关，首先研究USP7在DLBCL细胞系中的表达情况，然后通过数据库分析USP7在肿瘤组织中的表达情况；
第二步，明确USP7是否参与ABC型DLBCL的发生发展及其所发挥的具体作用：用USP7小分子抑制剂抑制USP7活性，CCK-8法观察ABC型DLBCL细胞增殖、PI染色和流式细胞术检测细胞凋亡的影响及应用Western blot、Real-time PCR 方法检测抑制剂对ABC型DLBCL BCR信号通路的影响，具体实施步骤为：
CCK-8检测：取对数生长期的细胞，完全培养基重悬，细胞计数；取无菌 96 孔板，设计0uM、0.5uM、1uM、5uM、10uM、20uM 六个P22077浓度组，每个浓度 4 个副孔；每孔接种 2×104cells，加含上述浓度药物的完全培养基至 200μl，37℃、5%CO2条件下继续培养48h，在各孔内加入 20μl CCK-8试剂，37℃孵育 4 小时；取出 96 孔板，放入酶标仪，设置检测波长为 450nm，检测并纪录 OD450 读数；
PI染色实验：取对数生长期细胞，以20000细胞／孔接种于96孔扳，同时给药处理，培养24或48h后加入终浓度为50uｇ／ｍＬ的ＰＩ染料，避光染色10min，采用荧光显微镜观察拍照；
流式细胞术：6 孔板内接种对数生长期的各组细胞，培养 24 小时；重悬后收集每孔细胞于单支的流式管内，离心去上清，PBS 洗涤细胞 2 次，每管中缓慢加入 1ml、-20℃预冷的 70%乙醇， 4℃过夜；离心去除乙醇，PBS 洗涤细胞，离心 5min；每管加入 500μl PI/RNase Staining Buffer 重悬细胞，室温下避光孵育 15min后上机检测。
应用Real-time PCR、Western blot方法检测抑制剂对ABC型DLBCL BCR信号通路的影响：用10uM P22077处理ABC型DLBCL细胞（HBL），分别提取mRNA和蛋白，Real-time PCR法检测 BTK, PLCG2, PKC 和 CD79B 及BCR-NFkB 信号通路靶基因IL-6, MYC, BATF3 和IRF4的mRNA水平；Western blot方法检测BTK和PLCG2的蛋白水平。
进一步的，所述第一步中研究USP7在DLBCL细胞系中的表达情况具体步骤为应用Western blot方法检测ABC型DLBCL及GCB型DLBCL细胞系中USP7 蛋白表达，和GCB-DLBCL亚型相比USP7在ABC型DLBCL中高表达，这种表达差异证实USP7参与ABC-DLBCL的发生。
进一步的，所述第一步中数据库分析显示和癌旁组织相比，USP7在肿瘤组织中高表达。
进一步的，所述第二步中USP7小分子抑制剂P22077可明显诱导DLBCL特别是ABC-DLBCL（HBL-1、SU-DHL-2）发生凋亡。
有益效果：
1、USP7 表达异常或者活性改变对疾病及肿瘤的发生发展均有重要作用。数据库分析显示和癌旁组织相比，USP7在肿瘤组织中高表达（见图1A、B）。这种表达差异提示我们USP7可能参与肿瘤（包括DLBCL）的发生。
2、免疫印迹显示，和GCB-DLBCL亚型相比，USP7在ABC型DLBCL中高表达（见图1C），提示USP7 可能参与ABC型DLBCL的发生。
3、目前很少有报导涉及USP7蛋白在淋巴瘤的研究，针对难治型且易耐药的ABC型DLBCL 开发相应的靶向药物迫在眉睫。
4、USP7小分子抑制剂P22077可明显诱导DLBCL特别是ABC-DLBCL（HBL-1、SU-DHL-2）发生凋亡（见图2），该发现不仅为理解ABC-DLBCL亚型的发病机制提供了新的视角，而且有望为ABC-DLBCL亚型治疗药物的研发提供有效的策略。
5、USP7小分子抑制剂P22077可显著下调ABC型DLBCL细胞BCR信号通路关键分子（见图3）。
6、将会具有良好的应用前景和市场竞争力，对改善我国民生和社会具有良好的促进作用。
附图说明
图1为本申请实施例1中 USP7在DLBCL中的表达水平图；
图2为本申请实施例1中抑制USP7活性可诱导DLBCL细胞凋亡测试图。
图3为本申请实施例1中USP7在ABC-DLBCL细胞BCR信号通路关键分子上调中发挥重要作用图。
具体实施方式
以下通过实施例说明本发明的具体步骤，但不受实施例限制。
在本发明中所使用的术语，除非另有说明，一般具有本领域普通技术人员通常理解的含义。
在下面结合具体实施例并参照数据进一步详细描述本发明。应理解，这些实施例只是为了举例说明本发明，而非以任何方式限制本发明的范围。
在以下实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。
实施例1
一种USP7抑制剂在治疗ABC-DLBCL药物中的应用，步骤为：
第一步，USP7表达与ABC型DLBCL的关系：确定USP7是否与ABC型DLBCL相关，首先研究USP7在DLBCL细胞系中的表达情况，应用Western blot方法检测ABC型DLBCL及GCB型DLBCL细胞系中USP7 蛋白表达，和GCB-DLBCL亚型相比USP7在ABC型DLBCL中高表达，这种表达差异证实USP7参与ABC-DLBCL的发生，然后通过数据库分析显示，和癌旁组织相比，USP7在肿瘤组织中高表达。
如图1 所示，USP7在DLBCL中的表达水平：A图：TCGA数据库分析显示在31种肿瘤组织中，USP7在胆管癌、胸腺瘤和DLBCL中表达较正常组织升高；B图：与对照组相比，USP7在DLBCL病人中高表达；C图：与GCB-DLBCL亚型（BJAB）相比， ABC-DLBCL（HBL-1，SU-DHL-2,OCL-Ly10）亚型中，USP7高表达。
第二步，明确USP7是否参与ABC型DLBCL的发生发展及其所发挥的具体作用：用USP7小分子抑制剂抑制USP7活性，CCK-8法观察ABC型DLBCL细胞增殖、PI染色和流式细胞术检测细胞凋亡的影响及应用Western blot、Real-time PCR 方法检测抑制剂对ABC型DLBCLBCR信号通路的影响。具体实施步骤为：
CCK-8检测：取对数生长期的细胞，完全培养基重悬，细胞计数；取无菌 96 孔板，设计0uM、0.5uM、1uM、5uM、10uM、20uM 六个P22077浓度组，每个浓度 4 个副孔；每孔接种 2×104cells，加含上述浓度药物的完全培养基至 200μl，37℃、5%CO2条件下继续培养48h，在各孔内加入 20μl CCK-8试剂，37℃孵育 4 小时；取出 96 孔板，放入酶标仪，设置检测波长为 450nm，检测并纪录 OD450 读数；
PI染色实验：取对数生长期细胞，以20000细胞／孔接种于96孔扳，同时给药处理，培养24或48h后加入终浓度为50uｇ／ｍＬ的ＰＩ染料，避光染色10min，采用荧光显微镜观察拍照；
流式细胞术：6 孔板内接种对数生长期的各组细胞，培养 24 小时；重悬后收集每孔细胞于单支的流式管内，离心去上清，PBS 洗涤细胞 2 次，每管中缓慢加入 1ml、-20℃预冷的 70%乙醇， 4℃过夜；离心去除乙醇，PBS 洗涤细胞，离心 5min；每管加入 500μl PI/RNase Staining Buffer 重悬细胞，室温下避光孵育 15min后上机检测。
如图2 所示，抑制USP7活性可诱导DLBCL细胞凋亡：CCK-8实验（A图）、PI染色（B图）和流式细胞术（C图）结果显示USP7小分子抑制剂P22077可明显诱导DLBCL特别是ABC-DLBCL（HBL-1、SU-DHL-2）发生凋亡。
应用Real-time PCR、Western blot方法检测抑制剂对ABC型DLBCL BCR信号通路的影响：用10uM P22077处理ABC型DLBCL细胞（HBL），分别提取mRNA和蛋白，Real-time PCR法检测 BTK, PLCG2, PKC 和 CD79B 及BCR-NFkB 信号通路靶基因IL-6, MYC, BATF3 和IRF4的mRNA水平；Western blot方法检测BTK和PLCG2的蛋白水平。
如图3所示，USP7在ABC-DLBCL细胞BCR信号通路关键分子上调中发挥重要作用。A图，P22077处理后BTK, PLCG2, PKC 和 CD79B的mRNA水平明显下调。B图，P22077处理后BTK和PLCG2的蛋白水平也明显下调。C图，P22077处理后，BCR-NFkB 信号通路靶基因IL-6,MYC, BATF3 和IRF4明显下调。
Claims (5)
1.一种USP7抑制剂在治疗ABC-DLBCL药物中的应用。
2.根据权利要求1所述的一种USP7抑制剂在治疗ABC-DLBCL药物中的应用，其特征在于步骤为：
第一步，USP7表达与ABC型DLBCL的关系：确定USP7是否与ABC型DLBCL相关，首先研究USP7在DLBCL细胞系中的表达情况，然后通过数据库分析USP7在肿瘤组织中的表达情况；
第二步，明确USP7是否参与ABC型DLBCL的发生发展及其所发挥的具体作用：用USP7小分子抑制剂抑制USP7活性，CCK-8法观察ABC型DLBCL细胞增殖、PI染色和流式细胞术检测细胞凋亡的影响及应用Western blot、Real-time PCR 方法检测抑制剂对ABC型DLBCL BCR信号通路的影响，具体实施步骤为：
CCK-8检测：取对数生长期的细胞，完全培养基重悬，细胞计数；取无菌 96 孔板，设计0uM、0.5uM、1uM、5uM、10uM、20uM 六个P22077浓度组，每个浓度 4 个副孔；每孔接种 2×104cells，加含上述浓度药物的完全培养基至 200μl，37℃、5%CO2条件下继续培养48h，在各孔内加入 20μl CCK-8试剂，37℃孵育 4 小时；取出 96 孔板，放入酶标仪，设置检测波长为 450nm，检测并纪录 OD450 读数；
PI染色实验：取对数生长期细胞，以20000细胞／孔接种于96孔扳，同时给药处理，培养24或48h后加入终浓度为50uｇ／ｍＬ的ＰＩ染料，避光染色10min，采用荧光显微镜观察拍照；
流式细胞术：6 孔板内接种对数生长期的各组细胞，培养 24 小时；重悬后收集每孔细胞于单支的流式管内，离心去上清，PBS 洗涤细胞 2 次，每管中缓慢加入 1ml、-20℃预冷的 70%乙醇， 4℃过夜；离心去除乙醇，PBS 洗涤细胞，离心 5min；每管加入 500μl PI/RNase Staining Buffer 重悬细胞，室温下避光孵育 15min后上机检测；
应用Real-time PCR、Western blot方法检测抑制剂对ABC型DLBCL BCR信号通路的影响：用10uM P22077处理ABC型DLBCL细胞（HBL），分别提取mRNA和蛋白，Real-time PCR法检测 BTK, PLCG2, PKC 和 CD79B 及BCR-NFkB 信号通路靶基因IL-6, MYC, BATF3 和IRF4的mRNA水平；Western blot方法检测BTK和PLCG2的蛋白水平。
3.根据权利要求2所述的一种USP7抑制剂在治疗ABC-DLBCL药物中的应用，其特征在于：所述第一步中研究USP7在DLBCL细胞系中的表达情况具体步骤为应用Western blot方法检测ABC型DLBCL及GCB型DLBCL细胞系中USP7 蛋白表达，和GCB-DLBCL亚型相比USP7在ABC型DLBCL中高表达，这种表达差异证实USP7参与ABC-DLBCL的发生。
4.根据权利要求2所述的一种USP7抑制剂在治疗ABC-DLBCL药物中的应用，其特征在于：所述第一步中数据库分析显示和癌旁组织相比，USP7在肿瘤组织中高表达。
5.根据权利要求2所述的一种USP7抑制剂在治疗ABC-DLBCL药物中的应用，其特征在于：USP7小分子抑制剂P22077可明显诱导DLBCL特别是ABC-DLBCL（HBL-1、SU-DHL-2）发生凋亡。
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