CN114958863A - Wdr20基因在制备肝细胞癌治疗药物中的应用 - Google Patents

Wdr20基因在制备肝细胞癌治疗药物中的应用 Download PDF

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CN114958863A
CN114958863A CN202210586895.6A CN202210586895A CN114958863A CN 114958863 A CN114958863 A CN 114958863A CN 202210586895 A CN202210586895 A CN 202210586895A CN 114958863 A CN114958863 A CN 114958863A
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hepatocellular carcinoma
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曹戟
杨波
何俏军
应美丹
蒋莉
袁梦
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Abstract

本发明提供一种WDR20基因在制备肝细胞癌治疗药物中的应用，以及靶向WDR20基因的多肽、小分子抑制剂和干扰RNAs在制备肝细胞癌治疗药物中的应用。研究表明在采用RNA干扰技术降低WDR20的表达后，对肝细胞癌BEL‑7402和Li‑7细胞的增殖有显著抑制作用，细胞的克隆形成能力和异种移植瘤生长受到显著抑制。因此，本发明不仅公开了WDR20基因的应用，而且为肝细胞癌提供了新的治疗靶点。

Description

WDR20基因在制备肝细胞癌治疗药物中的应用
技术领域
本发明属医药生物技术领域，具体涉及一种WDR20基因在制备肝细胞癌治疗药物中的应用。
背景技术
肝细胞癌是临床上最常见的恶性肿瘤之一，我国肝细胞癌的发病率位居全球首位，每年新发和死亡的肝细胞癌患者总数占全球的55％。除了肝脏移植和肝脏切除等主要治疗手段，肝细胞癌的一线用药主要为阿替利珠单抗联合贝伐珠单抗、多纳非尼和索拉非尼等，但仅适用于不宜进行外科手术的晚期患者且易发生耐药。在创新药物研发方面，目前临床上已发现的驱动因子主要为转录因子难以实现药物靶向。因此，肝细胞癌的诊断和治疗仍面临严峻挑战，寻找肝细胞癌发生发展过程中的新型潜在靶标和干预手段是目前较为迫切的需求。
WDR20蛋白作为去泛素化酶USP12和USP46的活化因子，在调控蛋白质翻译后修饰的过程中发挥重要作用。目前关于WDR20蛋白的研究报道较少，主要包括：1)调控去泛素化酶USP12的细胞内定位，增强USP12对雄激素受体等底物蛋白稳定性的调控作用，从而促进前列腺癌的发生发展；2)增强谷氨酸受体GLR-1的蛋白稳定性，参与突触发育和突触传递过程，在神经系统疾病中发挥重要作用；3)WDR20的表达下调与肾透明细胞癌的恶性转化密切相关。这些研究提示WDR20蛋白具有多种重要的生物学功能，但是WDR20基因在肝细胞癌中的作用尚没有文献报道，有待进一步研究。
发明内容
本发明的目的是提供WDR20基因在制备肝细胞癌治疗药物中的应用，是一种靶向WDR20基因的干扰siRNAs在制备肝细胞癌治疗药物中的应用。所述的WDR20基因核苷酸序列如SEQ ID NO:1所示，所述的靶向WDR20基因的氨基酸序列如SEQ ID NO:2所示。所述的干扰siRNAs的核苷酸序列分别为：
SEQ ID NO:3：5’CGAGAAAGATCACAAGCGA 3’ (﹟1)
SEQ ID NO:4：5’TTTGTAGACTGCCGAGTAA 3’ (﹟2)。
本发明所述应用是通过针对WDR20基因的siRNAs抑制WDR20的表达，实现对肝细胞癌的治疗。
以上所述药物的制剂形式为液体制剂或固体制剂。
本发明通过应用针对WDR20基因的siRNAs达到下调WDR20的作用，从而研究WDR20在肝细胞癌中的作用。2个针对WDR20基因的siRNAs(SEQ ID NO:3；SEQ ID NO:4)均能抑制WDR20的表达，进而抑制肝细胞癌。具体表现为对肝细胞癌BEL-7402和Li-7细胞的增殖能力和克隆形成能力有显著抑制作用，以及对BEL-7402异种移植瘤的生长有显著抑制作用。
本发明通过影响WDR20的表达实现对肝细胞癌的治疗。本发明采用RNA干扰技术降低WDR20后，肝细胞癌细胞的增殖能力和克隆形成能力受到显著的抑制，肝细胞癌异种移植瘤的生长受到显著的抑制。因此，本发明不仅公开了WDR20基因的应用，而且为肝细胞癌提供了新的治疗靶点。
本发明利用siRNA干扰技术，通过降低WDR20的表达可以显著抑制肝细胞癌BEL-7402和Li-7细胞的增殖能力和克隆形成能力，显著抑制BEL-7402异种移植瘤的生长。因此首次提出WDR20基因是肝细胞癌恶性进展的关键基因，WDR20的siRNAs分子可以作为有效干预手段，用于肝细胞癌的治疗。
本发明提供WDR20基因在制备肝细胞癌治疗药物中的用途，特别是WDR20 siRNA在制备肝细胞癌治疗药物中的用途。下调WDR20可以有效抑制肝细胞癌的增殖能力、克隆形成能力和异种移植瘤生长，为目前肝细胞癌的治疗药物的开发提供了新的方向，一定程度上解决临床上肝细胞癌治疗药物单一的局面。总之，下调WDR20可以抑制肝细胞癌的增殖能力、克隆形成能力和异种移植瘤生长，为制备新的肝细胞癌治疗药物，提高患者疗效，改善耐药及相关预后情况提供了可能性。
附图说明
图1是2个针对WDR20基因的siRNA(SEQ ID NO:3；SEQ ID NO:4)均具有显著下调WDR20蛋白表达的作用。
图2是将针对WDR20基因的siRNA(SEQ ID NO:3；SEQ ID NO:4)应用于肝细胞癌BEL-7402和Li-7细胞，肝细胞癌的增殖曲线明显变缓。
图3是将针对WDR20基因的siRNA(SEQ ID NO:3；SEQ ID NO:4)应用于肝细胞癌BEL-7402和Li-7细胞，肝细胞癌的克隆形成能力受到明显的抑制。
图4是将针对WDR20基因的siRNA(SEQ ID NO:3；SEQ ID NO:4)应用于肝细胞癌BEL-7402细胞，BEL-7402细胞的异种移植瘤生长受到显著抑制。
具体实施方式
下面结合附图和实施例对本发明作进一步详细的说明。以下实施例仅用于说明本发明而不用于限制本发明的范围。
实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆:实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。
本发明所述的WDR20基因的应用，可参考常规的药物配置方法和实际开发。药物剂型和生物制剂为医学上认可的任何一种剂型，例如为粉剂、注射液、胶囊、片剂或口服液。
实施例1
将靶向不同序列的2个WDR20 siRNA(SEQ ID NO:3；SEQ ID NO:4)以及阴性对照NC，通过脂质体转染法将其导入肝细胞癌BEL-7402和Li-7细胞中(购自中国科学院细胞库)，96小时后收取细胞，细胞裂解液裂解细胞并利用WDR20的抗体(购自Bethyl公司)进行Western blot免疫印迹实验。结果发现，以上所有的WDR20 siRNA均能有效的抑制WDR20的蛋白表达。结果参见图1。
实施例2
将2个靶向不同序列的WDR20 siRNA(如SEQ ID NO:3；SEQ ID NO:4)以及阴性对照NC，通过脂质体转染法将其导入肝细胞癌BEL-7402和Li-7细胞中(购自中国科学院细胞库)，在处理D2后，消化并采用血细胞计数板计数，接种1000个细胞至96孔板培养，然后通过磺酰罗丹明B染色检测肝细胞癌细胞增殖曲线变化。结果显示，WDR20 siRNAs均能显著抑制肝细胞癌BEL-7402和Li-7细胞的增殖能力。结果参见图2。
实施例3
将2个靶向不同序列的WDR20 siRNA(如SEQ ID NO:3；SEQ ID NO:4)以及阴性对照NC，通过脂质体转染法将其导入肝细胞癌BEL-7402和Li-7细胞中(购自中国科学院细胞库)，在处理D2后，消化并采用血细胞计数板计数，接种2000个细胞至六孔板进行克隆培养。结果显示，WDR20 siRNAs均能显著抑制肝细胞癌BEL-7402和Li-7细胞的克隆形成能力。结果参见图3。
实施例4
将2个靶向不同序列的WDR20 siRNA(如SEQ ID NO:3；SEQ ID NO:4)以及阴性对照NC，通过脂质体转染法将其导入肝细胞癌BEL-7402细胞中(购自中国科学院细胞库)，在处理D4后，消化并采用血细胞计数板计数，以100μL无血清培液重悬2×106个BEL-7402细胞接种于裸小鼠腋下，持续监测裸小鼠移植瘤的生长情况。结果显示，WDR20 siRNAs能显著抑制肝细胞癌BEL-7402的异种移植瘤生长。结果参见图4。
序列表
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565
<210> 3
<211> 19
<212> DNA
<213> 人工序列(Unknow)
<400> 3
cgagaaagat cacaagcga 19
<210> 4
<211> 19
<212> DNA
<213> 人工序列(Unknow)
<400> 4
tttgtagact gccgagtaa 19

Claims (3)

1.一种靶向WDR20基因的干扰siRNAs在制备肝细胞癌治疗药物中的应用，其特征在于，所述WDR20基因的核苷酸序列如SEQ ID NO:1所示，所述的干扰siRNAs的核苷酸序列分别为：
SEQ ID NO:3：5’CGAGAAAGATCACAAGCGA 3’
SEQ ID NO:4：5’TTTGTAGACTGCCGAGTAA 3’。
2.根据权利要求1所述的应用，其特征在于，所述应用是通过针对WDR20基因的siRNAs抑制WDR20的表达，实现对肝细胞癌的治疗。
3.根据权利要求1所述的应用，其特征在于，所述药物的制剂形式为液体制剂或固体制剂。
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CN101278059A (zh) * 2005-07-28 2008-10-01 肿瘤疗法科学股份有限公司 诊断和治疗肾细胞癌的方法
EP2481813A1 (en) * 2011-02-01 2012-08-01 Centro di Riferimento Oncologico - Istituto Nazionale Tumori - Aviano Markers of cutaneous melanoma and uses thereof
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CN101278059A (zh) * 2005-07-28 2008-10-01 肿瘤疗法科学股份有限公司 诊断和治疗肾细胞癌的方法
EP2481813A1 (en) * 2011-02-01 2012-08-01 Centro di Riferimento Oncologico - Istituto Nazionale Tumori - Aviano Markers of cutaneous melanoma and uses thereof
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