CN113980963A - 一种寡核苷酸rna双链分子及其在制备治疗恶性肿瘤药物中的应用 - Google Patents
一种寡核苷酸rna双链分子及其在制备治疗恶性肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种寡核苷酸RNA双链分子及其在制备治疗恶性肿瘤药物中的应用。本发明首次把VGF作为恶性肿瘤,尤其是黑色素瘤的治疗靶点,设计出针对VGF的siRNA:siRNA‑1和siRNA‑2,该siRNA对VGF蛋白选择型高、特异性强,对VGF蛋白有显著的抑制作用,可作为VGF特异性核苷酸药物分子;另外,该核苷酸序列能够显著抑制肿瘤增殖、诱导肿瘤细胞凋亡、抑制肿瘤细胞干性、抑制肿瘤细胞迁移和侵润,而且能够显著减小体内肿瘤的体积和重量,明显抑制肿瘤的生长增殖。因此,该核苷酸药物分子或其药学上可以接受的盐或溶剂合物有望成为治疗恶性肿瘤的药物。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种寡核苷酸RNA双链分子及其在制备治疗恶性肿瘤药物中的应用。
背景技术
恶性肿瘤是当代人类健康的一大杀手。目前临床上常用的肿瘤治疗方法有:化疗、放疗、手术治疗等,但肿瘤治疗仍存在着诸多问题,比如:肿瘤的耐药、转移、术后转移以及药物和射线的毒副作用等问题。近年来,随着生命科学的进步,肿瘤的治疗开始向靶向治疗发展,利用小干扰核苷酸治疗就是其中一种靶向治疗手段。
小干扰核苷酸(siRNA)是一类长度为20-25个碱基对双链RNA分子,能够形成RNA诱导的沉默复合物(RISC),沉默特定基因。siRNA作为肿瘤治疗药物最大的优点是它能高效并且特异地抑制同源mRNA的表达水平,特异性好。虽然哺乳动物细胞中的siRNA效应是较短暂的,但siRNA载体的应用已能够使RNA抑制效应在哺乳动物中遗传。故小干扰核苷酸药物具有良好的应用前景。
理论上,siRNA药物可应用于肿瘤发生、发展和转移过程中任何有基因异常高表达的任何环节。目前小干扰核苷酸药物在肿瘤治疗领域的策略主要针对以下方面。一、针对肿瘤相关融合基因转录产物;二、针对过表达的癌基因或凋亡抑制因子;三、针对肿瘤耐药基因;四、针对肿瘤血管生成因子及受体;五、等位基因特异性抑制。
VGF是一类用神经生长因子(neural growth factor inducible gene,NGF)处理鼠肾上腺嗜铬细胞瘤细胞后快速诱导产生的可分泌的神经肽前体蛋白。有研究(TheJournal of Neuroscience,2003,23(34):10800-8)表明,许多神经营养因子如脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)和神经营养因子-3(neurotrophin-3,NT-3)同样也能诱导神经元细胞中VGF表达。此外,VGF是一类具有相对较高保守性的多肽,在人、小鼠、马、牛的氨基酸序列上约有85%的序列具有一致性。人源的VGF含有615个氨基酸,分子量约68kD,,其可以被切割成具有特定神经元生物活性的不同肽。VGF的剪接肽与许多神经内分泌作用有关,在许多疾病中发挥重要作用,特别是与能量代谢、疼痛、生殖和认识。虽然目前对VGF衍生的活性神经肽发挥其生理作用的分子机制和信号事件的研究尚处于起步阶段。但有少数研究(Cancer Res,2017,11:3013-3026,EndocrRelat Cancer,2019,7:643-658,Cell Stem Cell,2018,4:514-528.e5)表明VGF在肿瘤的形成过程的多个环节中发挥作用,如果能够开发出针对VGF的小干扰核苷酸药物,则有望通过抑制VGF靶点治疗恶性肿瘤。
综上所述,靶向VGF的药物具有良好的前景,但目前针还没有针对VGF靶蛋的药物,这极大程度上限制了VGF作为靶点的药物开发与应用。而VGF作为一个具有前景的肿瘤治疗靶点,迫切需要开发能阻断VGF的小核苷酸类药物及VGF作为靶点治疗恶性肿瘤的用药方案。
发明内容
本发明的目的在于针对恶性肿瘤,特别是黑色素瘤,本发明提供一种寡核苷酸RNA双链分子。本发明发现siVGF-1和siVGF-2核苷酸药物分子能够特异性降低肿瘤细胞中VGF的表达,同时能够显著抑制肿瘤增殖、诱导肿瘤细胞凋亡、抑制肿瘤细胞干性、抑制肿瘤细胞迁移和侵润,而且能够显著减小体内肿瘤的体积和重量,明显抑制肿瘤的生长增殖。因此,此核苷酸药物分子在制备抗恶性肿瘤药物中具有广泛的用途。
本发明的另一目的在于提供一种表达载体。
本发明的另一目的在于提供一种宿主细胞。
本发明的另一目的在于提供上述寡核苷酸RNA双链分子或其药学上可以接受的盐或溶剂合物在制备抑制VGF蛋白活性的药物中的应用。
本发明的另一目的在于提供上述寡核苷酸RNA双链分子或其药学上可以接受的盐或溶剂合物在制备治疗恶性肿瘤药物中的应用。
为了实现本发明的上述目的,本发明提供了如下技术方案:
一种寡核苷酸RNA双链分子,其序列为如下核苷酸序列中的一条或几条:
siVGF-1:
正义链:5’-GAAUUACAUCGAGCACGUGCU-3’(如SEQ ID NO:1所示)
反义链:(如SEQ ID NO:2所示)
siVGF-2:
正义链:5’-GACGAUCGACAGCCUCAUUGA-3’(如SEQ ID NO:3所示)
反义链:(如SEQ ID NO:4所示)。
本发明研究发现,特定结构的siRNA核苷酸序列siVGF-1和siVGF-2能够特异性降低肿瘤细胞中VGF的表达,同时能够显著抑制肿瘤增殖、诱导肿瘤细胞凋亡、抑制肿瘤细胞干性、抑制肿瘤细胞迁移和侵润,而且能够显著减小体内肿瘤的体积和重量,明显抑制肿瘤的生长增殖,在制备抗恶性肿瘤药物中具有广泛的用途。
一种表达载体,含有上述寡核苷酸RNA双链分子。
一种宿主细胞,含有上述寡核苷酸RNA双链分子,或含有上述表达载体。
上述寡核苷酸RNA双链分子或其药学上可以接受的盐或溶剂合物在制备抑制VGF蛋白活性的药物中的应用。
经研究发现,本发明的寡核苷酸RNA双链分子siVGF-1和siVGF-2可抑制恶性肿瘤细胞尤其黑色素瘤细胞侵袭、浸润、生长、增殖和克隆。
上述寡核苷酸RNA双链分子或其药学上可以接受的盐或溶剂合物在制备治疗恶性肿瘤药物中的应用。
优选地,所述药物为抑制恶性肿瘤细胞生长和/或增殖的药物。
优选地,所述药物为抑制恶性肿瘤细胞转移和/或侵润的药物。
优选地,恶性肿瘤包括但不限于:黑素瘤、胃癌、乳腺癌、直肠癌、非小细胞肺癌、急性淋巴细胞白血病、急性髓细胞白血病、肾上腺皮质癌、艾滋病相关癌症、艾滋病相关淋巴癌、肛门癌、肝胆外管癌、膀胱癌、骨癌、脑干胶质瘤、脑瘤、支气管腺瘤、伯基特氏淋巴瘤、类癌瘤、未知原发癌、中枢神经系统淋巴癌、子宫颈癌、肾癌、喉癌、血癌、肝癌、前列腺瘤、唾液腺癌、肉瘤、小肠癌、软组织肉瘤、子宫肉瘤、睾丸癌、卵巢癌、横纹肌样瘤、滑膜肉瘤、间皮瘤、皮肤癌、口腔癌、输卵管肿瘤、腹膜肿瘤、神经胶质瘤、神经胶母细胞瘤、骨髓瘤。
优选地,所述药物与G蛋白抑制剂联用,G蛋白抑制剂包括但不限于GQ127。
具体地,通过细胞模型和裸鼠皮下细胞移植瘤模型实验,发现siVGF-1和siVGF-2核苷酸RNA双链分子能够特异性降低肿瘤细胞中VGF的表达,同时能够显著抑制肿瘤增殖、诱导肿瘤细胞凋亡、抑制肿瘤细胞干性、抑制肿瘤细胞迁移和侵润,而且能够显著减小体内肿瘤的体积和重量,明显抑制肿瘤的生长增殖。核苷酸药物分子与G蛋白抑制剂GQ127联用能够显著增强其效果。
术语“药学上可接受的”是指某载体、稀释剂或赋形剂,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“可接受的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。
更为优选地,所述药学上可以接受的盐为药学上可以接受的无机盐或有机盐。
具体地,药学上可以接受的盐包括但不限于:硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐,甲烷磺酸盐(甲磺酸盐)、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐、和双羟萘酸盐;或者铵盐(例如伯胺盐、仲胺盐、叔胺盐、季铵盐)、金属盐(例如钠盐、钾盐、钙盐、镁盐、锰盐、铁盐、锌盐、铜盐、锂盐、铝盐)。
优选地,所述药物的剂型为注射剂、胶囊剂、片剂、丸剂或颗粒剂。
相对于现有技术,本发明具有如下的优点及效果:
本发明提供的siVGF-1和siVGF-2寡核苷酸RNA双链分子,对VGF蛋白选择型高、特异性强,对VGF蛋白有显著的抑制作用,可作为VGF特异性核苷酸药物分子;另外,该核苷酸序列能够显著抑制肿瘤增殖、诱导肿瘤细胞凋亡、抑制肿瘤细胞干性、抑制肿瘤细胞迁移和侵润,而且能够显著减小体内肿瘤的体积和重量,明显抑制肿瘤的生长增殖。因此,该核苷酸药物分子或其药学上可以接受的盐或溶剂合物在制备治疗恶性肿瘤的药物中具有广泛的用途。
附图说明
图1为人源癌症细胞株(肺癌PC-9、胃癌AGS、三阴性乳腺癌MDA-MB-231、肠癌HCT-116)中利用siVGF-1和siVGF-2沉默VGF基因后细胞活力的测试结果图;
图2为黑色素瘤细胞株MP41和92-1利用siVGF-1和siVGF-2沉默VGF基因后的细胞计数实验结果图;图2A为MP41细胞实验结果,图2B为92-1细胞实验结果。
图3为黑色素瘤细胞株MP41和92-1利用siVGF-1和siVGF-2沉默VGF基因后的EDU细胞增殖检测实验结果图;图3A为MP41细胞EDU染色结果,图3B为92-1细胞染色结果,图3C为MP41增殖活性细胞技术统计,图3D为92-1增殖活性细胞技术统计。
图4为黑色素瘤细胞株MP41和92-1利用siVGF-1和siVGF-2沉默VGF基因后利用流式细胞术检测细胞凋亡结果图;图4左边为流式细胞分析结果,右边为流式分析统计。
图5为黑色素瘤细胞株MP41和92-1利用siVGF-1和siVGF-2沉默VGF基因后的细胞划痕实验结果图。
图6为黑色素瘤细胞株MP41和92-1利用siVGF-1和siVGF-2沉默VGF基因后的transwell细胞侵袭实验结果图。
图7为黑色素瘤细胞株MP41和92-1利用siVGF-1和siVGF-2沉默VGF基因后的成球实验。
图8为siVGF单用或者与G蛋白抑制剂GQ127联用在动物模型抑制黑色素瘤生长实验结果图;实验分为Vehicle组、siControl组、siVGF-1组、GQ127 10mg/kg组和GQ127 10mg/kg+siVGF-1组,图8A为各个分组肿瘤体积随着时间的增长曲线,图8B为各个分组在实验终点肿瘤组织的重量,图8C为各个分组代表性肿瘤组织图片。
具体实施方式
以下结合实施例和附图进一步解释本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,本发明所用试剂和材料均为市购。
本发明各实施例中提及的序列信息如下:
1.VGF基因CDS区序列(如SEQ ID NO:5):
ATGAAAGCCC TCAGATTGTC GGCTTCCGCC CTCTTCTGCC TTCTGCTGAT CAACGGGTTAGGGGCAGCAC CCCCTGGTCG CCCTGAGGCG CAGCCTCCTC CTCTCAGCTC TGAGCATAAA GAGCCGGTAGCCGGGGACGC AGTGCCCGGG CCAAAGGATG GCAGCGCCCC AGAGGTCCGA GGCGCTCGGA ATTCCGAGCCGCAGGACGAG GGAGAGCTTT TCCAGGGCGT GGATCCCCGG GCGCTGGCCG CGGTGCTGCT GCAGGCACTCGACCGTCCCG CCTCACCCCC GGCACCAAGC GGCTCCCAGC AGGGGCCGGA GGAAGAAGCA GCTGAAGCTCTGCTGACCGA GACCGTGCGC AGCCAGACCC ACAGCCTCCC GGCGCCGGAG AGCCCGGAGC CCGCGGCTCCGCCTCGCCCT CAGACTCCGG AGAATGGGCC CGAGGCGAGC GATCCCTCCG AGGAGCTCGA GGCGCTAGCGTCCCTGCTCC AGGAACTGCG AGATTTCAGT CCAAGTAGCG CCAAGCGCCA GCAGGAGACG GCGGCAGCAGAGACGGAAAC CCGCACGCAC ACGCTGACCC GAGTGAATCT GGAGAGCCCG GGGCCAGAGC GCGTATGGCGCGCTTCCTGG GGAGAGTTCC AGGCGCGTGT CCCGGAGCGC GCGCCCCTGC CGCCCCCGGC CCCCTCTCAATTCCAGGCGC GTATGCCCGA CAGCGGGCCC CTTCCCGAAA CCCACAAGTT CGGGGAAGGA GTGTCCTCCCCCAAAACACA CCTAGGCGAG GCATTGGCAC CCCTGTCCAA GGCGTACCAA GGCGTGGCCG CCCCGTTCCCCAAGGCGCGC CGGCCGGAGA GCGCACTCCT GGGCGGCTCC GAGGCGGGCG AGCGCCTTCT CCAGCAAGGGCTGGCGCAGG TGGAGGCCGG GCGGCGGCAG GCGGAGGCCA CGCGGCAGGC CGCGGCGCAG GAAGAGCGGCTGGCCGACCT CGCCTCGGAC CTGCTGCTCC AGTATTTGCT GCAGGGCGGG GCCCGGCAGC GCGGCCTCGGGGGTCGGGGG CTGCAGGAGG CGGCGGAGGA GCGAGAGAGT GCAAGGGAGG AGGAGGAGGC GGAGCAGGAGAGACGCGGCG GGGAGGAGAG GGTGGGGGAA GAGGATGAGG AGGCGGCCGA GGCGGAGGCA GAGGCGGAGGAGGCGGAGAG GGCGCGGCAG AACGCGCTCC TGTTCGCGGA GGAGGAGGAC GGGGAAGCCG GCGCCGAGGACAAGCGCTCC CAGGAGGAGA CGCCGGGCCA CCGGCGGAAG GAGGCCGAGG GGACAGAGGA GGGCGGGGAGGAGGAGGACG ACGAGGAGAT GGATCCGCAG ACGATCGACA GCCTCATTGA GCTGTCCACC AAACTCCACCTGCCAGCGGA CGACGTGGTC AGCATCATCG AGGAGGTGGA GGAGAAGCGG AAGCGGAAGA AGAACGCCCCTCCCGAGCCC GTGCCGCCCC CCCGTGCCGC CCCCGCCCCC ACCCACGTCC GCTCCCCGCA GCCCCCGCCCCCCGCCCCCG CTCCCGCACG AGACGAGCTG CCGGACTGGA ACGAGGTGCT CCCGCCCTGG GATCGGGAGGAGGACGAGGT GTACCCGCCA GGGCCGTACC ACCCTTTCCC CAACTACATC CGGCCGCGGA CACTGCAGCCGCCCTCGGCC TTGCGCCGCC GCCACTACCA CCACGCCTTG CCGCCTTCGC GCCACTATCC CGGCCGGGAGGCCCAGGCGC GGCGCGCGCA GGAGGAGGCG GAGGCGGAGG AGCGCCGGCT GCAGGAGCAG GAGGAGCTGGAGAATTACAT CGAGCACGTG CTGCTCCGGC GCCCGTGA
2.VGF蛋白序列(如SEQ ID NO:6):
MKALRLSASA LFCLLLINGL GAAPPGRPEA QPPPLSSEHK EPVAGDAVPG PKDGSAPEVRGARNSEPQDE GELFQGVDPR ALAAVLLQAL DRPASPPAPS GSQQGPEEEA AEALLTETVR SQTHSLPAPESPEPAAPPRP QTPENGPEAS DPSEELEALA SLLQELRDFS PSSAKRQQET AAAETETRTH TLTRVNLESPGPERVWRASW GEFQARVPER APLPPPAPSQ FQARMPDSGP LPETHKFGEG VSSPKTHLGE ALAPLSKAYQGVAAPFPKAR RPESALLGGS EAGERLLQQG LAQVEAGRRQ AEATRQAAAQ EERLADLASD LLLQYLLQGGARQRGLGGRG LQEAAEERES AREEEEAEQE RRGGEERVGE EDEEAAEAEA EAEEAERARQ NALLFAEEEDGEAGAEDKRS QEETPGHRRK EAEGTEEGGE EEDDEEMDPQ TIDSLIELST KLHLPADDVV SIIEEVEEKRKRKKNAPPEP VPPPRAAPAP THVRSPQPPP PAPAPARDEL PDWNEVLPPW DREEDEVYPP GPYHPFPNYIRPRTLQPPSA LRRRHYHHAL PPSRHYPGRE AQARRAQEEA EAEERRLQEQ EELENYIEHV LLRRP-
3.siVGF-1:5’-GAAUUACAUCGAGCACGUGCU-3’
4.siVGF-2:5’-GACGAUCGACAGCCUCAUUGA-3’
下面结合实施例,进一步阐述本发明。
实施例1:siVGF细胞株的构建和表达
1)92-1细胞、MP41细胞、MDA-MB-231细胞、PC-9细胞、HCT-116细胞和AGS细胞分别在100mm细胞培养皿中用含10%血清的RIPM1640培养基(92-1细胞、MP41细胞、PC-9细胞、HCT-116细胞和AGS细胞)或10%血清的DMEM高糖培养基(MDA-MB-231细胞)培养,待细胞生长至汇集度达到70-80%。
2)消化细胞,以每孔100000个细胞把各细胞株分别接种到6孔板中,培养过夜。
3)待各细胞贴壁后吸去细胞培养基,六孔板中每孔加入800μl无血清的RIPM1640培养基或DMEM高糖培养基。
4)按需处理的六孔板孔数,配置以下溶液:
溶液1:每份3μL dhramofect+97μl opti-MEM,按所需处理的孔数配若干份。
溶液2:每份2.5μl VGF小干扰RNA+97.5μl opti-MEM,按所需处理的孔数配若干份。
溶液1和溶液2分别在室温孵育5min,之后将溶液1和溶液2混合均匀,室温孵育20min。孵育完毕后,按每孔200μl混合溶液加入到六孔板中。
5)将六孔板板置于37℃的CO 2培养箱培养6h,之后吸去细胞中的培养基,换成10%血清的RIPM1640培养基或DMEM高糖培养基培养。
实施例2:siVGF抑制胃癌、肺癌、三阴性乳腺癌、结直肠癌等细胞的增殖
1)细胞转染
按实施例1中的方法,分别转染得到siControl、siVGF-1、siVGF-2的MDA-MB-231、PC-9、HCT-116和AGS细胞。
2)细胞铺板
将转染得到的15种细胞按照2000个/孔接种到96孔板上,每孔加入含10%血清的RIPM1640培养基(PC-9、HCT-116和AGS细胞)或DMEM高糖培养基(MDA-MB-231细胞)至100μl,每种细胞重复接种三个孔。同时,在三个孔中加入100μl含10%血清的RIPM1640培养基,另外三个孔加入10%血清DMEM作为空白对照。将96孔板放入培养箱中,培养72h。
3)CCK8细胞增殖检测试剂盒测定细胞活力
取出96孔板,每孔中加入10μlCCK8溶液,加液过程中需要避光操作,然后放入37℃培养箱中进行避光孵育。孵育每隔一定时间,用酶标仪测定450nm处的OD值,测量OD值在0.8-1.5之间,若OD值未到0.8则需继续避光孵育。孵育总时间应在30min-4h之间。测量每孔的OD值减去相应的空白培养基的平均OD值即为结果。结果如图1所示。从图1可知,各癌症细胞株经过siVGF-1和siVGF-2处理后细胞活性下降,提示siVGF-1和siVGF-2对多种恶性肿瘤细胞株生长增殖的抑制。
实施例3:si-VGF抑制黑色素瘤细胞生长、增殖
1)细胞转染
按实施例1中的方法,转染得到siCONTROL、siVGF-1、siVGF-2的MP41细胞和siCONTROL、siVGF-1、siVGF-2的92-1细胞
2)细胞铺板
将转染得到的6种细胞按照1×105个/孔接种到6孔板上,每孔加入含10%血清的RIPM1640培养基至1ml,每种细胞重复接种6个孔,其中3个孔用于三天后细胞计数,剩余3个孔用于五天后细胞计数。
3)细胞计数
三天后取出6孔板,吸去培养基,每孔加入1mlPBS洗涤,弃去PBS后用300μl胰酶室温消化1min。随后每孔加入1ml含10%血清的RIPM1640培养基终止消化,分开收集给细胞悬液,2000rpm离心2min,弃去上清。用1ml含10%血清的RIPM1640培养基重悬细胞,进行细胞计数。
五天后,将剩余的6孔板取出,重复上述步骤,进行细胞计数。结果如图2所示。从图2可知,利用siVGF-1和siVGF-2处理3天和5天后,MP41和92-1存活细胞数较siControl组大幅减少;siVGF-1和siVGF-2可以抑制黑色素瘤细胞增殖、生长。
实施例4:利用EDU染色实验测定siVGF抑制黑色素瘤细胞增殖
1)样品处理:
以100000/孔在六孔板中培养92-1和MP41细胞。按细胞实施例1(1)中细胞转染的方法给细胞转染siControl、siVGF-1和siVGF-2。转染72h后,加入EdU试剂培养2h。
2)固定与染色
弃去样品的培养基,加入4%多聚甲醛固定15min。之后用PBS洗去残留的多聚甲醛,然后用含0.3%TritonX-100的PBS溶液处理15min。洗去破膜剂后,每孔加入100μlHoechst 33342孵育30min。之后用PBS洗去Hoechst 33342。
3)成像
用荧光显微镜拍摄细胞,结果如图3所示。从图3可知,siVGF-1和siVGF-2能显著抑制MP41和92-1细胞增殖。
实施例5:流式细胞术检测siVGF诱导肿瘤细胞发生细胞凋亡
1)样品处理:
以100000/孔在六孔板中培养92-1和MP41细胞。按细胞实施例1(1)中细胞转染的方法给细胞转染siControl、siVGF-1和siVGF-2。转染72h后吸去培养基,并消化细胞。把消化下来的细胞收集在离心管中1000rpm离心1min。离心完毕后,向各组细胞分别加400μl结合液,置于冰上。
2)细胞染色
向细胞中加入Annexin V-FITC染料2.5μl,轻轻吹打均匀,4℃避光静置15min,之后加入PI染料5μl,轻轻吹打均匀,4℃静置5min。
3)象限划分
清洗流式细胞仪,对siControl组样品进行进样,并以横坐标为Green B,纵坐标为Red B划分好象限。
4)流式细胞分选凋亡细胞
设定细胞数为10000进行流式细胞分选,结果如图4所示。从图4可知,结果显示siVGF-1和siVGF-2处理后的细胞凋亡明显增多,提示siVGF-1和siVGF-2有促进肿瘤凋亡的作用。
实施例6:siVGF降低黑色素瘤细胞迁移能力
1)细胞转染
以100000/孔在六孔板中培养92-1和MP41细胞。按细胞实施例1(1)中细胞转染的方法给细胞转染siControl、siVGF-1和siVGF-2。
2)划痕
转染后待细胞长至密度在90%-100%之间,用枪头沿着尺子在六孔板中划痕,注意力度一致使划痕均一。之后吸去培养基,用PBS洗涤细胞。然后重新加入培养基。
3)显微镜成像
把六孔板置于显微镜中,用4倍镜对划痕处进行拍摄。每个孔拍摄三个视野,结果如图5所示。从图5可知,在经siVGF-1和siVGF-2处理24h后,MP41和92-1细胞划痕回复能力下降,表明siVGF-1和siVGF-2抑制了MP41和92-1细胞的迁移能力。
实施例7:siVGF降低黑色素瘤细胞侵润能力
1)细胞转染
按实施例1中的方法,转染得到siControl、siVGF-1、siVGF-2的MP41细胞和siControl、siVGF-1、siVGF-2的92-1细胞
2)细胞铺板
以1×106个/孔把上述6种细胞分别接种到transwell板的上孔中,加入含10%血清的RIPM1640培养基到每孔300μl体系,同时,transwell板的下孔中加入500μl含10%血清的RIPM1640培养基,培养24h,待细胞贴壁。
3)细胞侵袭
取出transwell板,把上孔的培养基换成无血清的RIPM1640培养基,下孔培养基更换为含20%血清的RIPM1640培养基,培养48h。
4)染色和成像
取走transwell板上孔,并把transwell板下孔中的培养基吸走,每孔加入300-400μl的4%多聚甲醛,固定15min。固定完毕后,吸取多聚甲醛,沿transwell板壁向每孔加入PBS,冲洗1-2。之后向每孔加入300-400μl结晶紫,避光染色30min,吸去结晶紫。然后使用超纯水进行冲洗,冲洗掉残留的结晶紫,然后自然风干。
等待transwell板中细胞风干后,用4倍显微镜拍摄下细胞侵袭情况,结果如图6所示。从图6可知,经siVGF-1和siVGF-2处理后,MP41细胞和92-1细胞侵袭至transwell下孔的数量减少,说明siVGF-1和siVGF-2有抑制黑色素瘤细胞浸润的作用。
实施例8:siVGF抑制黑色素瘤细胞干性成球
1)细胞转染
按实施例1中的方法,转染得到siControl、siVGF-1、siVGF-2的MP41细胞和siControl、siVGF-1、siVGF-2的92-1细胞
2)肿瘤干细胞成球实验
将上述得到的6种细胞用成球培养基(含0.4%BSA+5μg/ml胰岛素+20ng/ml EGF+20ng/ml FGF的DMEM-F12培养基)重悬。之后以每孔2000个细胞分别接种到低吸附6孔板中。加成球培养基到每孔含1ml液体。
每三天分别收集每孔中的细胞悬液,离心后弃去上清,用新的成球培养基轻轻重悬细胞,重新接种在6孔板中。15天后用20倍显微镜记录细胞成球状态,结果如图7所示。从图7可知,相对于siControl组,siVGF-1组和siVGF-2组肿瘤细胞成球能力明显降低。说明siVGF-1和siVGF-2抑制类MP41和92-1细胞干性。
实施例9:siVGF单用或者与G蛋白抑制剂GQ127联用在动物模型抑制黑色素瘤生长
1)移植瘤模型构建
以3×107个细胞/只把MP41接种到Balb/c裸鼠背部两侧皮下,当肿瘤体积达到100mm3的时候。把裸鼠随机平均分组,每组7只,共5组,分别为空白对照组,siControl组,siVGF组,GQ127组和GQ127+siVGF-1组,并记为第0天。
3)给药
从第0天开始,空白组每日腹腔注射助溶剂,GQ127 10mg/kg组每日腹腔注射10mg/kg的GQ127。siControl组、siVGF-1组和GQ127 10mg/kg+siVGF-1三组每三天瘤内注射由siControl或siVGF:RNA转染试剂=2:1的转染复合物。每三天记录一次裸鼠肿瘤体积。
3)抗肿瘤活性测定
给药18天后,处死裸鼠并取出裸鼠背部皮下肿瘤,比较肿瘤大小与肿瘤重量。结果如图8所示。从图8可知,单用siVGF-1明显抑制肿瘤生长,而联合G蛋白抑制剂GQ127和siVGF-1治疗荷瘤小鼠,肿瘤抑制效果更加明显。说明siVGF-1明显抑制肿瘤生长,联用G蛋白抑制剂GQ127则有明显的协同抗肿瘤作用。
综合以上结果,本发明证明了siVGF核苷酸片段对多种恶性肿瘤,尤其是黑色素瘤的治疗作用,为进一步的临床应用开发奠定了基础。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 中山大学
<120> 一种寡核苷酸RNA双链分子及其在制备治疗恶性肿瘤药物中的应用
<160> 6
<170> SIPOSequenceListing 1.0
<210> 2
<211> 21
<212> RNA
<213> 寡核苷酸RNA双链分子(siRNA-1)
<400> 2
gaauuacauc gagcacgugc u 21
<210> 2
<211> 21
<212> RNA
<213> 寡核苷酸RNA双链分子(siRNA-1)
<400> 2
cuuaauguag cucgugcacg a 21
<210> 3
<211> 21
<212> RNA
<213> 寡核苷酸RNA双链分子(siRNA-2)
<400> 3
gacgaucgac agccucauug a 21
<210> 4
<211> 21
<212> RNA
<213> 寡核苷酸RNA双链分子(siRNA-2)
<400> 4
cugcuagcug ucggaguaac u 21
<210> 5
<211> 1848
<212> DNA/RNA
<213> VGF基因CDS区序列(VGF基因CDS区序列)
<400> 5
atgaaagccc tcagattgtc ggcttccgcc ctcttctgcc ttctgctgat caacgggtta 60
ggggcagcac cccctggtcg ccctgaggcg cagcctcctc ctctcagctc tgagcataaa 120
gagccggtag ccggggacgc agtgcccggg ccaaaggatg gcagcgcccc agaggtccga 180
ggcgctcgga attccgagcc gcaggacgag ggagagcttt tccagggcgt ggatccccgg 240
gcgctggccg cggtgctgct gcaggcactc gaccgtcccg cctcaccccc ggcaccaagc 300
ggctcccagc aggggccgga ggaagaagca gctgaagctc tgctgaccga gaccgtgcgc 360
agccagaccc acagcctccc ggcgccggag agcccggagc ccgcggctcc gcctcgccct 420
cagactccgg agaatgggcc cgaggcgagc gatccctccg aggagctcga ggcgctagcg 480
tccctgctcc aggaactgcg agatttcagt ccaagtagcg ccaagcgcca gcaggagacg 540
gcggcagcag agacggaaac ccgcacgcac acgctgaccc gagtgaatct ggagagcccg 600
gggccagagc gcgtatggcg cgcttcctgg ggagagttcc aggcgcgtgt cccggagcgc 660
gcgcccctgc cgcccccggc cccctctcaa ttccaggcgc gtatgcccga cagcgggccc 720
cttcccgaaa cccacaagtt cggggaagga gtgtcctccc ccaaaacaca cctaggcgag 780
gcattggcac ccctgtccaa ggcgtaccaa ggcgtggccg ccccgttccc caaggcgcgc 840
cggccggaga gcgcactcct gggcggctcc gaggcgggcg agcgccttct ccagcaaggg 900
ctggcgcagg tggaggccgg gcggcggcag gcggaggcca cgcggcaggc cgcggcgcag 960
gaagagcggc tggccgacct cgcctcggac ctgctgctcc agtatttgct gcagggcggg 1020
gcccggcagc gcggcctcgg gggtcggggg ctgcaggagg cggcggagga gcgagagagt 1080
gcaagggagg aggaggaggc ggagcaggag agacgcggcg gggaggagag ggtgggggaa 1140
gaggatgagg aggcggccga ggcggaggca gaggcggagg aggcggagag ggcgcggcag 1200
aacgcgctcc tgttcgcgga ggaggaggac ggggaagccg gcgccgagga caagcgctcc 1260
caggaggaga cgccgggcca ccggcggaag gaggccgagg ggacagagga gggcggggag 1320
gaggaggacg acgaggagat ggatccgcag acgatcgaca gcctcattga gctgtccacc 1380
aaactccacc tgccagcgga cgacgtggtc agcatcatcg aggaggtgga ggagaagcgg 1440
aagcggaaga agaacgcccc tcccgagccc gtgccgcccc cccgtgccgc ccccgccccc 1500
acccacgtcc gctccccgca gcccccgccc cccgcccccg ctcccgcacg agacgagctg 1560
ccggactgga acgaggtgct cccgccctgg gatcgggagg aggacgaggt gtacccgcca 1620
gggccgtacc accctttccc caactacatc cggccgcgga cactgcagcc gccctcggcc 1680
ttgcgccgcc gccactacca ccacgccttg ccgccttcgc gccactatcc cggccgggag 1740
gcccaggcgc ggcgcgcgca ggaggaggcg gaggcggagg agcgccggct gcaggagcag 1800
gaggagctgg agaattacat cgagcacgtg ctgctccggc gcccgtga 1848
<210> 6
<211> 615
<212> PRT
<213> VGF蛋白序列(VGF蛋白序列)
<400> 6
Met Lys Ala Leu Arg Leu Ser Ala Ser Ala Leu Phe Cys Leu Leu Leu
1 5 10 15
Ile Asn Gly Leu Gly Ala Ala Pro Pro Gly Arg Pro Glu Ala Gln Pro
20 25 30
Pro Pro Leu Ser Ser Glu His Lys Glu Pro Val Ala Gly Asp Ala Val
35 40 45
Pro Gly Pro Lys Asp Gly Ser Ala Pro Glu Val Arg Gly Ala Arg Asn
50 55 60
Ser Glu Pro Gln Asp Glu Gly Glu Leu Phe Gln Gly Val Asp Pro Arg
65 70 75 80
Ala Leu Ala Ala Val Leu Leu Gln Ala Leu Asp Arg Pro Ala Ser Pro
85 90 95
Pro Ala Pro Ser Gly Ser Gln Gln Gly Pro Glu Glu Glu Ala Ala Glu
100 105 110
Ala Leu Leu Thr Glu Thr Val Arg Ser Gln Thr His Ser Leu Pro Ala
115 120 125
Pro Glu Ser Pro Glu Pro Ala Ala Pro Pro Arg Pro Gln Thr Pro Glu
130 135 140
Asn Gly Pro Glu Ala Ser Asp Pro Ser Glu Glu Leu Glu Ala Leu Ala
145 150 155 160
Ser Leu Leu Gln Glu Leu Arg Asp Phe Ser Pro Ser Ser Ala Lys Arg
165 170 175
Gln Gln Glu Thr Ala Ala Ala Glu Thr Glu Thr Arg Thr His Thr Leu
180 185 190
Thr Arg Val Asn Leu Glu Ser Pro Gly Pro Glu Arg Val Trp Arg Ala
195 200 205
Ser Trp Gly Glu Phe Gln Ala Arg Val Pro Glu Arg Ala Pro Leu Pro
210 215 220
Pro Pro Ala Pro Ser Gln Phe Gln Ala Arg Met Pro Asp Ser Gly Pro
225 230 235 240
Leu Pro Glu Thr His Lys Phe Gly Glu Gly Val Ser Ser Pro Lys Thr
245 250 255
His Leu Gly Glu Ala Leu Ala Pro Leu Ser Lys Ala Tyr Gln Gly Val
260 265 270
Ala Ala Pro Phe Pro Lys Ala Arg Arg Pro Glu Ser Ala Leu Leu Gly
275 280 285
Gly Ser Glu Ala Gly Glu Arg Leu Leu Gln Gln Gly Leu Ala Gln Val
290 295 300
Glu Ala Gly Arg Arg Gln Ala Glu Ala Thr Arg Gln Ala Ala Ala Gln
305 310 315 320
Glu Glu Arg Leu Ala Asp Leu Ala Ser Asp Leu Leu Leu Gln Tyr Leu
325 330 335
Leu Gln Gly Gly Ala Arg Gln Arg Gly Leu Gly Gly Arg Gly Leu Gln
340 345 350
Glu Ala Ala Glu Glu Arg Glu Ser Ala Arg Glu Glu Glu Glu Ala Glu
355 360 365
Gln Glu Arg Arg Gly Gly Glu Glu Arg Val Gly Glu Glu Asp Glu Glu
370 375 380
Ala Ala Glu Ala Glu Ala Glu Ala Glu Glu Ala Glu Arg Ala Arg Gln
385 390 395 400
Asn Ala Leu Leu Phe Ala Glu Glu Glu Asp Gly Glu Ala Gly Ala Glu
405 410 415
Asp Lys Arg Ser Gln Glu Glu Thr Pro Gly His Arg Arg Lys Glu Ala
420 425 430
Glu Gly Thr Glu Glu Gly Gly Glu Glu Glu Asp Asp Glu Glu Met Asp
435 440 445
Pro Gln Thr Ile Asp Ser Leu Ile Glu Leu Ser Thr Lys Leu His Leu
450 455 460
Pro Ala Asp Asp Val Val Ser Ile Ile Glu Glu Val Glu Glu Lys Arg
465 470 475 480
Lys Arg Lys Lys Asn Ala Pro Pro Glu Pro Val Pro Pro Pro Arg Ala
485 490 495
Ala Pro Ala Pro Thr His Val Arg Ser Pro Gln Pro Pro Pro Pro Ala
500 505 510
Pro Ala Pro Ala Arg Asp Glu Leu Pro Asp Trp Asn Glu Val Leu Pro
515 520 525
Pro Trp Asp Arg Glu Glu Asp Glu Val Tyr Pro Pro Gly Pro Tyr His
530 535 540
Pro Phe Pro Asn Tyr Ile Arg Pro Arg Thr Leu Gln Pro Pro Ser Ala
545 550 555 560
Leu Arg Arg Arg His Tyr His His Ala Leu Pro Pro Ser Arg His Tyr
565 570 575
Pro Gly Arg Glu Ala Gln Ala Arg Arg Ala Gln Glu Glu Ala Glu Ala
580 585 590
Glu Glu Arg Arg Leu Gln Glu Gln Glu Glu Leu Glu Asn Tyr Ile Glu
595 600 605
His Val Leu Leu Arg Arg Pro
610 615
Claims (10)
1.一种寡核苷酸RNA双链分子,其特征在于,其序列为如下核苷酸序列中的一条或几条:
siVGF-1:
正义链:5’-GAAUUACAUCGAGCACGUGCU-3’
反义链:5’-CUUAAUGUAGCUCGUGCACGA-3’
siVGF-2:
正义链:5’-GACGAUCGACAGCCUCAUUGA-3’
反义链:5’-CUGCUAGCUGUCGGAGUAACU-3’。
2.一种表达载体,其特征在于,含有如权利要求1所述寡核苷酸RNA双链分子。
3.一种宿主细胞,其特征在于,含有如权利要求1所述寡核苷酸RNA双链分子,或含有如权利要求2所述表达载体。
4.权利要求1所述寡核苷酸RNA双链分子或其药学上可以接受的盐或溶剂合物在制备抑制VGF蛋白活性的药物中的应用。
5.权利要求1所述寡核苷酸RNA双链分子或其药学上可以接受的盐或溶剂合物在制备治疗恶性肿瘤药物中的应用。
6.根据权利要去5所述应用,其特征在于,所述药物为抑制恶性肿瘤细胞生长和/或增殖的药物。
7.根据权利要求5所述应用,其特征在于,所述药物为抑制恶性肿瘤细胞转移和/或侵润的药物。
8.根据权利要求5所述应用,其特征在于,所述药物与G蛋白抑制剂联用。
9.根据权利要求5所述应用,其特征在于,所述药物还包括药学上可接受的载体、稀释剂或赋形剂中的一种或几种。
10.根据权利要求5所述应用,其特征在于,所述药物的剂型为注射剂、胶囊剂、片剂、丸剂或颗粒剂。
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