CN107496394A - 一种miR‑21基因抑制剂及用于治疗宫颈癌的用途 - Google Patents
一种miR‑21基因抑制剂及用于治疗宫颈癌的用途 Download PDFInfo
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Abstract
本发明涉及一种miR‑21基因抑制剂及用于治疗宫颈癌的用途。本发明证实，萘醌衍生物A、C、D、E能有效抑制miR‑21表达，可以制备成miR‑21表达抑制剂；该化合物通过抑制miR‑21表达使得MMP‑2蛋白表达量下调进而可以有效抑制宫颈癌细胞增殖和转移侵袭，可以开发成抑制宫颈癌生长和转移的药物。
Description
技术领域
本发明涉及基因治疗领域，尤其涉及一种miR-21基因抑制剂及用于治疗宫颈癌的用途。
背景技术
已知miR-21在多种肿瘤细胞中表达异常，如在宫颈癌细胞株中表达明显上调，miR-21抑制剂可以有效抑制宫颈癌细胞的增殖，并促进其凋亡(参考文献：miR-21抑制剂对细胞增殖和MMP2蛋白表达的影响，解剖科学进展，2015)。
发明内容
本发明的目的在于提供一种miR-21基因抑制剂及用于治疗宫颈癌的用途。
为实现上述目的，本发明提供了以下技术方案：
如下结构的化合物用于制备miR-21抑制剂的用途，化合物的结构为：
其中，R为(CH2)n，n为2或4或5或6。
优选地，R为(CH2)n，n优选4。
一种miR-21抑制剂组合物，包含上述的化合物，还包含药学上可以接受的载体，制成药学上可以接受的剂型。
优选地，所述药学上可以接受的载体包括一种或多种固体、半固体或液体辅料等。
优选地，所述药学上可以接受的剂型包括注射剂、片剂、胶囊剂、颗粒剂、丸剂、糖浆剂、散剂、膏剂等。
上述的化合物在制备抑制宫颈癌增殖的药物中的应用。
上述的化合物在制备抑制宫颈癌转移的药物中的应用。
上述的组合物在制备抑制宫颈癌增殖的药物中的应用。
上述的组合物在制备抑制宫颈癌转移的药物中的应用。
本发明的优点：
本发明证实，萘醌衍生物A、C、D、E能有效抑制miR-21表达，可以制备成miR-21表达抑制剂；该化合物通过抑制miR-21表达使得MMP-2蛋白表达量下调进而可以有效抑制宫颈癌细胞增殖和转移侵袭，可以开发成抑制宫颈癌生长和转移的药物。
附图说明
图1是萘醌A-E对HeLa细胞中miR-21表达水平(miR-21/U6)的影响。
图2是5μM萘醌A-E孵育24h后MMP-2蛋白表达量比较。
图3是萘醌A、C-E对HeLa细胞增殖抑制作用的IC50值。
具体实施方式
实施例1：
一、实验材料
各萘醌化合物参照文献方法自制，化学结构如下表：
人宫颈癌HeLa细胞由本公司长期冻存，使用前进行复苏。
RPMI-1640培养基、胎牛血清均购于美国GIBCO公司。
二、实验方法
1、细胞培养和分组
人宫颈癌HeLa细胞培养于胎牛血清浓度为10％的RPMI-1640培养基中，内含100μg/mL链霉素及100U/mL青霉素，培养箱内CO2体积分数为5％，温度为37℃，饱和湿度为95％，每日观察细胞的生长情况。2-3d传代1次，取对数生长期的HeLa细胞进行实验。
取对数生长期的HeLa细胞，调整细胞密度为5×104个/ml，随机分组如下：
萘醌A孵育组：分别使用含0.04、0.2、1、5、25、100μM萘醌A的培养基孵育24h；
萘醌B孵育组：分别使用含0.04、0.2、1、5、25、100μM萘醌B的培养基孵育24h；
萘醌C孵育组：分别使用含0.04、0.2、1、5、25、100μM萘醌C的培养基孵育24h；
萘醌D孵育组：分别使用含0.04、0.2、1、5、25、100μM萘醌D的培养基孵育24h；
萘醌E孵育组：分别使用含0.04、0.2、1、5、25、100μM萘醌E的培养基孵育24h；
对照组：使用不添加药物的空白培养基孵育24h。
2、RT-PCR法测定miR-21表达水平
提取总RNA：收集各组培养24h的HeLa细胞，按德国QIAGEN有限公司产品miRNeasyMini kit试剂盒说明书进行样本总RNA提取。用超微量核酸蛋白测定仪(Thermo美国)测定提取样本的总RNA浓度及纯度，待用于后续实验。
逆转录合成cDNA：按照QIAGEN miScript Ⅱ RT kit反转录试剂盒说明书进行，反应体系20μl：5×HIFlex Buffer 4μl，10×Nucleics Mix 2μl，RT Enzyme Mix 2μl，TotalRNA(浓度约20ng/μl)+RNase-Free H2O2共12μl。反应条件：37℃60min，95℃5min。反应在美国Bio-Rad C1000Touch PCR仪上进行。
实时荧光定量PCR反应：采用QIAGEN miScript SYBR Green PCRkit试剂盒，反应体系20μl：2×Quantitect SYBR Green PCR Master Mix 10μl，10×miScript PrimerAssay 2μl，10×miScript Universal Primer 2μl，RNase-FreeH2O2 5μl，模板cDNA 1μl。MiR-21特异性引物及U6内参引物均购自德国QIAGEN有限公司产品。反应在荧光定量PCR仪(Rotor Gene-Q德国)上进行，反应条件：95℃15min，1个循环；94℃15s，55℃30s，70℃30s，40个循环。每个样本做3个复孔，在相同反应条件下同时检测miR-21和U6的扩增情况，程序运行结束后利用Rotor-Gene Q Series Software软件进行数据分析，计算miR-21相对U6表达量。
3、Western印迹测定孵育处理对MMP-2蛋白表达量的影响
收集各组HeLa细胞，用PBS缓冲液洗涤3次后，将细胞重悬于细胞裂解液中，冰浴6min，使细胞充分裂解离心，收集上清液，分装冻存配置BCA工作液；分别吸25μL标准品，待测样品至微孔板对应孔中，每孔加入200μLBCA工作液，震荡6s以彻底混合均匀。盖好微孔板，7℃孵育6min，冷却至室温。测量各孔590nm吸光度值，测得的每个标准孔和待测样品孔的吸光度值分别减去空白孔平均吸光度值。以校正过的BSA标准蛋白测量值对其浓度(mg/L)做图绘制标准曲线，使用标准曲线定量待测样品蛋白浓度，SDS聚丙烯酰胺凝胶电泳完毕后对凝胶进行半干转膜。转膜完毕取出PVDF膜，置于含50mg/L脱脂奶粉的TTBS封闭液中，于室温封闭2h与一抗结合，洗膜。二抗结合，抗体结合区带用化学发光法检测，信号强度用Bio1D图像分析软件进行相对定量分析。
4、MTT法检测细胞增殖率
各组孵育24h后，加入5mg/ml的MTT继续培养4h，取结晶，加入二甲基亚砜充分溶解，于酶标仪570nm波长处检测OD值，计算各给药组相对对照组的增殖抑制率。
5、Transwell细胞转移试验
将各组孵育24h的HeLa细胞(3×105个)悬浮于250μL无血清的RPMI-1640培养基中，并接种于铺有30μL Matrigel基质胶的24孔transwell板上室。下室为600μL含10％胎牛血清的RPMI-1640培养基。常规培养48h后，用棉签弃去上层细胞，下层细胞用4％多聚甲醛进行固定并用结晶紫染色。将固定染色的细胞置于倒置相差显微镜下拍照并任选5个视野进行计数，取平均值。实验重复3次。
三、实验结果
1、孵育处理对miR-21表达量的影响
如表1和图1所示，与对照组相比，萘醌A、D、E的1、5、25、100μM剂量组可见miR-21表达水平显著下调(P＜0.05)，0.04、0.2μM剂量组miR-21表达量未见明显区别(P＞0.05)；与对照组相比，萘醌C各剂量组均可见miR-21表达水平显著下调(P＜0.05)；与对照组相比，萘醌B各剂量组miR-21表达量均未见明显区别(P＞0.05)。
表1萘醌A-E对HeLa细胞中miR-21表达水平(miR-21/U6)的影响
该结果表明，萘醌A、C、D、E均可以下调HeLa细胞中miR-21表达水平，其中萘醌C作用效果最强，萘醌B在测试浓度范围内不能下调HeLa细胞中miR-21表达水平，萘醌A、C、D、E为HeLa细胞中miR-21表达水平的有效抑制剂。
2、孵育处理对MMP-2蛋白表达量的影响
与对照组相比，萘醌A、D、E组1、5、25、100μM浓度孵育24h可见MMP-2蛋白表达水平显著下调，0.04、0.2μM浓度孵育24h后MMP-2蛋白表达量未见明显变化；与对照组相比，萘醌C组各浓度孵育24h均可见MMP-2蛋白表达水平显著下调；与对照组相比，萘醌B组各浓度孵育24h后MMP-2蛋白表达量均未见明显变化。
图2为5μM萘醌A-E孵育24h后MMP-2蛋白表达量比较。
已知MMP-2属MMPs家族的明胶酶类，也叫明胶酶A，子宫颈癌组织中MMP-2的表达升高，MMP-2高表达导致细胞外基质和血管基底膜的降解加速，促进肿瘤细胞增殖、血管生成、侵袭以及转移。抑制MMP-2可以抑制肿瘤细胞的增殖、侵袭和转移。
3、孵育处理对HeLa细胞增殖率的影响
细胞增殖抑制试验结果显示，萘醌A、D、E以剂量依赖方式抑制细胞的增殖，1、5、25、100μM剂量组HeLa细胞的存活率与对照组存在显著性差异(P＜0.05)；萘醌C以剂量依赖方式抑制细胞的增殖，0.04、0.2、1、5、25、100μM剂量组HeLa细胞的存活率与对照组存在显著性差异(P＜0.05)；萘醌B各剂量组对HeLa细胞增殖率的抑制作用不明显，HeLa细胞的存活率与对照组的差异不显著(P＞0.05)。
萘醌A、C-E的IC50值如表2和图3：
表2萘醌A、C-E对HeLa细胞增殖抑制作用的IC50值
| 组别 | IC50值(μM) | 组别 | IC50值(μM) |
| 萘醌A | 18.5 | 萘醌D | 19.3 |
| 萘醌C | 0.4 | 萘醌E | 17.2 |
结果表明，萘醌C的IC50值显著低于萘醌A、D、E，对HeLa细胞增殖抑制作用最强。
4、孵育处理对HeLa细胞转移侵袭能力的影响
如表3所示，与对照组相比，萘醌A、D、E的1、5、25、100μM剂量组穿过微孔滤膜的细胞数显著低于对照组(P＜0.05)，0.04、0.2μM剂量组穿过微孔滤膜的细胞数与对照组无显著性差异(P＞0.05)；萘醌C各剂量组穿过微孔滤膜的细胞数均显著低于对照组(P＜0.05)；萘醌B各剂量组穿过微孔滤膜的细胞数与对照组均无显著性差异(P＞0.05)。
该结果表明，萘醌A、C、D、E均可以抑制HeLa细胞转移侵袭，其中萘醌C作用效果最强，萘醌B在测试浓度范围内对HeLa细胞转移侵袭能力无显著影响，萘醌A、C、D、E为HeLa细胞侵袭转移能力的有效抑制剂。
表3萘醌A-E各剂量组HeLa细胞转移侵袭细胞数量/个
上表可见萘醌A、C、D、E为HeLa细胞侵袭转移能力的有效抑制剂。
上述实施例证明，萘醌A、C、D、E能有效抑制miR-21表达，可以制备成miR-21表达抑制剂；该化合物通过抑制miR-21表达使得MMP-2蛋白表达量下调进而可以有效抑制宫颈癌细胞增殖和转移侵袭，可以开发成抑制宫颈癌生长和转移的药物。
实施例2：
该实施例提供的是一种萘醌C的注射液。
该注射液的溶液为0.9％氯化钠水溶液。
萘醌C在纯水中为微溶，但是在0.9％氯化钠水溶液中则为可溶，既可以制成低浓度的萘醌C注射液，又可以制成高浓度的萘醌C注射液，灵活性高。
本领域技术人员应当知道，上述具体实施方式仅用于解释本发明，本发明的保护范围并不局限于上述具体实施方式。
Claims (9)
1.如下结构的化合物用于制备miR-21抑制剂的用途，化合物的结构为：
其中，R为(CH2)n，n为2或4或5或6。
2.根据权利要求1所述的用途，其特征在于：R为(CH2)n，n优选4。
3.一种miR-21抑制剂组合物，其特征在于：包含权利要求1或2所述的化合物，还包含药学上可以接受的载体，制成药学上可以接受的剂型。
4.根据权利要求3所述的组合物，其特征在于：所述药学上可以接受的载体包括一种或多种固体、半固体或液体辅料等。
5.根据权利要求3所述的组合物，其特征在于：所述药学上可以接受的剂型包括注射剂、片剂、胶囊剂、颗粒剂、丸剂、糖浆剂、散剂、膏剂等。
6.权利要求1或2所述的化合物在制备抑制宫颈癌增殖的药物中的应用。
7.权利要求1或2所述的化合物在制备抑制宫颈癌转移的药物中的应用。
8.权利要求4或5所述的组合物在制备抑制宫颈癌增殖的药物中的应用。
9.权利要求4或5所述的组合物在制备抑制宫颈癌转移的药物中的应用。
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