CN111118011B - 一种抑制hsa_circ_0027478表达的siRNA及其应用 - Google Patents
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Abstract
本发明公开了一种抑制人hsa_circ_0027478环状RNA表达的核苷酸及其应用，其特征是：所述的核苷酸特异性结合于人hsa_circ_0027478环状RNA，所述核苷酸的序列由GCACUACUGAGGACCCUGAUGCU序列或者互补序列中的18‑22个连续核苷酸序列组成，特别是其包含序列：GCACUACUGAGGACCCUGA和UACUGAGGACCCUGAUGCU。本发明抑制人hsa_circ_0027478环状RNA，能够有效抑制A549和XWLC‑05细胞中hsa_circ_0027478环状RNA表达，与抗肿瘤药物联合可以增加其抑制其生长和增殖，从而有效治疗多种肿瘤。
Description
技术领域
本发明属于医学材料技术和药物领域 ，具体地本发明涉及一种环状RNAs核苷酸，尤其是涉及人环状RNAs核苷酸。该核苷酸可与hsa_circ_0027478互补，从而抑制人hsa_circ_0027478的表达，与其他抗肿瘤药物其起到抗肿瘤的作用。
背景技术
环状RNA（circRNA）是一类特殊的非编码RNA分子，在生物体内广泛表达，具有高度保守序列，因其呈封闭环状结构，不受RNA外切酶影响，表达更稳定且不易降解。
研究表明，circRNA分子富含microRNA结合位点，可起到miRNA海绵的作用，解除miRNA对其靶基因的抑制作用，升高靶基因的表达水平。同时还具有调控基因转录、结合多种蛋白等功能。
人类肿瘤形成的重要因素之一是表观遗传学的改变，大量研究发现非编码RNA在表观遗传学调控中扮演着越来越重要的角色，其组成高度复杂的调控网络，调节细胞的增殖、肿瘤的发生发展等各项生命活动。
circRNA通过与肿瘤疾病关联的miRNA相互作用，在肿瘤疾病中发挥着重要的调控作用。提示circRNA 能够作为一项理想的新型肿瘤诊断标志物和潜在靶点，为肿瘤的诊断和靶向治疗提供新的思路。
RNA干扰(RNA interference，RNAi)技术利用双链小RNA高效、特异性降解细胞内同源RNA从而沉默靶基因，从而实现干扰靶基因的功能。
发明内容
本发明的目的在于提供一种能够特异高效地抑制hsa_circ_0027478表达的siRNA及其应用。
本发明的目的是这样实现的，包括合成核苷酸的序列由GCACUACUGAGGACCCUGAUGCU(SEQ ID NO.1)序列中的18-22个连续核苷酸序列组成或者互补序列中的18-22个连续核苷酸序列组成。特别是其包含序列：GCACUACUGAGGACCCUGA(SEQ IDNO.2)和UACUGAGGACCCUGAUGCU(SEQ ID NO.3)或者互补序列。核苷酸为核糖核苷酸、脱氧核糖核苷酸或者核糖核苷酸与脱氧核糖核苷酸的嵌合体。核苷酸进一步被核糖修饰、碱基修饰、磷酸骨架修饰、氟代修饰、硫代修饰、甲氧基修饰、胆固醇修饰的一种或几种。核苷酸和其他抗肿瘤治疗药物特别是三价无机砷。制备治疗癌症药物中的应用。癌症包括 ：肝癌、贲门癌、结胃癌、、鼻咽癌、卵巢癌、前列腺癌症、慢性或急性白血病、脑瘤、食道 癌、口腔癌、尿道癌、皮肤癌、直肠癌、中耳癌、骨癌、肠癌、胆囊癌、喉癌、牙龈癌、肺癌、胰腺癌、乳腺癌、宫颈癌、、大肠癌、 睾丸癌、内分泌系统的癌症、淋巴细胞性淋巴瘤。本研究受国家自然科学基金的支持（81860572）。
本发明（优点）：发明的核苷酸具有很好的hsa_circ_0027478抑制效果，作用于特异性的靶位点，特异性强、毒性低、副作用小和修饰半衰期长，可以与多种抗肿瘤药物合用。
具体实施方式
下面对本发明作进一步的说明，但不以任何方式对本发明加以限制，基于本发明教导所作的任何变换或替换，均属于本发明的保护范围。
具体实施方式
实施例
本实施例中的沉默RNA序列为：GCACUACUGAGGACCCUGA(SEQ ID NO.2)和UACUGAGGACCCUGAUGCU(SEQ ID NO.3)以及互补序列,所有的序列都是从5端到3端,所有序列都在末端加上dTdT。hsa_circ_0027478的RNA序列信息存在于UCSC数据库中。本课题受本研究受国家自然科学基金的支持（81860572）。
对照合成
首先，由上海吉玛制药技术有限公司合成核苷酸，合成包含其互补序列的双链RNA序列，对照组使用吉玛制药技术有限公司的阴性对照siRNA货号为A06001序列为对照组的阴性对照。
细胞培养：将A549或者XWLC-05细胞在含有10％胎牛血清的1640培养基于37℃，5％CO2条件下培养。以2500个每孔铺于96孔板内。RNA转染采用百代公司Rfect转染试剂进行转染，通过荧光定量PCR来经常RNA干扰的效率。以下分别为对照组、沉默组1、沉默组的沉默效率，A549细胞分别为： 1.009±0.081，0.231±0.021，0.172±0.029；XWLC-05细胞分别为1.070±0.042，0.271±0.018, 0.206±0.024,数据使用2^-ΔΔCt表示。
荧光定量使用的引物：hsa_circ_0027478上游：TGGCACTACTGAGGACCCT(SEQ IDNO.4)下游：GCTCTCCATGCTTGACCACA(SEQ ID NO.5)，内参采用“陈江容,张若冰,张媛,胡娟,周梅,何越峰.砷及其代谢产物对P21基因表达的影响[J].职业与健康,2018,34(23):3213-3216.”文章中的ACTB基因。
两个细胞使用96孔板转染转染后48小时加入砷，亚砷酸钠溶于培养基中，不加砷的加入等量培养基，亚砷酸钠的终浓度为A549为60微摩尔每升，XWLC-05细胞砷的终浓度为40微摩尔每升，再培养48小时后MTS检测细胞活力。用Promega公司MTS检测，采用490nm吸光度，计算细胞活力。
未加砷对照组：为使用阴性对照片段后不加入亚砷酸钠，本组的活力定为100.0%。未加砷实验组1：核苷酸片段1沉默的结果。未加砷实验组2：沉默核苷酸片段2沉默的结果。加砷对照组：为使用阴性对照片段后加入亚砷酸钠的结果。加砷实验组1：沉默核苷酸片段1沉默后加入亚砷酸钠的结果。加砷实验组2：沉默核苷酸片段2沉默后加入亚砷酸钠的结果。以下为各组的细胞活力均为百分比（%）：
未加砷对照组：A549为103.0±4.7，XWLC-05为102.1±3.7，
未加砷实验组1： A549为94.5±2.9， XWLC-05为94.7±2.5，
未加砷实验组2: A549为94.8±2.8，XWLC-05为95.4±3.1，
加砷对照组： A549为91.1±4.1，XWLC-05为86.8±3.2，
加砷实验组1： A549为63.7±2.9，XWLC-05为56.9±3.5，
加砷实验组2： A549为64.2±1.9，XWLC-05为58.7±2.6。
序列表
<110> 昆明医科大学
<120> 一种抑制hsa_circ_0027478表达的siRNA及其应用
<140> 1
<141> 2019-12-24
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tggcactact gaggaccct 19
<210> 5
<211> 20
<212> DNA
<213> 人工序列(rengongxulie)
<400> 5
gctctccatg cttgaccaca 20
Claims (3)
1.一种抑制人hsa_circ_0027478环状RNA表达的核苷酸在制备治疗肺癌药物中的应用，其特征在于所述核苷酸的序列为GCACUACUGAGGACCCUGA及其互补序列或者是UACUGAGGACCCUGAUGCU及其互补序列。
2.一种药物组合物在制备治疗肺癌药物中的应用，其特征在于所述的药物组合物包含权利要求 1所述的核苷酸和亚砷酸钠。
3.根据权利要求2所述的药物组合物在制备治疗肺癌药物中的应用，其特征在于组合物中亚砷酸钠在治疗肺癌的作用浓度为40-60 uM。
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| CN111733158B (zh) * | 2020-02-11 | 2022-09-06 | 昆明医科大学 | 一种抑制hsa_circ_0003599表达的siRNA及其应用 |
| CN111118012B (zh) * | 2020-02-11 | 2022-09-06 | 昆明医科大学 | 一种抑制hsa_circ_0051680表达的siRNA及其应用 |
| CN111647597B (zh) * | 2020-02-11 | 2022-09-06 | 昆明医科大学 | 一种抑制hsa_circ_0027479表达的siRNA及其应用 |
| CN111647598B (zh) * | 2020-02-11 | 2022-09-06 | 昆明医科大学 | 一种抑制hsa_circ_0027477表达的siRNA及其应用 |
| CN111394351B (zh) * | 2020-03-18 | 2023-11-07 | 济南爱新卓尔医学检验有限公司 | 一种抑制DICER1-AS1表达的siRNA及其应用 |
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