WO2018170766A1 - Sirna of human programmed death ligand 2 gene and application thereof - Google Patents
Sirna of human programmed death ligand 2 gene and application thereof Download PDFInfo
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- WO2018170766A1 WO2018170766A1 PCT/CN2017/077608 CN2017077608W WO2018170766A1 WO 2018170766 A1 WO2018170766 A1 WO 2018170766A1 CN 2017077608 W CN2017077608 W CN 2017077608W WO 2018170766 A1 WO2018170766 A1 WO 2018170766A1
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- 108020004459 Small interfering RNA Proteins 0.000 title abstract description 12
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 title description 6
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 claims abstract description 20
- 230000014509 gene expression Effects 0.000 claims abstract description 13
- 230000000692 anti-sense effect Effects 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 4
- 108091081021 Sense strand Proteins 0.000 claims abstract description 3
- 201000010099 disease Diseases 0.000 claims abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 claims abstract 3
- 230000002159 abnormal effect Effects 0.000 claims abstract 2
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 claims description 6
- 230000009368 gene silencing by RNA Effects 0.000 claims description 6
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000012634 fragment Substances 0.000 claims 3
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 abstract description 13
- 108020004999 messenger RNA Proteins 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 12
- 239000004055 small Interfering RNA Substances 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 238000003753 real-time PCR Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 230000000139 costimulatory effect Effects 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 238000002123 RNA extraction Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 102000048119 human PDCD1LG2 Human genes 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Definitions
- the present invention belongs to the field of molecular genetics, and more particularly to a siRN capable of inhibiting human programmed death ligand 2
- Non-small cell lung cancer is a common malignant tumor in the world, and its incidence is increasing year by year. Studying NSCLC tumor recurrence factors and tumor immune escape mechanisms has important theoretical significance and clinical application value. T lymphocytes are important effector cells that mediate tumor immune responses, and T cell activation requires TCR-mediated antigen-specific signaling and costimulatory molecule-mediated costimulatory signals.
- PD-L2 Programmed death ligand 2
- B7-H1 is a negative T cell costimulatory molecule in the B7 family
- PD-L2 inhibits proliferation of CD4 and CD8 T cells by binding to its receptor PD-1
- activation negative regulation of the body's immune response process, thereby mediating tumor immune escape, promoting tumor growth
- the role of PD-L2 in tumor escape has an important role in the prevention and treatment of tumors, but the lack of specificity in the prior art
- the vector that inhibits the expression of the PD-L2 gene makes the related research not well developed.
- RNAi small interfering RNA
- siPDL2 sequence is as follows: [0007] Justice strand: 5,- GAGGGAAGUGAACAGUGCU-3' (SEQ ID NO: l);
- Antisense strand 5,-AGCACUGUUCACUUCCCUC-3' (SEQ ID NO: 2).
- 1 is a schematic diagram showing the results of quantitative PCR detection of PD-L2 gene expression levels after HepG2 cells transfected with siPDL2.
- Total RNA extraction Total RNA of PD-L2 cells normal and transfected with siPDL2 was extracted using the QIAGEN RNeasy Mini Kit.
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Provided is a siRNA capable of efficiently and specifically inhibiting mRNA level expression of a PD-L2 gene, the sequences thereof being: sense strand: 5'-GAGGGAAGUGAACAGUGCU-3'(SEQ ID NO:1); and antisense strand: 5'-AGCACUGUUCACUUCCCUC-3'(SEQ ID NO:2). Also provided is an application of the siRNA for preparing drugs for treating diseases related with abnormal PD-L2 gene expression.
Description
说明书 发明名称：一种人程序性死亡配体 2基因的 siRNA及其应用 技术领域 Description: A human programmed death ligand 2 gene siRNA and its application
[0001] 本发明属于分子遗传学领域， 尤其涉及一种能抑制人程序性死亡配体 2的 siRN [0001] The present invention belongs to the field of molecular genetics, and more particularly to a siRN capable of inhibiting human programmed death ligand 2
A及其应用。 A and its application.
背景技术 Background technique
[0002] 非小细胞肺癌 （non-small cell lung cancer, NSCLC) 是当前世界的常见恶性肿 瘤， 其发病率有逐年增加的趋势。 研究 NSCLC肿瘤复发因素及肿瘤免疫逃逸机 制， 具有重要的理论意义和临床应用价值。 T淋巴细胞是介导肿瘤免疫应答的重 要效应细胞， T细胞活化需要 TCR介导的抗原特异性信号和共刺激分子介导的共 刺激信号。 [0002] Non-small cell lung cancer (NSCLC) is a common malignant tumor in the world, and its incidence is increasing year by year. Studying NSCLC tumor recurrence factors and tumor immune escape mechanisms has important theoretical significance and clinical application value. T lymphocytes are important effector cells that mediate tumor immune responses, and T cell activation requires TCR-mediated antigen-specific signaling and costimulatory molecule-mediated costimulatory signals.
技术问题 technical problem
[0003] 程序性死亡配体 2 (PD-L2) /B7-H1是 B7家族中一个负性 T细胞共刺激分子， PD-L2通过与其受体 PD-1结合， 抑制 CD4和 CD8T细胞的增殖和活化， 负性调控 机体免疫应答过程， 从而介导肿瘤免疫逃逸， 促进肿瘤生长， 因此对 PD-L2在肿 瘤逃逸中作用的研究对于肿瘤的防治具有重要的作用， 但现有技术中缺乏特异 抑制 PD-L2基因表达的载体使得相关研究无法很好地幵展。 [0003] Programmed death ligand 2 (PD-L2) / B7-H1 is a negative T cell costimulatory molecule in the B7 family, PD-L2 inhibits proliferation of CD4 and CD8 T cells by binding to its receptor PD-1 And activation, negative regulation of the body's immune response process, thereby mediating tumor immune escape, promoting tumor growth, so the role of PD-L2 in tumor escape has an important role in the prevention and treatment of tumors, but the lack of specificity in the prior art The vector that inhibits the expression of the PD-L2 gene makes the related research not well developed.
[0004] RNA干扰（RNA interference, RNAi)现象最早是由 Jorgensen等在发现的， 它 是一种高效、 特异性强的基因阻断技术， 近年来发展迅速， 很快就成为功能基 因组研究的有力工具， 可高效、 特异地抑制人 PD-L2基因表达， 进而为其功能研 究打下基础。 [0004] The phenomenon of RNA interference (RNAi) was first discovered by Jorgensen et al. It is a highly efficient and specific gene blocking technology, which has developed rapidly in recent years and soon became a powerful functional genomics research. The tool can effectively and specifically inhibit the expression of human PD-L2 gene, which lays a foundation for its functional research.
问题的解决方案 Problem solution
技术解决方案 Technical solution
[0005] 本发明的目的在于提供一种基于 RNAi技术的针对人 PD-L2基因 mRNA的小分子 干扰 RNA (siRNA) 。 [0005] It is an object of the present invention to provide a small interfering RNA (siRNA) directed against human PD-L2 gene mRNA based on RNAi technology.
[0006] 从 GenBank获得人 PD-L2基因的 cDNA序歹 ij， 根据 siRNA靶序列的基本原则， 针对其设计了一条 19 nt的 siRNA: siPDL2序列如下：
[0007] 正义链： 5，- GAGGGAAGUGAACAGUGCU-3' (SEQ ID NO: l) ； [0006] The cDNA sequence 歹ij of human PD-L2 gene was obtained from GenBank. According to the basic principle of siRNA target sequence, a 19 nt siRNA was designed: siPDL2 sequence is as follows: [0007] Justice strand: 5,- GAGGGAAGUGAACAGUGCU-3' (SEQ ID NO: l);
[0008] 反义链： 5，- AGCACUGUUCACUUCCCUC-3' (SEQ ID NO: 2) 。 Antisense strand: 5,-AGCACUGUUCACUUCCCUC-3' (SEQ ID NO: 2).
发明的有益效果 Advantageous effects of the invention
有益效果 Beneficial effect
[0009] 本发明提供的 siPDL2具有干扰效率高， 可高效、 特异地抑制 PD-L2基因表达的 优点， 可作为有力工具应用于制备治疗 PD-L2基因表达异常相关疾病的药物。 对附图的简要说明 The present invention provides siPDL2 which has the advantages of high interference efficiency, high and specific inhibition of PD-L2 gene expression, and can be used as a powerful tool for the preparation of a medicament for treating PD-L2 gene expression-related diseases. Brief description of the drawing
附图说明 DRAWINGS
[0010] 图 1为 HepG2细胞转染 siPDL2后定量 PCR检测 PD-L2基因表达水平的结果示意图 实施该发明的最佳实施例 1 is a schematic diagram showing the results of quantitative PCR detection of PD-L2 gene expression levels after HepG2 cells transfected with siPDL2. BEST MODE FOR CARRYING OUT THE INVENTION
本发明的最佳实施方式 BEST MODE FOR CARRYING OUT THE INVENTION
[0011] 下面结合附图与具体实施例对本发明做进一步的说明。 以下实施例中所使用的 技术， 包括 PCR扩增与检测、 细胞转染、 RNA提取等分子生物学技术， 以及细 胞培养、 检测技术等， 除非特别说明， 均为本领域内的技术人员已知的常规技 术； 所使用的仪器设备、 试剂和细胞系等， 除非是本说明书特别注明， 均为一 般本领域的研究和技术人员可以通过公共途径获得的。 [0011] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments. The techniques used in the following examples, including molecular techniques such as PCR amplification and detection, cell transfection, RNA extraction, and cell culture, detection techniques, and the like, are known to those skilled in the art unless otherwise specified. Conventional techniques; apparatus, reagents, cell lines, and the like, unless otherwise specified in the specification, are generally available to those skilled in the art and are available in the public.
[0012] 实施例一靶向 PD-L2基因的 siRNA寡核苷酸序列的设计 [0012] Example 1 Design of siRNA Oligonucleotide Sequence Targeting PD-L2 Gene
[0013] 在 GenBank査找到 PD-L2的 mRNA全序列， 从 PD-L2基因起始密码子 AUG下游 幵始， 搜索 AA序列， 其 3'端相邻 19 nt序列作为候选靶点， 从中选择 GC含量在 40-50%的 siRNA序列， 经 BLAST同源性比对证实特异性后应用 RNA structure 4.4 软件对靶 mRNA序列的二级结构进行评估， 最后获得靶核苷酸序列 siPDL2， 其正 义链序列如 SEQ ID NO: 1， 反义链序列如 SEQ ID NO: 2所示。 [0013] Find the full sequence of PD-L2 mRNA in GenBank, search for the AA sequence from the downstream of the PD-L2 gene start codon AUG, and select the adjacent 19 nt sequence at the 3' end as a candidate target, and select GC from it. The siRNA sequence with 40-50% content was confirmed by BLAST homology alignment. The secondary structure of the target mRNA sequence was evaluated by RNA structure 4.4 software. Finally, the target nucleotide sequence siPDL2 was obtained, and the sense strand sequence was obtained. As SEQ ID NO: 1, the antisense strand sequence is set forth in SEQ ID NO: 2.
[0014] 实施例二 siRNA转染 HepG2细胞。 Example 2 siRNA was transfected into HepG2 cells.
[0015] HepG2细胞 （购自 ATCC) ， 用 DMEM完全培养基 （含 10%胎牛血清） 培养， 按照 15万个 /孔的比例铺 6孔板， 于 37°C、 5% C02培养 18 h。 用 Lipofectamine 3000转染试剂盒（Invitrogen)进行细胞转染， 方法按照产品说明。 转染吋， 用 100
pmol siPDL2转染 A375细胞， siRNA与脂质体比例为 100 pmol: 10 μί。 [0015] HepG2 cells (purchased from ATCC), cultured in DMEM complete medium (containing 10% fetal bovine serum), plated 6-well plates at a ratio of 150,000 cells/well, and cultured at 37 ° C, 5% CO 2 for 18 h. . Cell transfection was performed using the Lipofectamine 3000 Transfection Kit (Invitrogen) according to the product instructions. Transfected 吋, with 100 P375 was transfected into A375 cells with a ratio of siRNA to liposome of 100 pmol: 10 μί.
[0016] 实施例三定量 PCR检测平 PD-L2基因表达水平 [0016] Example 3 quantitative PCR detection of flat PD-L2 gene expression level
[0017] 提取总 RNA: 使用 QIAGEN RNeasy Mini Kit提取正常和转染 siPDL2的 PD-L2细 胞的总 RNA。 [0017] Total RNA extraction: Total RNA of PD-L2 cells normal and transfected with siPDL2 was extracted using the QIAGEN RNeasy Mini Kit.
[0018] 逆转录： 使用 FastQuant RT Super Mix (天根生化） 进行逆转录。 [0018] Reverse Transcription: Reverse transcription was performed using FastQuant RT Super Mix.
[0019] 定量 PCR: 使用 SYBR Premix Ex Taq (Tli RNaseH Plus) (大连宝生物） [0019] Quantitative PCR: Using SYBR Premix Ex Taq (Tli RNaseH Plus) (Dalian Bao Bio)
进行定量 PCR， 检测， 反应体系为 20 μί， 每个反应加入 1 L cDNA作为模板。 反应程序为： (1)95 °C 30 s , (2)95 °C 5s , (3)60°C 30s , (2)-(3)， 40个循环。 同吋 以 GAPDH为内参， 结果如图 1所示， 使用的定量 PCR引物如表 1所示： Quantitative PCR was carried out, and the reaction system was 20 μί, and 1 L cDNA was added as a template for each reaction. The reaction procedure is: (1) 95 °C 30 s, (2) 95 °C 5s, (3) 60 °C 30s, (2)-(3), 40 cycles. With GAPDH as the internal reference, the results are shown in Figure 1. The quantitative PCR primers used are shown in Table 1:
[0020] 表 1 [0020] Table 1
[0022] 如图 1所示， 转染 siPDL2后的 HepG2细胞， PD-L2基因的 mRNA表达水平与正常 HepG2细胞相比显著下降， 说明本发明的 siPDL2能够高效特异性抑制 PD-L2基因 的表达。 [0022] As shown in FIG. 1 , the mRNA expression level of PD-L2 gene in HepG2 cells transfected with siPDL2 was significantly decreased compared with normal HepG2 cells, indicating that siPDL2 of the present invention can efficiently and specifically inhibit the expression of PD-L2 gene. .
[0023] [0023]
工业实用性 Industrial applicability
[0024] 本发明提供的 siPDL2具有干扰效率高， 可高效、 特异地抑制 PD-L2基因表达的 优点， 可作为有力工具应用于制备治疗 PD-L2基因表达异常相关疾病的药物。
The siPDL2 provided by the present invention has the advantages of high interference efficiency, high-efficiency and specific inhibition of PD-L2 gene expression, and can be used as a powerful tool for preparing a medicament for treating an abnormality in PD-L2 gene expression.
Claims
[权利要求 1] 一种 RNA干扰片段， 其特征在于， 所述 RNA干扰片段的序列如下: [Claim 1] An RNA interference fragment, wherein the sequence of the RNA interference fragment is as follows:
正义链： 5'- GAGGGAAGUGAACAGUGCU-3' (SEQ ID NO: 1) 反义链： 5，- AGCACUGUUCACUUCCCUC-3' (SEQ ID NO: 2) 。 The sense strand: 5'-GAGGGAAGUGAACAGUGCU-3' (SEQ ID NO: 1) antisense strand: 5, - AGCACUGUUCACUUCCCUC-3' (SEQ ID NO: 2).
[权利要求 2] 权利要求 1中所述的 RNA干扰片段的应用， [Claim 2] The use of the RNA interference fragment of claim 1
其特征在于制备治疗 PD-L2基因表达异常相关疾病的药物。
It is characterized by the preparation of a medicament for treating a disease associated with abnormal expression of the PD-L2 gene.
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| CN102428179A (en) * | 2009-03-06 | 2012-04-25 | 国立大学法人三重大学 | Methods for enhancing T cell function |
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| CN102428179A (en) * | 2009-03-06 | 2012-04-25 | 国立大学法人三重大学 | Methods for enhancing T cell function |
Non-Patent Citations (4)
| Title |
|---|
| HOBO, W. ET AL.: "siRNA silencing of PD - LI and PD - L2 on dendritic cells augments expansion and function of minor histocompatibility antigen-specific CD 8+ T cells", BLOOD, vol. 116, no. 22, 25 November 2010 (2010-11-25), pages 4501 - 4511, XP055298201, ISSN: 0006-4971 * |
| ROZALI, E. N. ET AL.: "Programmed Death Ligand 2 in Cancer-Induced Immune Suppression", CLINICAL AND DEVELOPMENTAL IMMUNOLOGY, vol. 2012, 31 December 2012 (2012-12-31), pages 1 - 9, XP055539612, ISSN: 1740-2522 * |
| WANG, GUOYAN ET AL.: "PD-L1/PD-L2 on Human Placenta-Derived Mesenchymal Stem Cells Inhibits the IL 17 Secretion of Peripheral Blood T Cells", CHINESE JOURNAL OF CELLULAR AND MOLECULAR IMMUNOLOGY, vol. 29, no. 2, 31 December 2013 (2013-12-31), pages 132 - 136, ISSN: 1007-8738 * |
| ZHANG, SIYING ET AL.: "PD -Between L2 in Human Placenta Mesenchymal Stem Cells on the Expression and Its Biological Significance", JOURNAL OF HEZE MEDICAL COLLEGE, 31 December 2013 (2013-12-31), ISSN: 1008-4118 * |
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