WO2019037049A1 - Shrna of human erbb2 gene and applications - Google Patents
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- WO2019037049A1 WO2019037049A1 PCT/CN2017/098906 CN2017098906W WO2019037049A1 WO 2019037049 A1 WO2019037049 A1 WO 2019037049A1 CN 2017098906 W CN2017098906 W CN 2017098906W WO 2019037049 A1 WO2019037049 A1 WO 2019037049A1
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- the present invention relates to a human ERBB2 gene, and more particularly to a shRNA (short hairpin RNA) of a human ERBB2 gene and use thereof.
- shRNA short hairpin RNA
- ERBB2 is a 185 kDa cell membrane receptor encoded by the proto-oncogene ERBB2 and is a member of the epidermal growth factor receptor (EGFR) family.
- the family includes four members, ERBB1 (also known as EGFR, HERl), ERBB2 (also known as HER2), ERBB3 (HER3), and ERBB4 (HER4).
- ERBB2 is involved in the regulation of growth and development of normal tissues, promotes cell division and secretion of proteolytic enzymes, and enhances cell motility, but under pathological conditions, ERBB2 expression increases, thereby promoting tumor invasion and metastasis.
- ERBB2 has intracellular tyrosine kinase-like activity, plays a role in embryonic development and differentiation, is widely expressed in epithelial cells of human tissues, and is closely related to the survival and evolution of various tumors. . Therefore, the research on ERBB2 can greatly promote the development of tumor prevention and control, but the lack of vectors for specifically inhibiting the expression of ERBB2 gene in the prior art makes the related research not well developed.
- One of the technical problems to be solved by the present invention is to provide a shRNA of the human ERBB2 gene.
- the second technical problem to be solved by the present invention is to provide a shRNA of human ERBB2 gene.
- the present invention provides a shRNA of a human ERBB2 gene, including:
- sequence shown in SEQ ID NO: 1 and ERBB2-RNAi consisting of the sequence shown in SEQ ID NO: 2.
- the shRNA provided by the invention has high transduction efficiency and can efficiently and specifically inhibit the ERBB2 group of Raji cells. Due to the advantages of expression, it can be used as a powerful tool for the preparation of drugs for the treatment of diseases related to abnormal expression of ERBB2 gene.
- Figure 1 is a schematic diagram showing the results of Quantitative PCR detection of Raji cells after transduction of pLKO-ERBB2 vector.
- Kit was purchased from Omega bio-tek.
- the complete medium described below is a cell culture medium to which 10% fetal calf serum is added.
- the ERBB2-RNAi oligonucleotide chain was synthesized by Shanghai Shenggong Bioengineering Technology Service Co., Ltd.
- the synthesized shRNA oligonucleotides are mixed in equal amounts in a single strand and annealed to form a double-stranded ERBB2-RNAi.
- Age I and EcoR I double-cleavage pLKO.l-puro vector, Fermentas restriction enzymes Age I and EcoR I double digestion, 50 reaction system is as follows: 5 ⁇ L 10x FastDigest Buffer, 2 ⁇ L Age I , 2 EcoR I, 2 g pLK0.1-puro plasmid, ddH20 supplemented to 20ul, 37 ° C reaction for 30 min; [0019] 2) ligation, 2 L annealing of phosphorylated double-stranded DNA oligos, 1 ligase buffer, 1 double-digested pLKO. l-puro plasmid, 1 ligase, 5 L ddH20, reaction at 16 ° C for 5 h, Obtaining the ligation product pLKO-ERBB2 vector;
- Plasmid Mini Kit for endotoxin-free pLKO-ERBB2 vector extraction Plasmid Mini Kit for endotoxin-free pLKO-ERBB2 vector extraction.
- Raji cells were cultured, and 5,000,000 cells with good growth state were taken, and the cells were collected by centrifugation, then resuspended in 500 ⁇ L ⁇ PBS, mixed with 20 pL KO-ERBB2 vector, and then added to an electric shock cup, and electrotransformed using Invitrogen Neon electrotransfer system.
- Electroporation procedure 2.1 KV, 25 ⁇ , pulse shock once; Transfer the cells to a 6 cm dish containing 5 mL DMEM complete medium, gently shake the dish to mix the cells, and detect the expression of TL6 gene after 48 hours.
- Example 4 Fluorescence quantitative PCR was used to detect the expression level of ERBB2 gene.
- Raji cells inoculated with Raji cells and transduced pLKO-ERBB2 vector were separately cultured into cell culture flasks, and after 24 h of culture, total RNA of each group was extracted with Trizol, and PrimeScrip RT reagent was used.
- Kit reverse-transcribes mRNA into cDNA, and is diluted with 90 RNase-Free dH20 and stored at -20 °C.
- ERBB2 For the template, GAPDH was used as the internal reference, and the relative expression of ERBB2 was detected by real-time quantitative PCR (QPCR). The reaction conditions were set: 95 ° C for 10 s, 1 cycle; 95 ° C for 5 s, 54 ° C for 30 s, for 40 cycles. The relative expression of ERBB2 gene in each group was detected by SYBR Primescript RT-PCR Kit. The results are shown in Figure 1. The results showed that the expression of ERBB2 gene was significantly inhibited in Raji cells transfected with pLKO-ERBB2 vector, and the inhibitory efficiency of the interference fragment on the target gene was 84.4% ⁇ 4.1%, which proved that the pLKO-ERBB2 vector used in this experiment can specifically inhibit shRNA. The expression of the ERBB2 gene is very significant.
- the shRNA provided by the invention has the advantages of high transduction efficiency, high-efficiency and specific inhibition of ERBB2 gene expression in Raji cells, and can be used as a powerful tool for preparing a medicament for treating ERBB2 gene expression-related diseases.
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Abstract
An shRNA of a human ERBB2 gene. A positive-sense strand of a coding sequence of the shRNA is shown in SEQ ID NO:1, and an antisense strand of the coding sequence of the shRNA is shown in SEQ ID NO:2. The shRNA of the human ERBB2 gene can be used for the preparation of drugs for treating diseases related to expression anomalies of an ERBB2 gene.
Description
人 ERBB2基因的 shRNA及应用 shRNA and its application of human ERBB2 gene
技术领域 Technical field
[0001] 本发明涉及一种人 ERBB2基因, 特别是涉及一种人 ERBB2基因的 shRNA (短发 夹 RNA)及应用。 [0001] The present invention relates to a human ERBB2 gene, and more particularly to a shRNA (short hairpin RNA) of a human ERBB2 gene and use thereof.
背景技术 Background technique
[0002] ERBB2是原癌基因 ERBB2编码的 185kDa的细胞膜受体, 为表皮生长因子受体( EGFR)家族成员之一。 该家族包括 ERBB1 (又称 EGFR, HERl) 、 ERBB2 (又 称 HER2) 、 ERBB3 (HER3) 和 ERBB4 (HER4) 四个成员。 [0002] ERBB2 is a 185 kDa cell membrane receptor encoded by the proto-oncogene ERBB2 and is a member of the epidermal growth factor receptor (EGFR) family. The family includes four members, ERBB1 (also known as EGFR, HERl), ERBB2 (also known as HER2), ERBB3 (HER3), and ERBB4 (HER4).
[0003] ERBB2参与了正常组织的生长与发育调节, 可以促进细胞分裂和蛋白水解酶的 分泌, 并增强细胞的运动能力, 但在病理状态下, ERBB2表达增多, 进而促进 肿瘤的侵袭和转移。 [0003] ERBB2 is involved in the regulation of growth and development of normal tissues, promotes cell division and secretion of proteolytic enzymes, and enhances cell motility, but under pathological conditions, ERBB2 expression increases, thereby promoting tumor invasion and metastasis.
技术问题 technical problem
[0004] ERBB2具有细胞内酪氨酸激酶样活性, 在胚胎发育形成及分化中有一定的作用 , 在人类组织的上皮细胞中有广泛表达, 并且与多种肿瘤的生存和演进有密切 的关系。 因此对 ERBB2的研究可以大大促进肿瘤防治领域的发展, 但现有技术 中缺乏特异抑制 ERBB2基因表达的载体使得相关研究无法很好地幵展。 [0004] ERBB2 has intracellular tyrosine kinase-like activity, plays a role in embryonic development and differentiation, is widely expressed in epithelial cells of human tissues, and is closely related to the survival and evolution of various tumors. . Therefore, the research on ERBB2 can greatly promote the development of tumor prevention and control, but the lack of vectors for specifically inhibiting the expression of ERBB2 gene in the prior art makes the related research not well developed.
问题的解决方案 Problem solution
技术解决方案 Technical solution
[0005] 本发明要解决的技术问题之一是提供一种人 ERBB2基因的 shRNA。 One of the technical problems to be solved by the present invention is to provide a shRNA of the human ERBB2 gene.
[0006] 本发明要解决的技术问题之二是提供一种人 ERBB2基因的 shRNA [0006] The second technical problem to be solved by the present invention is to provide a shRNA of human ERBB2 gene.
在制备治疗 ERBB2基因表达异常相关疾病的药物。 In the preparation of a medicament for treating diseases associated with abnormal expression of the ERBB2 gene.
[0007] 为解决上述技术问题, 本发明提供一种人 ERBB2基因的 shRNA, 包括: 由编码[0007] In order to solve the above technical problem, the present invention provides a shRNA of a human ERBB2 gene, including:
SEQ ID NO: 1所示序列和编码 SEQ ID NO:2所示序列构成的 ERBB2-RNAi。 The sequence shown in SEQ ID NO: 1 and ERBB2-RNAi consisting of the sequence shown in SEQ ID NO: 2.
发明的有益效果 Advantageous effects of the invention
有益效果 Beneficial effect
[0008] 本发明提供的 shRNA具有转导效率高, 可高效、 特异地抑制 Raji细胞 ERBB2基
因表达的优点, 可作为有力工具应用于制备治疗 ERBB2基因表达异常相关疾病 的药物。 The shRNA provided by the invention has high transduction efficiency and can efficiently and specifically inhibit the ERBB2 group of Raji cells. Due to the advantages of expression, it can be used as a powerful tool for the preparation of drugs for the treatment of diseases related to abnormal expression of ERBB2 gene.
对附图的简要说明 Brief description of the drawing
附图说明 DRAWINGS
[0009] 图 1为转导 pLKO-ERBB2载体后 Raji细胞的荧光定量 PCR检测结果 ERBB2基因表 达结果示意图。 Figure 1 is a schematic diagram showing the results of Quantitative PCR detection of Raji cells after transduction of pLKO-ERBB2 vector.
实施该发明的最佳实施例 BEST MODE FOR CARRYING OUT THE INVENTION
本发明的最佳实施方式 BEST MODE FOR CARRYING OUT THE INVENTION
[0010] 下面结合附图与具体实施例对本发明做进一步的说明。 [0010] The present invention will be further described below in conjunction with the drawings and specific embodiments.
[0011] Raji细胞购自 ATCC, Trizol购自 Invitrogen公司, Endo-free Plasmid Mini [0011] Raji cells were purchased from ATCC, Trizol was purchased from Invitrogen, Endo-free Plasmid Mini
Kit购自 Omega bio-tek。 下文所述完全培养基为加入了 10%胎牛血清的细胞培养 基。 Kit was purchased from Omega bio-tek. The complete medium described below is a cell culture medium to which 10% fetal calf serum is added.
[0012] 实施例一 shRNA序列设计 [0012] Example 1 shRNA sequence design
[0013] (1) 根据人 ERBB2基因特征设计沉默序列, 设计的原则: 19bp的特异性结合 E RBB2序列的 GC含量为 45<¾-55<¾, 退火温度 45°C-65°C, 同吋要求序列起始的第 一个碱基为 G。 将选取的片段进行 BLAST与人基因组比对, 确保特异性。 [0013] (1) Designing a silent sequence according to the characteristics of human ERBB2 gene, the principle of design: 19 bp specific binding E RBB2 sequence GC content is 45<3⁄4-55<3⁄4, annealing temperature 45 °C-65 °C, the same The first base that requires the start of the sequence is G. The selected fragments were BLAST aligned with the human genome to ensure specificity.
[0014] (2) 以 Age I-GN18-TT-loop-81NC-EcoR I形式设计一段 59bp序列 ERBB2-RNAi , 81NC为 NG18的反向序列, 5'端为 Age I酶切位点, 3'端为 EcoR I酶切位点, 其 正义链序列如 SEQ ID No: 1所示, 反义链序列如 SEQ ID No: [0014] (2) Design a 59 bp sequence ERBB2-RNAi in the form of Age I-GN18-TT-loop-81NC-EcoR I, 81NC is the reverse sequence of NG18, and the 5' end is the Age I restriction site, 3' The end is an EcoR I restriction site, the sense strand sequence is shown in SEQ ID No: 1, and the antisense strand sequence is as SEQ ID No:
2所示。 ERBB2-RNAi寡核苷酸链由上海生工生物工程技术服务有限公司合成。 2 is shown. The ERBB2-RNAi oligonucleotide chain was synthesized by Shanghai Shenggong Bioengineering Technology Service Co., Ltd.
[0015] 实施例二 pLKO-ERBB2载体的构建 Example 2 Construction of pLKO-ERBB2 Vector
[0016] 将合成的 shRNA寡核苷酸单链等量混合, 退火形成双链的 ERBB2-RNAi。 [0016] The synthesized shRNA oligonucleotides are mixed in equal amounts in a single strand and annealed to form a double-stranded ERBB2-RNAi.
[0017] pLKO.l-puro载体 (Sigma Aldrich)全长 7086 bp, 选用限制性内切酶位点 Age[0017] pLKO.l-puro vector (Sigma Aldrich) full length 7086 bp, restriction endonuclease site selection Age
I和 EcoR I作为 DNA片段的插入位点, 应用不同 shRNA相对应 DNA片段的每种载 体构建具体步骤如下: I and EcoR I are used as insertion sites for DNA fragments, and the specific steps for constructing each vector using different shRNA corresponding DNA fragments are as follows:
[0018] 1) Age l和 EcoR I双酶切 pLKO.l-puro载体, Fermentas公司限制性内切酶 Age I和 EcoR I双酶切, 50 反应体系如下: 5 μL 10x FastDigest Buffer, 2 μL Age I , 2 EcoR I, 2 g pLK0.1-puro质粒, ddH20补至 20ul, 37°C反应 30 min;
[0019] 2) 连接, 2 L退火的磷酸化双链 DNA oligos , 1 连接酶 buffer, 1 双酶切 处理的 pLKO. l-puro质粒, 1 连接酶, 5 L ddH20, 16°C反应 5h, 获得连接产 物 pLKO-ERBB2载体; [0018] 1) Age l and EcoR I double-cleavage pLKO.l-puro vector, Fermentas restriction enzymes Age I and EcoR I double digestion, 50 reaction system is as follows: 5 μL 10x FastDigest Buffer, 2 μL Age I , 2 EcoR I, 2 g pLK0.1-puro plasmid, ddH20 supplemented to 20ul, 37 ° C reaction for 30 min; [0019] 2) ligation, 2 L annealing of phosphorylated double-stranded DNA oligos, 1 ligase buffer, 1 double-digested pLKO. l-puro plasmid, 1 ligase, 5 L ddH20, reaction at 16 ° C for 5 h, Obtaining the ligation product pLKO-ERBB2 vector;
[0020] 3) 转化; [0020] 3) conversion;
[0021] 4) 挑取阳性克隆培养并进行测序验证插入序列完全正确, 然后用 Endo-free [0021] 4) Pick positive clone culture and perform sequencing to verify that the insertion sequence is completely correct, then use Endo-free
Plasmid Mini Kit进行无内毒素的 pLKO-ERBB2载体提取。 Plasmid Mini Kit for endotoxin-free pLKO-ERBB2 vector extraction.
[0022] 实施例三 pLKO-ERBB2载体转导 Raji细胞。 Example 3 pLKO-ERBB2 vector transduced Raji cells.
[0023] 培养 Raji细胞, 取生长状态良好的细胞 5000000个, 离心收集细胞, 然后重悬于 500 μL· PBS中, 与 20 pLKO-ERBB2载体混匀后加入电击杯, 应用 Invitrogen Neon电转系统进行电转, 电转程序: 2.1 KV, 25 μΐΌ , 脉冲电击一次; 将细胞 转移至含5 mL DMEM完全培养基的6 cm皿中, 轻轻晃动皿使细胞混匀, 48 h后 检测 TL6基因表达情况。 [0023] Raji cells were cultured, and 5,000,000 cells with good growth state were taken, and the cells were collected by centrifugation, then resuspended in 500 μL·PBS, mixed with 20 pL KO-ERBB2 vector, and then added to an electric shock cup, and electrotransformed using Invitrogen Neon electrotransfer system. , Electroporation procedure: 2.1 KV, 25 μΐΌ, pulse shock once; Transfer the cells to a 6 cm dish containing 5 mL DMEM complete medium, gently shake the dish to mix the cells, and detect the expression of TL6 gene after 48 hours.
[0024] 实施例四荧光定量 PCR检测 ERBB2基因表达量。 [0024] Example 4 Fluorescence quantitative PCR was used to detect the expression level of ERBB2 gene.
[0025] 分别接种 Raji细胞和转导 pLKO-ERBB2载体的 Raji细胞细胞至细胞培养瓶, 培 养 24 h后, 用 Trizol提取各组细胞的总 RNA, 利用 PrimeScrip RT reagent [0025] Raji cells inoculated with Raji cells and transduced pLKO-ERBB2 vector were separately cultured into cell culture flasks, and after 24 h of culture, total RNA of each group was extracted with Trizol, and PrimeScrip RT reagent was used.
Kit将 mRNA逆转录为 cDNA, 加入 90 的 RNase-Free dH20稀释 cDNA, -20°C保 存。 Kit reverse-transcribes mRNA into cDNA, and is diluted with 90 RNase-Free dH20 and stored at -20 °C.
[0026] 取各组细胞的 cDNA 1 [0026] Take cDNA 1 of each group of cells
为模板, 以 GAPDH为内参, 实吋荧光定量 PCR (QPCR) 检测 ERBB2相对表 达量, 设置反应条件: 95°C 10s, 1个循环; 95°C 5s, 54°C 30s, 共 40个循环, 利用 SYBR Primescript RT-PCR Kit检测各组细胞 ERBB2基因相对表达量, 结果如 图 1所示。 结果显示转导 pLKO-ERBB2载体的 Raji细胞, ERBB2基因表达明显受 到抑制, 干扰片段对目的基因的抑制效率达 84.4%±4.1 %, 从而证明本实验中采 用的 pLKO-ERBB2载体携带 shRNA能特异抑制 ERBB2基因的表达, 且抑制效果 非常显著。 For the template, GAPDH was used as the internal reference, and the relative expression of ERBB2 was detected by real-time quantitative PCR (QPCR). The reaction conditions were set: 95 ° C for 10 s, 1 cycle; 95 ° C for 5 s, 54 ° C for 30 s, for 40 cycles. The relative expression of ERBB2 gene in each group was detected by SYBR Primescript RT-PCR Kit. The results are shown in Figure 1. The results showed that the expression of ERBB2 gene was significantly inhibited in Raji cells transfected with pLKO-ERBB2 vector, and the inhibitory efficiency of the interference fragment on the target gene was 84.4%±4.1%, which proved that the pLKO-ERBB2 vector used in this experiment can specifically inhibit shRNA. The expression of the ERBB2 gene is very significant.
[0027] 以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明, 不能认 定本发明的具体实施只局限于这些说明。 对于本发明所属技术领域的普通技术 人员来说, 在不脱离本发明构思的前提下, 还可以做出若干简单推演或替换,
都应当视为属于本发明的保护范围。 [0027] The above is a further detailed description of the present invention in conjunction with the specific preferred embodiments, and the specific embodiments of the present invention are not limited to the description. For those skilled in the art to which the present invention pertains, a number of simple deductions or substitutions may be made without departing from the inventive concept. All should be considered as belonging to the scope of protection of the present invention.
工业实用性 Industrial applicability
本发明提供的 shRNA具有转导效率高, 可高效、 特异地抑制 Raji细胞 ERBB2基 因表达的优点, 可作为有力工具应用于制备治疗 ERBB2基因表达异常相关疾病 的药物。
The shRNA provided by the invention has the advantages of high transduction efficiency, high-efficiency and specific inhibition of ERBB2 gene expression in Raji cells, and can be used as a powerful tool for preparing a medicament for treating ERBB2 gene expression-related diseases.
Claims
[权利要求 1] 一种人 ERBB2基因的 shRNA, 其特征在于,包括: 由编码 SEQ ID NO: [Claim 1] A shRNA of the human ERBB2 gene, comprising: encoding by SEQ ID NO:
1所示序列和编码 SEQ ID NO: 2所示序列构成的 ERBB2-RNAi。 The sequence shown in 1 and the ERBB2-RNAi consisting of the sequence shown in SEQ ID NO: 2.
[权利要求 2] 如权利要求 1所述的人 ERBB2基因的 shRNA在制备治疗 ERBB2基因表 达异常相关疾病的药物中的应用。 [Claim 2] The use of the shRNA of the human ERBB2 gene according to claim 1 for the preparation of a medicament for treating an abnormality-related disease of the ERBB2 gene.
[权利要求 3] 如权利要求 2所述的应用, 其特征在于: 所述的人 ERBB2基因的 shRN [Claim 3] The use according to claim 2, wherein: the shRN of the human ERBB2 gene
A是 ERBB2-RNAi。
A is ERBB2-RNAi.
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CN101918844A (en) * | 2007-06-18 | 2010-12-15 | 米迪缪尼有限公司 | Express the Synergistic treatment of the cell of EPHA2 and ERBB2 |
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DATABASE Nucleotide 1 August 2016 (2016-08-01), TAL, M., XP055578017, Database accession no. AH002823 * |
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