CN103266111A - Dual-target siRNA (small interfering ribonucleic acid) molecule and application thereof - Google Patents
Dual-target siRNA (small interfering ribonucleic acid) molecule and application thereof Download PDFInfo
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- CN103266111A CN103266111A CN2013102083856A CN201310208385A CN103266111A CN 103266111 A CN103266111 A CN 103266111A CN 2013102083856 A CN2013102083856 A CN 2013102083856A CN 201310208385 A CN201310208385 A CN 201310208385A CN 103266111 A CN103266111 A CN 103266111A
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Abstract
The invention relates to a dual-target siRNA (small interfering ribonucleic acid) molecule and an application thereof and in particular relates to a dual-target siRNA double-stranded molecule of target oncogenes NET-1 and Bcl2. The dual-target siRNA double-stranded molecule is characterized in that the sequence of the dual-target siRNA double-stranded molecule is composed of a positive-sense strand, an antisense strand 1 and an antisense strand 2, wherein the positive-sense strand is 5'-CCACAAUGGCUGAGCACUUAGGAUGACUGAGUACCUGAANn-3'(SEQID NO:1), the antisense strand 1 is 5'-AAGUGCUCAGCCAUUGUGGNn-3'(SEQ ID NO:2), and the antisense strand 2 is 5'-UUCAGGUACUCAGUCAUCCNn-3'(SEQ ID NO:3). The siRNA molecule can be applied to RNA interfering in preparation of a medicine used for regulating functions of NET-1 gene and Bcl2 gene in a cell as well as induction of tumour cell apoptosis, inhibition of tumour cell migration and inhibition of tumour cell invasion, and the aim of treating tumour is achieved.
Description
Technical field
The present invention relates to a kind of pair of target siRNA molecule and uses thereof, refer in particular to siRNA molecule and the application thereof of target tumor gene NET-1 and Bcl2.
Background technology
RNA disturbs (RNA interference, RNAi) be by double-stranded RNA (double-strand RNA, dsRNA) cause its homology messenger RNA(mRNA) (messenger RNA, mRNA) a kind of PTGS form of enzymolysis (Nature.1998,391:806-811).After long dsrna enters cell, by the combination of Dicer enzyme and cutting.The cleaved products length of Dicer enzyme is generally 20～25bp, and 3 ' end of every chain have the siRNA that 2 Nucleotide dangle (small interference RNA, siRNA).The chain of siRNA be incorporated in the reticent mixture that RNA-induces (RNA-induced silencing complex, RISC), with the sequence pairing of complementary RNA.RISC at first mediates the siRNA two strands and untwists, and is combined with said target mrna in sequence-specific mode with the siRNA of the strand of RISC coupling, and the catalyst component by RISC cuts said target mrna afterwards.The cutting said target mrna can suppress its translation, finally suppresses this expression of gene.Now being proved having great potentiality in multiple disease of viral infection and tumor treatment, is the treatment means that desirable blocking gene is expressed.
RNAi has broad application prospects at field of medicaments, as antiviral, antitumor and anti-inflammatory etc.Double-stranded interfere RNA can be designed to the long double chain form that is called the Dicer substrate that can be sheared by the Dicer enzyme, or short, do not need the Dicer enzyme to shear direct form as the RISC substrate.Synthetic double-stranded RNA and target gene sequences complementation are behind transfered cell or the organism, by endogenous genetic material identification, activator RNA i approach.Utilize this mechanism, RNAi sharply descends the target gene expression level.
The RNAi technology has been opened up a brand-new treatment field, and existing tens of kinds of siRNA medicines enter clinical stage in the world at present.Diseases such as the siRNA of application treatment senile macular degeneration SMD, diabetic macular edema, respiratory syncytial virus disease, noumenal tumour, liver cancer and acute injury of kidney are wherein arranged.
NET-1 is a kind of tumor-related gene (people such as Chen Li, clinical and experimental pathology magazine, 2003,19 (5): 488-492), be expressed in the multiple human histocyte.The NET-1 assignment of genes gene mapping is on 1P34.1.NET-1 gene and NET-2, NET-3, NET-4, NET-5, NET-6 and NET-7 are generically and collectively referred to as NET-X, belong to one of member of tetramer superfamily (Tetraspanin Superfamily), are macromolecular complex.Most of members are cell surface proteins, it is characterized in that having four hydrophobic regions, are present in extracellular commentaries on classics film functional zone with the cysteine residues element of transduceing, in the cells whose development regulation and control, transform, play a significant role in growth and the motion.The expression that studies show that NET-1 is relevant with cell proliferation, and (.Tumori.2010 such as Chen L, 96:744-750), the expression of NET-1 and function may become the potential target that development takes place cancer significantly to raise the formation of cancer.
The Bcl-2 gene is a kind of oncogene that extensively is present in the malignant cell, is positioned on the 18q21, is called as " survival genes " because it has the function that suppresses apoptosis and prolong cell survival.The albumen of Bcl-2 genes encoding mainly is distributed on mitochondrial inner membrane, nuclear membrane and the endoplasmic reticulum, think at present, Bcl-2 albumen can stability line plastochondria membrane voltage, stop plastosome to discharge cytokines such as Cyt C, AIF, suppress or block the apoptosis that multiple factor is brought out, in the regulation and control of mitochondrial apoptotic pathway, play a part the center regulatory factor (Nature.1999,399:483-487).In the normal body tissue; Bcl-2 distributes and relatively limits to; mainly at tissue expressions such as the epithelial cell of embryo's tissue, mature lymphocyte, active proliferation in early days and neurones; but unusual high expression level in many tumours such as bladder cancer, nasopharyngeal carcinoma, knot-rectum cancer, mammary cancer, liver cancer, cancer of the stomach, prostate cancer and lung cancer; and its expression level often with tumour cell to multiple chemotherapeutics and gamma-ray tolerance relevant (J Cell Biochem, 1996.60:23-32).Therefore, suppress the Bcl-2 of overexpression in the tumour cell, recover its normal apoptosis pathway and increase the New Policy that its susceptibility to chemotherapeutics and radiotherapy is the treatment tumour.
Summary of the invention
The technical problem to be solved in the present invention provides two target siRNA duplex molecules and the application thereof of a kind of target tumor gene NET-1 and Bcl2.
In order to solve the problems of the technologies described above, technical scheme of the present invention has provided two target siRNA duplex molecules of a kind of target tumor gene NET-1 and Bcl2, it is characterized in that its sequence is made up of following positive-sense strand, antisense strand 1 and antisense strand 2:
Positive-sense strand:
5’-CCACAAUGGCUGAGCACUUAGGAUGACUGAGUACCUGAANn-3’(SEQ?ID?NO：1)
Antisense strand 1:5 '-AAGUGCUCAGCCAUUGUGGNn-3 ' (SEQ ID NO:2),
Antisense strand 2:5 '-UUCAGGUACUCAGUCAUCCNn-3 ' (SEQ ID NO:3).
Wherein, N is cytosine(Cyt) C, guanine G, VITAMIN B4 A, thymus pyrimidine T, deoxidation cytosine(Cyt) dC, deoxy-guanine dG, deoxyadenine dA or deoxythymidine dT, and n represents the number of N, and n is 0～2 integer.
In other words, the backbone sequences of above-mentioned pair of target siRNA molecule is:
Positive-sense strand:
5’-CCACAAUGGCUGAGCACUUAGGAUGACUGAGUACCUGAA-3’(SEQ?ID?NO：4)
Antisense strand 1:5 '-AAGUGCUCAGCCAUUGUGG-3 ' (SEQ ID NO:5),
Antisense strand 2:5 '-UUCAGGUACUCAGUCAUCC-3 ' (SEQ ID NO:6).
Preferably, described N is dT, and n is 2.
Preferably, described n is 0.
Two target siRNA duplex molecules that the present invention also provides above-mentioned target tumor gene NET-1 and Bcl2 suppress application in the medicine of NET-1 gene and Bcl2 gene function in the cell in preparation.
The present invention also provides the application of two target siRNA duplex molecules in preparation treatment medicines resistant to liver cancer of above-mentioned target tumor gene NET-1 and Bcl2.
Experiment in vitro proves, the antisense strand of siRNA molecule of the present invention can be combined with the mRNA of NET-1 and Bcl2 gene specifically, and degraded mRNA transcribes the back translation process thereby disturb, inducing apoptosis of tumour cell, inhibition tumour cell shift and invasion and attack, reach the purpose for the treatment of tumour.
The invention has the beneficial effects as follows: siRNA molecule of the present invention can be applied to prepare the effect that performance RNA disturbs in the medicine of regulating NET-1 gene and Bcl2 gene function in the cell, inducing apoptosis of tumour cell, inhibition tumour cell shift and invasion and attack, reach the purpose for the treatment of tumour.
Description of drawings
Fig. 1 is the mRNA relative expression level figure as a result that real-time quantitative PCR detects different experiments group NET-1 and Bcl2 gene.
Fig. 2 is the growth curve chart that the CCK8 method detects the SMMC-7721 cell of different experiments group.
Fig. 3 is the invasion and attack figure as a result that Transwell cell invasion experiment detects different experiments group SMMC-7721 cell.
Fig. 4 is the apoptosis figure as a result of Flow cytometry different experiments group SMMC-7721 cell.Wherein, A is the FCM analytical results figure of different experiments group; B is the two quantitative column diagrams that dye positive cell of AnnexinV and PI.
Embodiment
For simplicity, hereinafter, term " siRNA ", " siRNA sequence " or " siRNA molecule " can be exchanged, and the meaning of their expressions is identical with scope.
Wherein, siRNA is the duplex structure that positive-sense strand and antisense strand annealing form.
SiRNA molecule of the present invention derives from the function conserved regions of NET-1 and Bcl2 gene open reading frame and designs.
The preparation of siRNA can be adopted several different methods, such as: chemical synthesis, in-vitro transcription, enzyme are cut long-chain dsRNA, the synthetic siRNA Expression element of vector expression siRNA, PCR etc., the investigator that appears as of these methods provides selectable space, can obtain gene silencing efficient better.
SiRNA molecule of the present invention can be used as the effective constituent that effective constituent, the especially antitumor drug of NET-1 gene and Bcl2 gene function medicine in the cell are regulated in preparation.
For application purpose, the siRNA molecule directly can be delivered medicine to the person that is subjected to medicine privileged site on one's body as medicine, such as tumor tissues.
The formulation of medicine of the present invention can be various ways, as long as be suitable for the administration of corresponding disease and keep the activity of siRNA molecule rightly.Such as, for the injection drug delivery system, formulation can be lyophilized powder.
Randomly, can comprise any pharmaceutically acceptable carrier and adjuvant in the said medicine formulation, as long as its activity that is suitable for corresponding drug delivery system and keeps the siRNA molecule rightly.
For the present invention is become apparent, now with preferred embodiment, and conjunction with figs. is described in detail below.
Following embodiment only is used for illustrating the present invention, is not to be to limit the invention.
Hepatoma cell strain SMMC-7721 purchases the cell research institute in the Shanghai Chinese Academy of Sciences, with the DMEM culture medium culturing that contains 10%FBS (Gibco company of Gibco company), add penicillin and Streptomycin sulphate (Invitrogen company) in the described substratum, the final concentration of penicillin and Streptomycin sulphate is respectively 100U/mL and 100 μ g/mL, is incubated at 37 ℃ of CO2gas incubator.
Step 2, siRNA in-vitro transfection
With online design software (Thermo siDESIGN Center and Invitrogen BLOCK-iTRNAiDesigner) design target NET-1 (gene pool accession number: AF065388) and Bcl2 (gene pool accession number: NM_000657.2) siRNA sequence NET-1siRNA and the Bcl2siRNA of gene.And design two target siRNA sequences of target NET-1 and Bcl2 gene simultaneously: DGT siRNA, design is that CN102191246, the Chinese invention patent that is called " many targets interfere RNA molecule and application thereof " carry out with reference to publication number, sequence sees Table 1
Getting the cell that is in logarithmic phase that cultivation obtains in the step 1, is 5 * 10 by 96 orifice plate inoculum densities
4/ hole, 24 orifice plates are by 1.5 * 10
5/ hole, 6 orifice plate inoculum densities are 1 * 10
6/ hole inoculating cell,, it is divided into the normal group of experimental group and not transfection siRNA, described experimental group comprises NET-1siRNA treatment group, Bcl2siRNA treatment group, DGT siRNA treatment group.Each experimental group adopts corresponding siRNA to use the transfection of liposome (Lipofectamine) 2000 (Invitrogen companies) in cell by operation instructions, making the siRNA final concentration is 50nM, behind 37 ℃ of cultivation 4h, nutrient solution changes the DMEM substratum (Gibco company of Gibco company) that contains 10%FBS (Gibco company of Gibco company) into
All experiments all repeat 3 times, and the result all represents with mean value+SD, carries out statistical analysis with SPSS16.0.Significant difference is checked with one-way analysis of variance and sided t.P＜0.05 shows significant difference.In all charts, * shows with normal group and compares significant difference.
Table 1:siRNA sequence and control sequence
Embodiment 2
Real-time quantitative PCR (RT-QPCR) detects the mRNA expression level
Carry out cell cultures and siRNA in-vitro transfection with the method for embodiment 1.Described in-vitro transfection adopts 96 orifice plates.
Behind the transfection 48h, cell total rna extracts with Trizol reagent (Invitrogen company), and detects with RT-QPCR test kit (available from Biomics Bioisystech Co., Ltd) by operation instructions.Primer sequence sees Table 2, PCR reaction conditions: 95 ℃ of pre-sex change 5min, 40 circulations are 95 ℃ of sex change 20s, 58 ℃ of annealing 30s, 72 ℃ of extension 30s.
Table 2:RT-QPCR detects and uses primer
Interpretation of result
As shown in Figure 1, DGT siRNA, NET-1siRNA and Bcl2siRNA have all effectively suppressed the mRNA expression of NET-1 and the Bcl2 gene of SMMC-7721 cell.Compare with normal group, DGTsiRNA suppresses NET-1 simultaneously and the Bcl2 gene reaches 56% and 62%.
Embodiment 3
Cell proliferation detects:
Carry out cell cultures and siRNA in-vitro transfection with the method for embodiment 1.Described in-vitro transfection adopts 96 orifice plates.When treating before the transfection that cell degree of converging reaches 60-80%, the cell of logarithmic phase is taped against in the 96 porocyte culture plates, inoculum density is 5 * 10
43 holes are repeated in/hole, as the sample (sample when being transfection 0) of untransfected.
NET-1siRNA treatment group when measuring transfection 24h, 48h, 72h and 96h respectively, the Bcl2siRNA treatment group, DGTsiRNA treatment group and normal group sample, and the OD value of the sample of above-mentioned untransfected, described measuring method is: the 100 μ L DMEM (Gibco company of Gibco company) that will mix and 10 μ L CCK8 (Cell Counting Kit-8, Japan Dojingo company) joins in each hole, incubator is hatched 4h, measure the OD value at wavelength 490nm place with microplate reader (Bio-Rad company), formulate growth curve.
Interpretation of result:
As shown in Figure 2, NET-1siRNA, Bcl2siRNA and DGT siRNA have significant cell growth-inhibiting (P＜0.05), DGT siRNA more remarkable effect (P＜0.01).
Embodiment 4
Cell invasion detects
Carry out cell cultures siRNA in-vitro transfection with the method for embodiment 1.Described in-vitro transfection adopts 24 orifice plates.
During 72h, detect cell migration with 24-well membrane filters (U.S. Corning Bioscience company) after the transfection.Detection method is: with 1.5 * 10
5Individual cell is taped against in the chamber with migration 24h in the DMEM substratum that contains serum (Gibco company of Gibco company).The cell of staying in the chamber is removed with cotton swab, moves to down cell in the chamber with 10% formaldehyde fixed 30s.At last, cell is with 0.1% violet staining 4min, is that 7.4 PBS damping fluid is washed 3 times with pH subsequently.Cell is counted in 200 times of magnification fields, 5 visuals field of counting under each condition.
Interpretation of result
Shown in A among Fig. 3, the result shows, the migrating cell number of normal group is 104, the NET-1siRNA treatment group is 36, the Bcl2siRNA treatment group is 28, DGT siRNA treatment group is 25, and the siRNA of target NET-1 and Bcl2 gene all can suppress the migration (P＜0.05) of SMMC-7721 cell, and the inhibition of DGT siRNA best (P＜0.05) (B among Fig. 3).
Embodiment 5
Flow cytometry (FCM) is measured apoptosis
Carry out cell cultures and siRNA in-vitro transfection with the method for embodiment 1.Described in-vitro transfection adopts 6 orifice plates.
Measure test kit (Nanjing KaiJi Biology Science Development Co., Ltd) with Annexin V-FITC apoptosis and carry out Annexin-V/propidium iodide (PI) double analysis.Behind the SMMC-7721 cell transfecting 48h, be that 7.4 PBS damping fluid is washed twice with 0.25% trysinization and pH.1 * 10
6Cell is resuspended with 500 μ L binding buffer liquid, and by the Annexin-V dyeing of operation instructions with 5 μ L FITC marks, adds 5 μ L PI and room temperature lucifuge and hatch 10min.Different experiments group cell carries out the fluidic cell test with BD FACS Calibur (BD Bioscience company), data CellQuest data acquisition analysis software (BDBioscience company).
Interpretation of result
As shown in Figure 4, the per-cent of apoptotic cell dyes the positive and represents with Annexin V and PI is two.Compare with normal group, siRNA has all suppressed NET-1 or the Bcl2 gene has significantly promoted apoptosis (P＜0.05), and DGT siRNA promotes apoptotic more remarkable effect (P＜0.05).
Claims (5)
1. two target siRNA duplex molecules of a target tumor gene NET-1 and Bcl2 is characterized in that its sequence is made up of following positive-sense strand, antisense strand 1 and antisense strand 2:
Positive-sense strand:
5’-CCACAAUGGCUGAGCACUUAGGAUGACUGAGUACCUGAANn-3’(SEQ?ID?NO：1)
Antisense strand 1:5 '-AAGUGCUCAGCCAUUGUGGNn-3 ' (SEQ ID NO:2),
Antisense strand 2:5 '-UUCAGGUACUCAGUCAUCCNn-3 ' (SEQ ID NO:3).
Wherein, N is cytosine(Cyt) C, guanine G, VITAMIN B4 A, thymus pyrimidine T, deoxidation cytosine(Cyt) dC, deoxy-guanine dG, deoxyadenine dA or deoxythymidine dT, and n represents the number of N, and n is 0～2 integer.
2. two target siRNA duplex molecules of target tumor gene NET-1 as claimed in claim 1 and Bcl2 it is characterized in that described N is dT, and n are 2.
3. two target siRNA duplex molecules of target tumor gene NET-1 as claimed in claim 1 and Bcl2 is characterized in that described n is 0.
4. two target siRNA duplex molecules of claim 1 described target tumor gene NET-1 and Bcl2 suppress application in the medicine of NET-1 gene and Bcl2 gene function in the cell in preparation.
5. the application of two target siRNA duplex molecules of claim 1 described target tumor gene NET-1 and Bcl2 in preparation treatment medicines resistant to liver cancer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103352036A (en) * | 2013-05-29 | 2013-10-16 | 南通大学附属医院 | SiRNA molecule targeting tumor related genes and application thereof |
| CN103937801A (en) * | 2014-05-13 | 2014-07-23 | 南通大学 | Multi-targeted siRNA (Small Interfering Ribose Nucleic Acid) molecule and application thereof to resisting tumor |
| WO2018103684A1 (en) * | 2016-12-08 | 2018-06-14 | 杭州康万达医药科技有限公司 | Method for establishing machine learning model for predicting toxicity of sirna against certain type of cell and use thereof |
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| US20050176667A1 (en) * | 2001-01-09 | 2005-08-11 | Alnylam Europe Ag | Compositions and methods for inhibiting expression of anti-apoptotic genes |
| CN102191246A (en) * | 2010-10-28 | 2011-09-21 | 百奥迈科生物技术有限公司 | Multi-target interfering nucleic acid molecule and application thereof |
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- 2013-05-29 CN CN2013102083856A patent/CN103266111A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050176667A1 (en) * | 2001-01-09 | 2005-08-11 | Alnylam Europe Ag | Compositions and methods for inhibiting expression of anti-apoptotic genes |
| CN102191246A (en) * | 2010-10-28 | 2011-09-21 | 百奥迈科生物技术有限公司 | Multi-target interfering nucleic acid molecule and application thereof |
Non-Patent Citations (1)
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| YUAN-YUAN WU ET AL.: "Inhibition of hepatocellular carcinoma growth and angiogenesis by dual silencing of NET-1 and VEGF", 《 J MOL HIST》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103352036A (en) * | 2013-05-29 | 2013-10-16 | 南通大学附属医院 | SiRNA molecule targeting tumor related genes and application thereof |
| CN103937801A (en) * | 2014-05-13 | 2014-07-23 | 南通大学 | Multi-targeted siRNA (Small Interfering Ribose Nucleic Acid) molecule and application thereof to resisting tumor |
| WO2018103684A1 (en) * | 2016-12-08 | 2018-06-14 | 杭州康万达医药科技有限公司 | Method for establishing machine learning model for predicting toxicity of sirna against certain type of cell and use thereof |
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Application publication date: 20130828 |