CN101481688A - SiRNA for inhibiting human KCTD1 gene expression and use thereof in pharmacy - Google Patents
SiRNA for inhibiting human KCTD1 gene expression and use thereof in pharmacy Download PDFInfo
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Abstract
The invention discloses a siRNA for inhibiting human KCTD1 gene expression and an application thereof in the pharmacy industry. In the invention, based on RNA interference technology, a cDNA sequence of a human KCTD1 gene is obtained from GenBank, according to the basic principle of siRNA target sequence selection, 21 ribonucleotide is designed and synthesized by a chemical method in connection with KCTD1 gene. The invention can efficiently and specifically inhibit mRNA and protein level expressions of the KCTD1 gene and specifically ease the inhabitation of the transcription activity of a transcription factor AP-2 by the KCTD1, thus the invention is applicable for preparing the drugs of resisting breast cancer.
Description
Technical field:
The present invention relates to a kind of siRNA, particularly relate to a kind of siRNA and application in the anti-breast cancer medicines preparation thereof that suppresses human KCTD 1 gene expression.
Background technology:
Mammary cancer is a disease that is subjected to the polygene network regulation.AP-2 is as an important transcription factor family, and numerous AP-2 that studies show that play important regulation in mammary cancer.Wherein AP-2 in cell growth and tumour generation, play important restraining effect (Cancer Res, 2004,64:631-638).In transgenic mice, AP-2 is crossed that the mortality ratio of expressing the back mammary gland cell increases and the cell that is in division stage sharply descends (Dev Biol, 2003,256:127-145).The expression amount that detects AP-2 in a large amount of diagnostic mammary cancer descends, and being accompanied by breast cancer cell propagation increases, and the cell growth rapidly; And that AP-2 expresses in the high tumor tissues cell proliferation and tumour deterioration degree is all very low, has pointed out tumor inhibition effect (J Pathol, 1999, the 189:514-520 of transcription factor AP-1-2; Clin Cancer Res, 2002,8:3487-3495).AP-2 also is widely used in diagnosing mammary cancer at present, and its high expression level is indicating patient's survival rate height, recover after the treatment well (Eur J Cancer, 2004,40:1485-1495).Immunohistochemistry result shows in the nucleus that the AP-2 expression amount descends, and this is getting in touch advancing of disease and tumour and worsens and increase, so this also point out the risk of breast cancer disease increase (Clin Cancer Res, 2002,8:3487-3495).There are some researches show effect that AP-2 suppresses tumour derive from the apoptosis of the stagnation of having induced the cell growth and cell (J Biol Chem, 2003,278:52093-52101).Further experiment show the mechanism of AP-2 anticancer growth may be by inducing cell cycle supressor P21WAF1 realize (Nat Genet, 1997,15:78-82).
KCTD1 to be the inventor find by yeast two-hybrid system screening human brain cDNA new and the interactional albumen of transcription factor AP-1-2, this is a new BTB/POZ albumen.The inventor finds that KCTD1 is a nucleus albumen, has transcriptional repression activity, the KCTD1 high expression level is in human mammary tissue and breast cancer cell line simultaneously, further prove by GST pull-down and co-immunoprecipitation to exist direct interaction between KCTD1 and the AP-2, and interaction zone is positioned activation structure territory and the conservative BTB/POZ structural domain of KCTD1 of AP-2.Cellular immunofluorescence shows that also two proteic location are overlapping fully, all is positioned in the nucleus.And the contriver finds that also in MDA-MB-453 cell KCTD1 has suppressed the transcriptional activation of AP-2 consumingly, and other BTB/POZ albumen (as three members of PDIP1 family) does not influence the transcriptional activity of AP-2.Therefore how reducing it according to these characteristics of KCTD1 and transcribe inhibit feature, is present problem demanding prompt solution thereby reach the propagation that suppresses breast cancer cell and then suppress tumour.
Summary of the invention
Purpose one of the present invention provides the siRNA that a specific specificity suppresses human KCTD 1 gene expression, and the 2nd, can produce the expression vector of above-mentioned siRNA; The 3rd, the application of the expression vector of above-mentioned siRNA or siRNA in the anti-breast cancer medicines preparation.
Purpose of the present invention is achieved through the following technical solutions:
One specific specificity suppresses the siRNA of human KCTD 1 gene expression, and its base sequence and site of action thereof are as follows:
Positive-sense strand 5 ' CGU CCC AGU UCA GCG AAU A 3 '
Antisense strand 5 ' UAU UCG CUG AAC UGG GAC G 3 '
Act on the 678-698 position of human KCTD 1 mRNA.
Described siRNA can pass through synthetic, and this siRNA has 2-6 dT to modify or 2-6 U modification 3 '.
The application of described siRNA in the anti-breast cancer medicines preparation.
The present invention is based on the RNA perturbation technique, obtain the cDNA sequence of human KCTD 1 gene from GenBank, fundamental principle according to the selection of siRNA target sequence, at the KCTD1 gene design 21 Nucleotide, ' hold two deoxyribonucleotides of interpolation (dTdT) to be the single catenary suspension structure at 3 of siRNA, with strengthen this siRNA in vivo with external stability, prevent the degraded.Employed siRNA entrusts Shanghai Ji Ma company synthetic by chemical method by the inventor oneself design among the present invention.
SiRNA of the present invention can efficiently suppress the expression of the mRNA and the protein level of KCTD1 gene specifically, other BTB albumen is not produced reticent effect.And this siRNA has also been alleviated the inhibition of KCTD1 to transcription factor AP-1-2 transcriptional activity specifically, and MTT analysis revealed KCTD1 crosses and expresses the growth that has promoted the MDA-MB-453 breast cancer cell simultaneously, and KCTD1-siRNA has then suppressed the propagation of breast cancer cell.Soft-agar cloning forms experimental result and shows as one man that also KCTD1-siRNA adding back breast cancer cell forms the number of cloning and sharply descends.Therefore, the present invention may provide a kind of anti-breast cancer therapeutic modality and medicine of brand-new mechanism of action.
Advantage of the present invention:
KCTD1-siRNA provided by the invention can specificity suppress the human KCTD 1 expression of gene, thereby reaches the generation of inhibition mammary cancer and the purpose of growth.This siRNA can be used for preparing the anti-breast cancer medicines of high specificity.
Description of drawings
Fig. 1: RT-PCR detects the inhibition of KCTD1siRNA to the mRNA level of KCTD1 gene
Fig. 2: Western Blotting detects the inhibition of KCTD1 siRNA to the KCTD1 protein level
Fig. 3: Luciferase analyzes the influence of KCTD1 siRNA to the transcriptional activity of AP-2
Fig. 4: MTT analyzes the influence of KCTD1 siRNA to breast cancer cell propagation
Fig. 5: soft-agar cloning forms the influence of experimental analysis KCTD1 siRNA to the breast cancer cell growth
Embodiment
The selection of embodiment 1:siRNA target sequence
KCTD1-siRNA provided by the present invention obtains according to the human KCTD 1 sequence that the contriver finds in GenBank, these RNA sequences meet following principle substantially: from the AUG initiation codon of transcript (mRNA), seek " AA " two and connect sequence, and write down its 3 ' 19 base sequences holding, as potential siRNA target site.Design during siRNA not at 5 ' and the 3 ' non-coding region of holding, reason is that these places have abundant modulin calmodulin binding domain CaM, thereby and these UTR are conjugated protein or translation initiation complex may influence siRNP endonuclease enzyme complex influences siRNA in conjunction with mRNA effect.GC content in general 21 Nucleotide finds effective fragment easilier in the lower fragment of GC content in the scope of 30%-70%.And to avoid the siRNA target sequence to form the continuous repetition of secondary structure and identical base, these structures can influence annealing pairing and the target spot specificity of siRNA.In addition, selected sequence and corresponding genome database (people, perhaps mouse, rat or the like) are compared, get rid of those and other encoding sequences/EST homologous sequence.For example use BLAST (www.ncbi.nlm.nih.gov/BLAST/).Also need RNA space structure picture at last with reference to the Sfold recommendation.We generally add the tail of two dTdT at 3 ' end of positive-sense strand, instruct siRNA to form the reticent mixture of RNAi, also avoid being subjected to the degraded of nuclease.
The contriver is according to above principle, and pair of sequences has been synthesized in design, and its concrete sequence is as follows:
Positive-sense strand 5 ' CGU CCC AGU UCA GCG AAU AdTdT 3 '
Antisense strand 5 ' UAU UCG CUG AAC UGG GAC GdAdG 3 '
Act on the 678-698 position of human KCTD 1 mRNA
It is synthetic to serve Hai Jima company after sequences Design is good, and the purity of the siRNA two strands that the present invention uses is greater than 99%, and the distilled water dissolving with DEPC handled just can be directly used in cell transfecting.
Embodiment 2:RT-PCR detects the gene silencing effect of KCTD1-siRNA.
The HEK293FT cell is that preserve in this laboratory, with 6 orifice plates at 37 ℃, 5% CO
2, cultivate with DMEM complete culture solution (adding 10% new-born calf serum, 2mM L-L-glutamic acid, penicillin and Streptomycin sulphate) in the 90% relative humidity incubator, treat cell density to 70%.With liposome Lipofectamine 2000 transfection reagent boxes KCTD1-siRNA is changed in the HEK293FT cell.The liposome transfection method is the nutrient solution that cell is changed into 1.5mL serum-free antibiotic-free before transfection.Every hole siRNA consumption is 100pM, is diluted to 250 μ L respectively with the nutrient solution of serum-free antibiotic-free, mixing gently, and room temperature leaves standstill 5min.Simultaneously liposome is diluted in the nutrient solution of 250 μ L serum-free antibiotic-frees and contains 5 μ L liposomes, mixing gently, room temperature leaves standstill 5min.The liposome of dilution is added equal-volume siRNA mixing, and room temperature leaves standstill 20min.With 500 μ LsiRNA/ liposome complexes mixing gently, be added dropwise in the cell, mixing gently, normal condition is cultivated.Allow behind DNA/ liposome complex and the cells contacting 6h, changed serum and antibiotic nutrient solution into.Continue to cultivate 36h, collecting cell.
Cell is directly added 500 μ L TRIzol lysing cell in culture plate, inhale with pipettor and beat several times.Place 10min in room temperature, the nucleic acid-protein mixture is separated fully.Add 100 μ L chloroforms then, thermal agitation 15sec, room temperature is placed 3min.4 ℃ of centrifugal 15min of 10000 * g.Sample is divided into three layers: bottom is yellow organic phase, and the upper strata is colourless water and a middle layer.RNA is mainly at aqueous phase, and the water volume is about 60% of used TRIzol reagent.Water is transferred in the new pipe, with the RNA of isopropanol precipitating aqueous phase.Add 250 μ L Virahols, room temperature is placed 10min.4 ℃ of centrifugal 10min of 10000 * g do not see the RNA precipitation before centrifugal, and centrifugal back gelatinous precipitate occurs in the pipe side and the pipe end.Remove supernatant.Precipitate with 75% washing with alcohol RNA.Every use 1mL TRIzol adds 1mL 75% ethanol at least.4 ℃ are no more than the centrifugal 5min of 7500 * g, abandon supernatant.Room temperature places drying or vacuum is drained the RNA precipitation, and the 5-10min that approximately dries in the air gets final product.Do not want the traditional vacuum drying, too drying can cause the solvability of RNA to reduce greatly.Adding 25-200 μ L does not have the water of RNase, inhales with the rifle head and beats several times, places 10min for 55-60 ℃ and makes the RNA dissolving.Running glue detects the quality of mRNA and measures concentration with ultraviolet spectrophotometer.
With total RNA is template, carries out reverse transcription with AMV ThermoScript II and random primer, first chain of synthetic cDNA.The reverse transcription system is 20 μ L, wherein contains the total RNA of 1 μ g, reverse transcription damping fluid, 5mM MgCl
2, 1mM dNTP, 3 ' the end random primer of 200pM, AMV ThermoScript II (Promega), RNA enzyme inhibitors.Reverse transcription program: 42 ℃ of 5min, 37 ℃ of incubation 50min reverse transcription, 75 ℃ of 5min deactivation ThermoScript II.Gained cDNA is in-20 ℃ of PCR reactions that store for future use or carry out immediately.Its reaction cumulative volume is under the condition of 20 μ L, wherein all contains in the reaction system: 2 μ L reaction buffers, 1U exTaq archaeal dna polymerase, 1 μ L template cDNA, KCTD1 and-the actin primer respectively adds 1 μ L.Response procedures: 94 ℃ of pre-sex change 3min at first, after carry out 30 circulations: 94 ℃ of sex change 30sec, 60 ℃ of annealing 30sec, 72 ℃ are extended 1min; Last 72 ℃ are extended 5min, 4 ℃ of terminations.After reaction is finished product being carried out agarose electrophoresis, takes pictures and analytical results with gel imaging system in EB dyeing back.The result shows that KCTD1 siRNA can reduce the mRNA level of KCTD1 gene effectively, and the siRNA of negative control does not influence (see figure 1) to the mRNA level of KCTD1 gene.
Embodiment 3:Western Blotting detects the influence of KCTD1 siRNA to the KCTD1 protein level.
(pCMV-Myc-PDIP1, pCMV-Myc-KCTD10 pCMV-Myc-TNFAIP1) make up by the laboratory and the exactness of its sequence of order-checking proof for pCMV-Myc-KCTD1 plasmid and other BTB plasmid.The cultivation and the transfection of HEK293FT cell are described with the front, and every hole adds 2 μ g DNA and 50pM siRNA.Inhale after transfection is finished and remove nutrient solution, PBS rinsing cell, exhaustion PBS, 1 * the lysis buffer (50mMTris-HCl (pH7.2), 150mM NaCl, 1% (v/v) Triton X-100 that add 100 μ L again, 1% (w/v) sodiumdeoxycholate, 0.1% (w/v) SDS) shake up.Place 15min in-80 ℃ of refrigerators, incubation 5min in 37 ℃ of incubators repeat to freeze once molten, make the abundant cracking of cell.Scrape with cell cell is scraped from aperture, change cell pyrolysis liquid and cell the centrifuge tube of 1.5mL over to liquid-transfering gun, place on ice.Vortex concussion 10-15sec, 12000 * g is in 4 ℃ of centrifugal 2min.Getting supernatant liquor is transferred in the clean centrifuge tube.
Protein sample at first used 15% SDS-polyacrylamide gel (SDS-PAGE) electrophoresis.To pvdf membrane, the protein with the film surface carries out specific detection with antigen antibody reaction to method (constant voltage 100v, 4 ℃ of electrotransfer 1.5h) by electrotransfer more then with the protein transfer printing.(10mM Tris-HCl (pH7.4) is 0.9%NaCl) as encapsulant sealing 60min with the TBS damping fluid that contains 10% skim-milk for the nylon membrane that transfer printing is good.The film submergence adds presses the mouse monoclonal antibody Myc of 1:1000 with the encapsulant dilution, shakes 1h and allow the antibody of dilution fully combine with pvdf membrane in shaking table.Wash film 4 times with the TBS damping fluid, each 10min.The sheep anti-mouse igg (diluting 2000 times) of horseradish peroxidase-labeled is added encapsulant as second antibody, make the film submergence wherein in shaking table, continue to shake 1h.Wash film 4 times with the TBS damping fluid.At last with the colour developing of DAB solution.The result shows that KCTD1 siRNA can suppress the expression of KCTD1 albumen in cell, and the siRNA of negative control is to the not influence of KCTD1 protein level.Find the expression not influence of KCTD1-siRNA to other BTB family protein (as three members of PDIP1 family) simultaneously, prompting KCTD1-siRNA specificity suppresses the expression of BTB albumen KCTD1; GAPDH contrasts as last sample, is consistent (see figure 2) with the applied sample amount that guarantees the total protein that each is organized.
Embodiment 4:Luciferase analyzes the influence of KCTD1-siRNA to the transcriptional activity of AP-2
The MDA-MB-453 cell is preserved for this laboratory.With 1640 culture medium culturing that contain 5 μ g/ml Regular Insulin, the cell of 24 orifice plates is cultivated and transfection, and 1 * lysis buffer (the Promega test kit provides) that the results back adds 100 μ L shakes up.Place 15min in-80 ℃ of refrigerators, incubation 5min in 37 ℃ of incubators repeat to freeze once molten, make the abundant cracking of cell.Pipette 20 μ L cell extracts with liquid-transfering gun and carry out the beta-galactosidase enzymes check and analysis, add 180 μ L analysis buffer,, have an amount of yellow substance to occur at 37 ℃ of incubation 10min.Because transfection has added the expression vector of LacZ simultaneously, and LacZ is a reporter gene that uses in the cell transfecting experiment usually, its coding beta-galactosidase albumen, this proteic expression level is very stable and detects easily, can by with the substrate ONPG rapid reaction yellowly product of sensitivity, writing time is with 100 μ L1M yellow soda ash termination reactions.Survey the OD value at the 420nm place with ultraviolet spectrophotometer, carry out quantitatively determining the concentration of cell extract according to the OD value.Use luciferase detection kit (Promega), every pipe sample is got 20 μ L and is added 100 μ L luciferase substrates measurement fluorescence intensity under TD-20/20Luminometer (Turner Designs), record experimental data.Found that KCTD1 has suppressed the transcriptional activity of transcription factor AP-1-2 to self promotor A2, but its restraining effect is removed basically after adding KCTD1-siRNA, and the siRNA of negative control does not influence (see figure 3) to the AP-2 promoter activity.
Embodiment 5:MTT analyzes the influence of KCTD1-siRNA to the breast cancer cell growth.
The MDA-MB-453 cell is inoculated in 24 orifice plates equally, carry out cell transfecting, put 37 ℃ afterwards, cultivate 24～72h under the 5%CO2 condition, 4h adds MTT10 μ L/ hole (concentration is 5mg/ml) before finishing, and abandons supernatant liquor after continuing to cultivate 4h, add dimethyl sulfoxide (DMSO) (DMSO) 100 μ L/ holes, carry out light absorption value on the microplate reader in vibrating about 10min on the vibrator, putting and detect, wavelength is 570nm.As shown in Figure 4,, suppressed the expression of AP-2alpha, thereby promoted the growth of MDA-MB-453 breast cancer cell when KCTD1 crosses expression; And add KCTD1 siRNA, and breast cancer cell is not bred basically, and prompting KCTD1 siRNA can suppress the growth of breast cancer cell.
Embodiment 6: soft-agar cloning forms the influence of experimental analysis KCTD1-siRNA to the breast cancer cell growth.
The MDA-MB-453 cell in vegetative period of taking the logarithm with 0.25% tryptic digestion and piping and druming gently, makes it to become unicellular, makes viable count, adjusts cell density to requirement of experiment with the RPMI-1640 that contains 20% foetal calf serum.Prepare the LMP agar liquid glucose of 1.2% and 0.7% two concentration respectively with distilled water, behind the autoclaving, maintain in 40 ℃ and can not solidify.After in the 1:1 ratio 1.2% agarose and 2 * 1640 substratum (calf serum that contains 2 * microbiotic and 20%) being mixed, get the 3mL mixed solution and inject diameter 6cm plate, cooled and solidified can be put CO as bottom-layer agar
2Standby in the incubator.Allow 0.7% agarose with after 2 * 1640 substratum mix in sterile test tube mutually in the 1:1 ratio, add the cell suspension of 0.2mL again in pipe, abundant mixing injects and is covered with 1.2% agarose bottom plate, by forming two agar layer.After treating that top-layer agar solidifies, insert in 37 ℃ of 5%CO2 incubators and cultivated 10～14 days.Plate is placed under the inverted microscope, and observation of cell clone number calculates rate of formation.As shown in Figure 5, KCTD1 crosses the formation that expression has promoted MDA MB 453 breast cancer cell line cell clones effectively, and disturbs back cell clone number sharply to descend KCTD1.
The application of embodiment 7:KCTD1-siRNA in the preparation anti-breast cancer medicines
Gained KCTD1-siRNA of the present invention is used to prepare the medicine of anti-breast cancer.Be used for human vivo medicine-feeding, can use separately or unite use with other medicines.
Claims (3)
1, a specific specificity suppresses the siRNA of human KCTD 1 gene expression, and its base sequence and site of action thereof are as follows:
Positive-sense strand 5 ' CGUCCCAGUUCAGCGAAUA 3 '
Antisense strand 5 ' UAUUCGCUGAACUGGGACG 3 '
Act on the 678-698 position of human KCTD 1 mRNA.
2, according to the siRNA described in the claim 1, can pass through synthetic, it is characterized in that this siRNA has 2-6 dT to modify or 2-6 U modification 3 '.
3, the application of a kind of siRNA described in claim 1 or 2 in the anti-breast cancer medicines preparation.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102373204A (en) * | 2010-08-27 | 2012-03-14 | 复旦大学附属金山医院 | Method for transcriptional gene expression regulation and application |
| CN101787368B (en) * | 2009-12-17 | 2013-03-27 | 湖南师范大学 | siRNA for restraining Z38 gene expression of human being and application thereof in preparing breast-tumor resisting medicine |
| CN103131775A (en) * | 2013-02-04 | 2013-06-05 | 安徽农业大学 | Method and application for detecting pig growth performance heterosis |
| CN107988224A (en) * | 2017-12-07 | 2018-05-04 | 湖南师范大学 | One species specificity suppresses shRNA and the application of KCTD1 gene expressions |
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2009
- 2009-01-04 CN CN200910042407XA patent/CN101481688B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101787368B (en) * | 2009-12-17 | 2013-03-27 | 湖南师范大学 | siRNA for restraining Z38 gene expression of human being and application thereof in preparing breast-tumor resisting medicine |
| CN102373204A (en) * | 2010-08-27 | 2012-03-14 | 复旦大学附属金山医院 | Method for transcriptional gene expression regulation and application |
| CN102373204B (en) * | 2010-08-27 | 2013-02-20 | 复旦大学附属金山医院 | Method for transcriptional gene expression regulation and application |
| CN103131775A (en) * | 2013-02-04 | 2013-06-05 | 安徽农业大学 | Method and application for detecting pig growth performance heterosis |
| CN107988224A (en) * | 2017-12-07 | 2018-05-04 | 湖南师范大学 | One species specificity suppresses shRNA and the application of KCTD1 gene expressions |
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