CN106591229A - Application of miR-34a and target gene NOTCH1 to preparation of mesenchymal stem cell based glioma targeting carrier - Google Patents
Application of miR-34a and target gene NOTCH1 to preparation of mesenchymal stem cell based glioma targeting carrier Download PDFInfo
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Abstract
The invention discloses application of miR-34a and target gene NOTCH1 to preparation of a mesenchymal stem cell based glioma targeting carrier. After miR-34a low expression of mesenchymal stem cells, cytotaxis of the mesenchymal stem cells to gliomas U87, gliomas U251 and gliomas C6 is enhanced completely, targeting performance is improved, and targeting specificity is achieved; after miR-34a low expression, gene NOTCH1 expression is up-regulated, and NOTCH1 protein content is increased evidently, so that miR-34a improves cytotaxis of the mesenchymal stem cells to gliomas U87, gliomas U251 and gliomas C6 by regulating the target gene NOTCH1. Medicines which inhibit miR-34a and up-regulate gene NOTCH1 and protein expression can be used for improving glioma targeting performance of the mesenchymal stem cells, and modified BMSC has no promotion effect on growth of glioma cells and can be made into the mesenchymal stem cell based glioma targeting carrier.
Description
Technical field
The invention belongs to stem cell field, be related to by carrier target tumor of stem cell organize, and in particular to miR-34a and
Applications of its target gene NOTCH1 in the glioma targeting vector based on mescenchymal stem cell is prepared.
Background technology
Mescenchymal stem cell (mesenchymal stem cell, MSC) is latent with self-renewal capacity and various differentiation
Can, new Therapeutic Method of the existing substantial amounts of experiment using this characteristic research relevant disease of MSC.Gene therapy be considered as after
One of most promising scheme of tumor is treated after the traditional remedies such as operation, radiation and chemotherapy.The matter of utmost importance of gene therapy is
Suitable carrier is selected, and the tumprigenicity that becomes of mescenchymal stem cell makes which be expected to become the effective carrier of therapy of tumor.
With regard to targeting of the mescenchymal stem cell to tumor.Scott A.Bergfeld etc. are in article Bone marrow-
In derived mesenchymal stem cells and the tumor microenvironment between detailed overview bone marrow
The relation of mesenchymal stem cells and tumor, tumor tissues have the effect for recruiting that mesenchymal stem cells MSCs enter its tumor microenvironment
[Cancer Metastasis Rev(2010)29:249-261].Nobuhiro Hata etc. are in research article PDGF-BB
In Mediates the Tropism of Human Mesenchymal Stem Cells for Malignant Gliomas
Confirm that people's interstital stem cell has the function [Neurosurgery.2010 of targeting glioma；66(1):144-157].Subsequently,
Seong Muk Kim etc. are in research article CXC chemokine receptor 1enhances the ability of
human umbilical cord blood-derived mesenchymal stem cells to migrate toward
Find in gliomas that Gro-beta-T receptor can strengthen targeting [Biochem Biophys of the interstital stem cell to glioma
Res Commun.2011,741-746].Yang little Li etc. has found that MSC has the effect (mescenchymal stem cell of targeting colon cancer tissue
The impact of the nude mouse tumor formed by colon cancer cell Hct-116, Chinese cell and stem cell magazine in May, 2015 volume 5 the 2nd
Phase).Cui Fengming etc. has found that Marrow Mesenchymal Stem Cells are migrated to pancreatic cancer cell in vitro, in vivo to Pancreatic Adenocarcinoma targeting
Aggregation (experimentation of the mesenchymal stem cells MSCs as gene therapy for pancreatic carcinoma carrier, volume 39 the 4th of modern medicine 2011
Phase).Also research confirms that MSC can targeting renal carcinoma tissue [Therapeutic potential of human mesenchymal
stem cells producing IL-12 in a mouse xenograft model of renal cell
carcinoma.Cancer Lett,2010,290(2):157-166]。
With regard to mescenchymal stem cell and the relation of tumor, it is facilitation or inhibitory action.Scott A.Bergfeld
Deng in survey article Bone marrow-derived mesenchymal stem cells and the tumor
Point out in microenvironment, current scientific circles are for mescenchymal stem cell is the growth of promotion tumor or suppresses tumor
Production also there is serious fissure in a party, mescenchymal stem cell is to the influence of different types of tumor and indefinite.[Cancer
Metastasis Rev(2010)29:249-261]
From prior art as can be seen that MSC has and draws materials that convenient, amplification in vitro ability is strong, efficiency gene transfection is high and low
The advantages of immunogenicity, can be used as the target cell (carrier) of the seed cell in organizational project and gene therapy.But, by MSC
At least also need to solve two problems as the targeting vector of tumor tissues:First, MSC is repaiied by technologies such as genetic engineerings
Decorations, further improve the targeting of the specific tumors tissue of MSC；Second, if MSC has facilitation to specific tumors, need
Reverse this facilitation.The MSCs of intravenous injection genetic modification to the antitumor action of pulmonary, brain and Subcutaneous tumor
Have been reported that [Human bone marrow-derived mesenchymal stem cells in the treatment of
gliomas.Cancer Res,2005,65:3307-3318；Antitumor effect of genetically
engineered mesenchymal stem cells in a rat gliomas model.Gene Ther,2004,11:
1155-1164；Mesenchymal stem cells:potential precursors for tumor stroma and
targeted delivery vehicles for anticancer agents.JNatl Cancer Inst,2004,96:
1593-1603；Adipose tissue-derived human mesenchymal stem cells mediated
prodrug cancer gene therapy.Cancer Res,2007,67:6304-6313]。
The content of the invention
The present invention is intended to provide a kind of glioma targeting vector based on mescenchymal stem cell, by technique for gene engineering pair
MSC is modified, and improves targetings of the MSC to glioma.
Technical scheme is announced as follows：
NOTCH1 genes are being prepared for improving the application in medicine of the mescenchymal stem cell to glioma targeting.
Further, the mescenchymal stem cell is mesenchymal stem cells MSCs.
A kind of glioma targeting vector, the carrier are the mescenchymal stem cell processed through said medicine.
NOTCH1 albumen is being prepared for improving the application in medicine of the mescenchymal stem cell to glioma targeting.
Further, the mescenchymal stem cell is mesenchymal stem cells MSCs.
A kind of glioma targeting vector, the carrier are the mescenchymal stem cell processed through said medicine.
The negative regulation non-coding RNA miR-34a of NOTCH1 genes is being prepared for improving mescenchymal stem cell to colloid
Application in the medicine of tumor targeting.
Further, the mescenchymal stem cell is mesenchymal stem cells MSCs.
A kind of glioma targeting vector, the carrier are the mescenchymal stem cell processed through said medicine.
The inhibitor of above-mentioned miR-34a is used to improve application of the mescenchymal stem cell to glioma targeting.
Invention effect：
Present invention discover that after to the miR-34a low expressions of mescenchymal stem cell, mescenchymal stem cell is to glioma U87, glue
Matter tumor U251, the tropism of glioma C6 all strengthen, and targeting increases；After miR-34a low expressions, in NOTCH1 gene expressions
Adjust, NOTCH1 protein contents are significantly raised, it was demonstrated that miR-34a is dry thin to improve mesenchyme by adjusting its target gene NOTCH1
Born of the same parents are to glioma U87, glioma U251, glioma C6 tropism.Suppress miR-34a, raise NOTCH1 genes and albumen table
The medicine for reaching can be used for improving targeting of the mescenchymal stem cell to glioma, and the BMSC of the modification is to glioma cell
Growth can make the glioma targeting vector based on mescenchymal stem cell without facilitation.
Description of the drawings
Relative expression quantities of the Fig. 1 for each group miR-34a；
Fig. 2 is each group NOTCH1 albumen relative expression quantity；
Fig. 3 is each group mesenchymal stem cells MSCs to glioma U87 migrating cell number；
Fig. 4 is each group mesenchymal stem cells MSCs to glioma U251 migrating cell number；
Fig. 5 is each group mesenchymal stem cells MSCs to glioma C6 migrating cell number；
Fig. 6 is inhibitor groups mesenchymal stem cells MSCs to cancer of pancreas PANC-1 and NIH/3T3 migration of fibroblast cells
Number.
Specific embodiment
Technical scheme is introduced with reference to specific embodiment.The experiment material especially do not emphasized in following embodiments
Material is normal experiment material, has no special requirements, and is all the conventional material that those skilled in the art are readily available.Use bio information
Learn the target gene of online software PicTar, TargetScan and MicroCosm prediction miR-34a and carry out interpretation of result, it is comprehensive
Document report and inventor's early stage preliminary experiment, determine the target gene that gene NOTCH1 is miR-34a.
Embodiment 1：Impacts of the miR-34a Targeted-control gene NOTCH1 to BMSC transfer behaviores
First, experiment material
1st, miR-34a mimics and miR-34a inhibitor (being purchased from the sharp rich biology in Guangzhou)
(1) miR-34a mimics double-stranded sequences：
Positive-sense strand：5’-UGGCAGUGUCUUAGCUGGUUGU-3’
Complementary strand：5’-ACAACCAGCUAAGACACUGCCA-3’
(2) miR-34a mimics NC double-stranded sequences：
Positive-sense strand：5’-UCACAACCUCCUAGAAAGAGUAGA-3’
Complementary strand：5’-UCUACUCUUUCUAGGAGGUUGUGA-3’
(3) miR-34a inhibitor sequences：
5’-ACAACCAGCUAAGACACUGCCA-3’
(4) miR-34a inhibitor NC sequences：
5’-UCUACUCUUUCUAGGAGGUUGUGA-3’
2nd, miR-34a and U6qRT-PCR primer sequences (being synthesized by Shanghai Ji agate design)
MiR-34a reverse transcriptase primers：5’-GTCGTATCCAGTGCGTGTCGTGGAGTCGGCAATTGCACTGGATACGAC
AACAACC-3’；
F：5’-GGGTGGCAGTGTCTTAGC-3’；R：5’-CAGTGCGTGTCGTGGAGT-3’.
U6 reverse transcriptase primers：5’-GCGCGTGAGCAGGCTGGAGAAATTAACCACGCGCGGAACG-3’；
F：CGCAAGGATGACACG；R：GAGCAGGCTGGAGAA.
Instrument and material that other instruments and material are commonly used in being molecular biology and cytobiology, nothing are important to
Ask.
2nd, experimental technique
1st, cell culture
(1) separation and Culture of BMSC
The healthy male SD rat of 4～6 60～80g of week old weights is taken, neck is taken off and is put to death, under aseptic condition, separate femur and shin
Bone, washes medullary cavity with DMEM culture fluid (Gibco companies of the U.S.), obtains mixed cell suspension.Centrifugation, abandons supernatant, and addition contains
The DMEM of 10% hyclone makes cell suspension, is inoculated in culture bottle, is positioned over 37 DEG C, 5%CO2Culture.48h is changed first
Liquid, it is seen that fusiform cell adherent growth.Liquid is changed per 3d；The form and growing state of daily microscope observation of cell.Cell fusion
During up to 80-90%, Secondary Culture.
(2) glioma U87, glioma U251, glioma C6, the fibroblastic trainings of cancer of pancreas PANC-1 and NIH/3T3
Support：Glioma U87, glioma U251, glioma C6, cancer of pancreas PANC-1 and NIH/3T3 fibroblast are preserved for our company.
By glioma cell, pancreatic cancer cell and fibroblast with the DMEM culture medium culturings containing 10% hyclone, growth shape is taken
The good cell dissociation subpackage of condition is passed on.
2nd, the transfection of BMSC
Took for the 4th generation or BMSC that the 5th generation passed on is transfected.Day before transfection, by the BMSC of exponential phase with 5 ×
104/ 400 μ L are layered in 24 orifice plates；When cell fusion reaches 60-70%, by the lipo3000 (U.S. Invitrogen of 0.75 μ L
Company) it is dissolved in opti-MEM (Gibco companies, the U.S.) of the 200 μ L without serum, gently blow 15 points of even rear incubation at room temperature
Clock；20 μM of 10 μ L of mimics or mimics NC or inhibitor or inhibitor NC are dissolved in into 200 μ L without blood
In clear opti-MEM, gently blow even rear incubation at room temperature 15 minutes；By the opti-MEM containing lipo3000 with contain mimics
Or mimics NC or inhibitor or inhibitor NC opti-MEM mixing, featheriness repeatedly with ensure lipo3000 and
Mimics, mimics NC, inhibitor, inhibitor NC is fully contacted, and incubation at room temperature adds corresponding each after 15 minutes
In the BMSC cells of hole, after being incubated at room temperature 5 hours, the liquid in plate is washed with PBS off, be replaced by the trainings of the DMEM containing 10% hyclone
Foster base continues culture 48 hours.
It is grouped as follows：Blank control group；Mimics groups；Mimics NC groups；Inhibitor groups；Inhibitor NC groups.
Blank control group is the BMSC for not carrying out any process.
3rd, qRT-PCR determines the expression of miR-34a in BMSC after transfection
The total serum IgE of above-mentioned transfectional cell is extracted using Trizol test kits, ultraviolet spectrophotometer surveys A260, A280 value,
Calculate rna content.Reverse transcription is carried out using specificity miR-34a reverse transcription primers and U6 internal references reverse transcription primer.Will be 1 μ g total
RNA reverse transcriptions be cDNA, reverse transcription condition：16 DEG C of 30min, 42 DEG C of 30min, 95 DEG C of 10min.CDNA specimen is placed in -20 DEG C of guarantors
Deposit.Enter performing PCR amplification, reaction condition by template of cDNA：95 DEG C of 3min, 95 DEG C of 15s, 62 DEG C of 40s, totally 40 circulations.With 2-△△CtMethod calculates the relative expression quantity of miR-34a.
4th, Western Blot determine the expression of Notch1 albumen in BMSC after transfection
The each group cell after transfection 48h is taken, is washed with the PBS of pre-cooling 3 times and is sucked residual cleaning mixture as far as possible；Split with RIPA
Solution liquid carries out protein cleavage, with absorbance (A) value at 2000 UV spectrophotometer measuring 260nm, 280nm of NanoDrop,
5 × SDS sample-loading buffers, 95 DEG C of degeneration after mixing are added in the protein supernatant for taking A260/280nm values about 0.55
5min；By 100 μ g proteins applied sample amount Jing 100g/L SDS-PAGE electrophoresis (80V, 20min).Protein is transferred by wet transfer printing
To pvdf membrane；50g/L defatted milk powder solution room temperature closes 2h, adds the anti-human β-actin monoclonal antibodies of Mus (1：3000 dilutions)
And the anti-human Notch1 monoclonal antibodies of Mus (1：1000 dilutions) 4 DEG C be incubated overnight, PBS is washed 3 times, each 10min；Radix Cochleariae officinalises peroxide
The goat anti-mouse IgG (1 of compound enzyme (HRP) labelling：2000 dilutions) incubation at room temperature 2h, PBS washes 3 times, each 15min.Use ECL
The luminous development in luminescent solution darkroom, JS680B gel image analysers collection image, Image J software analysis to calculate Notch1 grey
Angle value/β-actin gray values.
5th, BMSC migrations experiment (Transwell methods)
BMSC migration experiments are carried out using Transwell dual-chamber cultures system, is specifically included：
The 75 μ L of Matrigel (3.9g/L) being initially charged on the polycarbonate membrane of room on the Transwell after dilution, polymerization
Into after gel with the upper and lower room 4h of DMEM balance Transwell.Add in room under Transwell upper obtained by 600 μ L culture 48h
State glioma, cancer of pancreas, fibroblast supernatant；Upper room is with 1 × 105Individual/hole accurately adds 100 μ of DMEM suspensions of BMSC
L.5%CO2After incubator cultivates 24h in 37 DEG C, room liquid is discarded, it is careful to take out upper room, wiped above film not with wet cotton swab
Through the cell of film.Haematoxylin dyeing, rinses rear Clearmont bilaterals mounting well, and 80 DEG C are dried.Observe under inverted microscope
Through the cell number of film.Every film central authorities, peripheral part is each takes 3 visuals field at random, counts in each visual field through the thin of micropore
Born of the same parents' number.
2nd, experimental result
1st, inverted microscope observation mesenchymal stem cells MSCs metamorphosis
Primary cell：When being just inoculated with, majority is rounded, and sharpness of border, light transmission are good, and single spherical is floated in culture bottle.
After inoculation 24h, there is a little attached cell in culture bottle bottom.During 3d, adherent cell gradually deforms, and most is in spindle or shuttle
Shape.During 7d, cell essentially becomes spindle shape, and the visible filament shape synapse of respective cells, this rapid schizogamy of phase cell, quantity are bright
Aobvious to increase, now cell is in the aggregation growth of colony sample.
Passage cell：It is substantially adherent in 24～48h, bottom of bottle can be paved with five or six days, it is neat and orderly.To the 3rd generation or
In 4th generation, was obtained the BMSC that enough, purity is high, growth performance is good.
2nd, the expression of miR-34a after transfecting
Transfection miR-34a inhibitor BMSC cells (inhibitor groups) in miR-34a expressions it is notable under
Adjust, which is as shown in Figure 1 with the relative expression quantity of blank control group and negative control group (inhibitor NC groups)；Transfection miR-
MiR-34a expressions in the BMSC cells (mimics groups) of 34a mimics are significantly raised, itself and blank control group and feminine gender
The relative expression quantity of matched group (mimics NC groups) is as shown in Figure 1.
3rd, the expression of NOTCH1 albumen after transfecting
NOTCH1 expressing quantities in the BMSC cells (inhibitor groups) of transfection miR-34a inhibitor are notable
Raise, which is as shown in Figure 2 with the relative expression quantity of blank control group and negative control group (inhibitor NC groups)；Transfection miR-
NOTCH1 expressing quantities in the BMSC cells (mimics groups) of 34a mimics are significantly lowered, itself and blank control group and the moon
The relative expression quantity of property matched group (mimics NC groups) is as shown in Figure 2.
4th, migrate experimental result (each group migrating cell number)
Compare with blank control group with mimics NC groups, mimics groups mesenchymal stem cells MSCs are thin to three kinds of gliomas
The transfer ability of born of the same parents is substantially reduced；Compare with blank control group with inhibitor NC groups, inhibitor groups medulla mesenchyma is done
Cell is significantly improved to the transfer ability of three kinds of glioma cells.Fig. 3-5 list mimics groups, mimics NC groups,
The ratio of inhibitor groups, inhibitor NC group migrating cell numbers and blank control group migrating cell number.The result proves,
The mesenchymal stem cells MSCs that miR-34a is lowered are moved to glioma U87, glioma U251, the culture supernatant of glioma C6
Shifting trend.But the mesenchymal stem cells MSCs that miR-34a is lowered are to the fibroblastic culture of cancer of pancreas PANC-1 and NIH/3T3
Without obvious migration trend, this proves that the mesenchymal stem cells MSCs that miR-34a is lowered have to the targeting of glioma to supernatant
Specificity, as shown in Figure 6.
Embodiment 2：Impacts of the BMSC of modification to growth of glioma cells
Inventor have studied the mesenchymal stem cells MSCs of miR-34a downwards to glioma U87, glioma U251, colloid
The impact of tumor C6 growth, do not it is found that its growth to glioma cell has facilitation.
The invention demonstrates that after to the miR-34a low expressions of mescenchymal stem cell, mescenchymal stem cell is to glioma U87, glue
Matter tumor U251, the tropism of glioma C6 all strengthen, and targeting increases；After miR-34a low expressions, in NOTCH1 gene expressions
Adjust, NOTCH1 protein contents are significantly raised, it was demonstrated that miR-34a is dry thin to improve mesenchyme by adjusting its target gene NOTCH1
Born of the same parents are to glioma U87, glioma U251, glioma C6 tropism.Suppress miR-34a, raise NOTCH1 genes and albumen table
The medicine for reaching can be used for improving targeting of the mescenchymal stem cell to glioma, and the BMSC of the modification is to glioma cell
Growth can make the glioma targeting vector based on mescenchymal stem cell without facilitation.
Above-mentioned specific embodiment is only used for explanation technical scheme, it will be appreciated by those skilled in the art that, this
Bright protection domain is not limited to above-mentioned specific embodiment.
Claims (10)
1.NOTCH1 genes are being prepared for improving the application in medicine of the mescenchymal stem cell to glioma targeting.
2. application according to claim 1, it is characterised in that：The mescenchymal stem cell is mesenchymal stem cells MSCs.
3. a kind of glioma targeting vector, it is characterised in that：The carrier is through the drug treating mistake described in claim 1 or 2
Mescenchymal stem cell.
4.NOTCH1 albumen is being prepared for improving the application in medicine of the mescenchymal stem cell to glioma targeting.
5. application according to claim 4, it is characterised in that：The mescenchymal stem cell is mesenchymal stem cells MSCs.
6. a kind of glioma targeting vector, it is characterised in that：The carrier is through the drug treating mistake described in claim 4 or 5
Mescenchymal stem cell.
The negative regulation non-coding RNA miR-34a of 7.NOTCH1 genes is being prepared for improving mescenchymal stem cell to glioma
Application in the medicine of targeting.
8. application according to claim 7, it is characterised in that：The mescenchymal stem cell is mesenchymal stem cells MSCs.
9. a kind of glioma targeting vector, it is characterised in that：The carrier is through the drug treating mistake described in claim 7 or 8
Mescenchymal stem cell.
10. the inhibitor of the miR-34a described in claim 7 is answered to glioma targeting for improving mescenchymal stem cell
With.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102958534A (en) * | 2010-01-13 | 2013-03-06 | 昂考梅德药品有限公司 | Notch1 binding agents and methods of use thereof |
| US20160362689A1 (en) * | 2012-08-29 | 2016-12-15 | City Of Hope | Differentially expressed microrna molecules for the treatment and diagnosis of cancer |
-
2017
- 2017-01-20 CN CN201710051710.0A patent/CN106591229A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102958534A (en) * | 2010-01-13 | 2013-03-06 | 昂考梅德药品有限公司 | Notch1 binding agents and methods of use thereof |
| US20160362689A1 (en) * | 2012-08-29 | 2016-12-15 | City Of Hope | Differentially expressed microrna molecules for the treatment and diagnosis of cancer |
Non-Patent Citations (3)
| Title |
|---|
| CLAUDIA J. ET AL.: "《MicroRNA-34a promotes genomic instability by a broad suppression of genome maintenance mechanisms downstream of the oncogene KSHV-vGPCR》", 《ONCOTARGET》 * |
| SACHIN S. RATHOD ET AL.: "《Tumor suppressive miRNA-34a suppresses cell proliferation and tumor growth of glioma stem cells by targeting Akt and Wnt signaling pathways》", 《FEBS OPEN BIO》 * |
| SEONG MUK KIM ET AL.: "《CXC chemokine receptor 1 enhances the ability of human umbilical cord blood derived mesenchymal stem cells to migrate toward gliomas》", 《BIOCHEMICAL AND BIOPHYSICAL RESARCH COMMUNICATION》 * |
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