CN104840976A - MiR125 and use thereof in regulating protooncogene Pokemon expression - Google Patents
MiR125 and use thereof in regulating protooncogene Pokemon expression Download PDFInfo
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Abstract
The invention discloses MiR125 and use thereof in regulating protooncogene Pokemon expression. The MiR125 is taken as a target spot for treating liver cancer; the target spot is used for preparing medicines for treating the liver cancer.
Description
Technical field
The present invention relates to biomedical treatment field, the proto-oncogene Pokemon of particularly miR125 and regulation and control thereof expresses the effect in liver cancer treatment.
Background technology
Although earlier stage cancer patients has carried out radical excision and auxiliary treatment at present, but still has very large recurrence and the risk of transfer.Gene therapy will beyond operation, radiation and chemotherapy, become a kind of new oncotherapy means, especially to the sensitivity improving chemotherapy, radiotherapy, reduce the aspect such as tumor recurrence and transfer and have certain, even even more important effect, become the ingredient that in combined therapy of tumour one is important.The curative effect chosen for gene therapy of target gene plays vital effect.Wherein, proto-oncogene Pokemon is positioned at the upstream of many tumor suppressor genes and proto-oncogene, by ARF-HDM2-p53 and Rb-E2F path, tumor development is regulated, cancerous cell can be made to obtain aging resistance and dead ability, therefore, target gene is it can be used as to contribute to the radical cure of tumor.Pokemon is one of POK transcription inhibitory factor family member, and it comprises an amino terminal POZ/BTB domain and c-terminus Kr ü ppel type zinc finger structure territory, is the important factor of the growth of T lymphocyte, bone-marrow-derived lymphocyte and erythron and maturation.Pokemon gene the tumors such as breast carcinoma, hepatocarcinoma and lymphoma unconventionality expression oncogene transform and tumor generating process in play an important role.Emphasis is that the disappearance of Pokemon gene in cell can not impact the normal growth of cell, and this is that the specific anti-cancer drugs designing low side effect provides possibility.
Microrna (microRNA, or miRNA) is that a class is about 18-25 nucleotide by the length of endogenous gene codes, and noncoding strand small RNA molecular, is extensively present in the middle of eukaryotic cell.MiRNA is not only conservative on the gene location of plant and animal, and gene order also presents very high homology.MiRNA can not be translated into protein, and they participate in the expression of post-transcriptional level regulator gene usually.Ripe miRNA needs to be combined with multiple proteins to form ribonucleoprotein complex if will play a role, silencing complex (RNA-induced silencing complex is induced also referred to as RNA, RISC), this complex can identify the specific region of target gene and combine with it, thus checks the translation of said target mrna.In animal, RISC normally with the 3'UTR(non-coding region of target gene mRNA) combine, and intracellular nuclease can identify this complex, the duplex structure of degraded miRNA and mRNA formation, cause mRNA normally cannot translate protein, thus realize the regulation and control to gene expression.A series of research shows, the propagation of miRNA and cell and break up closely related, in each physiological function of body, as cancer, aging, metabolism, cell differentiation etc., play important regulating action, have profound significance for rationale and practical application.
MiR-125 is one of miRNA family member.As far back as 2007, the people such as Scott just found that miR-125 is as the miRNA of potential suppression breast carcinoma, can suppress the expression of ERBB2 and ERBB3, thus reach the object suppressing Cells Proliferation of Human Breast Cancer and transfer in breast cancer cell.And then miR-125 can suppress the expression of HuR to carry out antiproliferative effect in breast carcinoma to have again research group to report.EGFR can by the transfer regulating the expression of miR-125 to suppress pulmonary carcinoma.Soon, find that miR-125 is by targeting ERBB2, inhibits the propagation of stomach cancer cell at a research group of Japan.There are some researches show again that miR-125 can infect HBV virus transcription recently, lower the expression of surface antigen.Recent domestic scholars is studied the expression of miR-125 in hepatocarcinoma, finds that miR-125 is low expression in liver cancer tissue, and miR-125a suppresses propagation and the transfer of hepatoma carcinoma cell by targeting MMP11 and VEGF.The low expression of miR-125a in another discovery hepatoma Hep G 2 cells, and process LAN miR-125a can Inhibit proliferaton, apoptosis-induced and G0/G1 phase cell block, may play the effect of antioncogene in the developing of hepatocarcinoma.
The prompting of the present factor complicated for possibility numerous in onset of liver cancer process and concrete molecular mechanism wherein is also nowhere near, in view of Pokemon is as the importance of target gene, there is not been reported whether to participate in the expression of Pokemon for miR-125, and the acquisition of this experimental result will provide important guiding for the exploitation of hepatocarcinoma new drug.
Summary of the invention
The technical problem to be solved in the present invention is to provide the purposes of proto-oncogene Pokemon expression at the target spot as Hepatoma therapy of miR125 and regulation and control thereof.
In order to solve the problems of the technologies described above, the purposes that the proto-oncogene Pokemon that the invention provides miR125 and regulation and control thereof expresses: as the target spot of Hepatoma therapy.
Improvement as the purposes that the proto-oncogene Pokemon of miR125 of the present invention and regulation and control thereof expresses: utilize this target spot to prepare the medicine of Hepatoma therapy.
In the present invention: tested by luciferase reporter gene, we find 3 ' the UTR(noncoding region of miR-125 energy and Pokemon) regiospecificity combination, thus suppress its fluorescence activity.Further by real-time fluorescence quantitative PCR and immunoblot experiment (Western blot) research, we find that miR-125 can suppress the mRNA of Pokemon and the expression of albumen, prompting miR-125 is the expression being regulated and controled this target gene by the mRNA level of the Pokemon that degrades.Remove by building specificity 3 ' the UTR genetic fragment that miR-125 may act on Pokemon, we find that miR-125 can not suppress it active, and prompting miR-125 specificity combines with 3 ' the UTR region of Pokemon and plays a role.After endogenous expression by siRNA special suppression Pokemon, significantly reduce the multiplication capacity that the body of hepatoma carcinoma cell is interior and external.Above-mentioned experiment confirms that miR-125 can suppress the expression of its downstream target gene Pokemon, thus inhibits the vivo and vitro of hepatoma carcinoma cell to breed, and then reaches the object of Hepatoma therapy.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, the specific embodiment of the present invention is described in further detail.
Fig. 1 is luciferase reporter gene experimental verification Pokemon is the target gene of miR-125.
In Fig. 1, pMIR-report represents vehicle Control group, miR125+pMIR-3 ' UTR represents the Reporter gene vector transfection stably express miR-125 hepatoma carcinoma cell group of 3 ' UTR fragment of the miR125 action target spot containing Pokemon gene mRNA, and miRcontrol+pMIR-3 ' UTR represents the Reporter gene vector transfection control hepatoma carcinoma cell group of the miR-125 binding site of the 3 ' UTR containing Pokemon gene mRNA.
Fig. 2 is that luciferase reporter gene prompting miR-125 specific effect is in 3 ' the UTR seed region of Pokemon.
In Fig. 2, pMIR-report group, miR125+pMIR-3 ' UTR group are all identical with Fig. 1 with miRcontrol+pMIR-3 ' UTR group, and miR125+pMIR-3 ' UTR-D represents that specificity removes 3 ' the UTR vehicle group of the Pokemon of miR-125 seed region.
Fig. 3 is the mRNA level in-site that realtime fluorescent quantitative PCR experiment prompting miR-125 can lower Pokemon.
In Fig. 3, HepG2-125 represents the HepG2 groups of cells of stably express miR-125, and HepG2-NC represents matched group.
Fig. 4 is the target gene that western blot tests that prompting Pokemon is miR-125.
In Fig. 4, HepG2-125 represents the HepG2 groups of cells of stably express miR-125, and HepG2-NC represents matched group.
Detailed description of the invention
embodiment 1: the two fluorescent reporter gene carriers building Pokemon gene
Test kit (Gibco company) is used to extract hepatoma carcinoma cell total serum IgE, synthetic cell cDNA.Concrete operation method refers to test kit description.Build 3 ' UTR fragment of the miR125 action target spot containing Pokemon gene mRNA, design specific primer sequences, forward primer sequence is: 5'-GGTCGCAGAAGGTGGAGA-3', and downstream primer sequence is: 5'-GGTCGTAGTTGTGGGCAAA-3'.PCR reaction system is set to 25 μ L, wherein template 1 μ L, dNTP mix 12.5 μ L, forward primer and downstream primer (20 μm of ol/l) each 0.5 μ L, ddH
2o 10.5 μ L.PCR response parameter is 94 DEG C of denaturation 2 min, 94 DEG C of degeneration 30 s, and 55 DEG C of annealing 30 s, 72 DEG C extend 60 s, 30 circulations.This PCR fragment is cloned into luciferase reporter gene carrier pMIR-REPORT, enzyme action is identified, and confirms that Product Sequence is correct through order-checking.
embodiment 2: the structure stablizing the hepatoma cell line of process LAN miR-125
According to the cDNA sequence of the people source miR125 included in Genebank and Xho I (5 '), the Eco for the required introducing of clone
ri (3 ') two restriction enzyme sites, design upstream and downstream two primers: miR125 forward primer sequence: 5 '-CTATGTTTGAATGAGGCTTCAG-3 '; MiR125 downstream primer sequence: 5 '-CGCGTCGCCGCGTGTTTAAACG-3 '.Performing PCR reacts, and PCR reaction system with embodiment 1, PCR reaction condition is: 94 DEG C of denaturation 5 min, 94 DEG C of degeneration 30 s, and 55 DEG C of annealing 30 s, 72 DEG C extend 60 s, 30 circulations.Utilize Xho I, Eco
ri enzyme action object fragment and pEGFP-N3 carrier carry out enzyme action and are connected, and order-checking confirms that product pEGFP-miR125 sequence is correct.PEGFP-miR125 and the pEGFP-N3 empty plasmid transfection built spread in the HepG2 cell of 6 orifice plates to prior by liposome Lipofectamine2000 transfection, concrete transfection method is shown in transfection reagent description.Within first week, select 700 μ g/ml G418 high pressure screening cells, after cell mortality, use 350 μ g/ml G418 instead maintain screening, through the lasting screening of month, obtain stable process LAN miR125 monoclonal cell strain.
embodiment 3: two fluorescent reporter gene experimental verification Pokemon are target genes of miR125
To stablize the hepatoma cell line HepG2-miR125 of process LAN miR-125 or HepG2 compared with control cells according to 1.5 × 10
5/ hole is inoculated into 24 orifice plates, cultivates 24h; With Lipofectamine2000 reagent, pMIR-Pokemon-3 ' UTR or pMIR-control empty carrier are entered HepG2-miR125 or HepG2-control cell with control plasmid pRL-TK cotransfection respectively; After transfection 48h, suck cells and supernatant, and wash 1 time with PBS; Every hole adds 200 μ L cell pyrolysis liquids, the centrifugal 10min of 12,000 rpm; Get cleer and peaceful Luciferase Assay Reagent II (Luciferase Assay Reagent II on 20 μ L, LAR II) 100 μ L mix, LUC Photinus pyralis LUC Photinus pyralis FL is detected active at TD-20/20 fluorescence radiation meter, be recorded as the first reading, then add 100 μ L Stop & Glo reagent, after fully mixing in 10 min, second time detects reading and detects renilla luciferase activity; Result represents relative to the ratio of renilla luciferase activity with LUC Photinus pyralis LUC Photinus pyralis FL activity, and analyzes.
The hepatoma carcinoma cell of result display Reporter gene vector pMIR-Pokemon-3 ' UTR transfection stably express miR-125, cell fluorescence element enzymatic activity significantly reduces (p<0.05) (Fig. 1) compared with the hepatoma carcinoma cell of carrier transfection expression contrast miRNA.Result shows that Pokemon is the target gene of miR-125, and miR-125 carries out negative regulation by the target site of 3 ' UTR of Pokemon gene mRNA to its expression.
embodiment 4: the seed region of two fluorescent reporter gene experimental verification miR125
In order to determine that miR-125 is played a role by the seed region of the 3 ' UTR acting on Pokemon mRNA further, we design primer, construct specificity remove 3 ' the UTR carrier that miR-125 may act on the Pokemon of seed region by PCR.PCR primer sequence is as follows: forward primer sequence is: 5'-GCACACTGAACGTCAAGA-3', and downstream primer sequence is: 5'-CGTAGTAGTACTCTGTAGA-3'.PCR reaction system and response parameter detailed in Example 1.Luciferase reporter gene experiment concrete grammar detailed in Example 3.Proved by luciferase reporter gene experiment, after eliminating the seed region of miR-125 effect, fluorescence activity there is no change (Fig. 2), and prompting miR-125 plays a role by acting on the seed region of the 3 ' UTR of Pokemon.
embodiment 5: real-time fluorescence quantitative PCR checking Pokemon is miR125 target gene
MiRNA is generally 3 ' UTR incomplete pairing, the mRNA of degraded target gene or hinder it to transcribe and reach and regulate the protein expression level of target gene, and play the effect regulating cell-signaling pathways by the mRNA with target gene.We have detected the change of the mRNA level in-site of Pokemon target gene further by real-time fluorescence quantitative PCR.Illustrate according to PCR kit and amplification instrument, adopt 50 μ L reaction systems: cDNA 5 μ L, 2 × PCR Master 25 μ L, 25 mmol/l MgCl
22 μ L, Pokemon forward primer (10 μm of ol/l) 2 μ L, Pokemon downstream primer (10 μm of ol/l) 2 μ L.β-actin forward primer (10 μm of ol/l) 2 μ L, β-actin downstream primer (10 μm of ol/l) 2 μ L, ddH
2o 10 μ L.Reaction condition: denaturation 94 DEG C of 5 min; 94 DEG C of 1 min, 56 DEG C of 50 s, 72 DEG C of 1 min totally 30 circulation; 72 DEG C extend 10 min, 4 DEG C of insulation 30 min.
The mRNA level in-site of result prompting Pokemon significantly lowers (Fig. 3) in the HepG2 cell of stably express miR-125, and prompting miR-125, by combining with the 3 ' UTR of Pokemon, degrades the mRNA level of target gene.
it is miR125 target gene that embodiment 6:Western Blot detects checking Pokemon further
Collect the HepG2 cell of stably express miR-125, with PBS washed cell 2 times, then add 100 μ L cell pyrolysis liquid cell lysis, boiling water boiling 5 min, in centrifugal 10 min of 12000 rpm 4 DEG C, gets supernatant and measures protein concentration, every hole loading 50 μ g total protein, run glue with 10 % polyacrylamide gel to be separated, turn pvdf membrane, use primary antibodie in 4 DEG C of overnight incubation, wash film, use two anti-room temperature labelling 1 h, DAB method develops the color, and takes a picture or scanning preservation.With β-actin for internal reference.
Tested by Western Blot, have detected the expression of Pokemon at protein level further, find when miR-125 process LAN, the expression (Fig. 4) of Pokemon can be suppressed.
the structure of embodiment 7:Pokemon specific siRNA
Lower the expression of Pokemon in the developing effect of hepatocarcinoma to study further, we are specific siRNA for Pokemon gene design, positive-sense strand: 5 '-CUCGCUGGUUUCUAUGAGUUU-3'; Antisense strand: 3'-UUGAGCGACCAAAGAUACUCA-5'.The HepG2 cell being in exponential phase is carried out trypsinization, and (cell number is about 5 × 10 to make cell suspension
4/ ml) be inoculated in 6 orifice plates, be cultured to cell fusion degree and reach about 40% and namely can be used for transfection.Be dissolved in by siRNA dry powder in the sterilized water without RNA enzyme, configuration final concentration is the siRNA solution of 20pmol/L.During transfection, the lipofectamine2000 of the siRNA solution and 5 μ L of getting 10 μ L is respectively diluted in 250 μ L serum-free mediums (Opti-MEM) respectively, and at room temperature hatch 5 min, then by above-mentioned siRNA solution and the mixing of lipofectamine2000 solution, after complex and left at room temperature 20 min, after the siRNA-liposome complex of 500 μ L is mixed with 1.5 mL plasma-free DMEM medium, be added in Tissue Culture Plate, be changed to 10% FBS-DMEM culture medium after 6 h, after 48 h, collecting cell carries out RT-PCR detection.Result shows that the relative intensity of the mrna expression of cellular control unit is 0.729, and the relative intensity of the mrna expression of siRNA transfection group is 0.597, suppression ratio significant difference (
p<0.05), illustrate that this siRNA successfully can lower the mRNA level in-site of target gene.
embodiment 8: the expression lowering endogenous Pokemon can suppress the propagation of hepatoma carcinoma cell
The HepG2 cell being in exponential phase is inoculated in 24 orifice plates, is cultured to cell fusion degree and reaches about 40%, carry out cell transfecting (transfection procedure is with reference to embodiment 2).In 37 DEG C after transfection, 5% CO
2cultivate 24 h under condition, before end, 4h adds MTT 10 μ L/ hole (concentration is 5mg/mL), and abandon supernatant after continuing to cultivate 4h, add dimethyl sulfoxide (DMSO) 100 μ L/ hole, on agitator, shake about 10min, microplate reader 490nm detects OD value.Using transfection, the HepG2 cell of negative control siRNA is as negative control, not add the HepG2 cell of any siRNA process as blank, and inhibitory rate of cell growth=(negative control group A value-transfection group A value)/negative control group A value × 100%.Result shows, and compared with transfection negative control siRNA group, after transfection POKEMON-siRNA, HepG2 cell proliferation rate significantly reduces, and the growth inhibition ratio of HepG2 cell is 16.5%.By MTT experiment, we find that downward Pokemon can suppress the multiplication capacity of hepatoma carcinoma cell, further illustrate, and miR-125 inhibits the propagation of hepatoma carcinoma cell by regulation and control Pokemon.
embodiment 9: the expression lowering endogenous Pokemon can suppress the tumor growth of tumor bearing nude mice
Select 5-6 SPF level female BAl BIc/c nude mice in age in week, after cell trypsinization is become single cell suspension, carry out cell counting, suspend 3 × 10 with the culture fluid of 0.4 mL
6cell, with disposable syringe, pallium cell injection is subcutaneous to the right axil of nude mice.When Subcutaneous tumor is grown to enough large, by its aseptic taking-up, in normal saline, be cut into the tumor mass of 2 × 2 mm sizes.With the trocar, tumor block is transplanted to oxter on the right side of nude mice, when tumor block diameter about 4 mm, nude mice is divided into 2 groups at random, blank group and siRNA group, often organize 6.Adopt intratumor injection, dosage is 40 μ g/, adopts microsyringe injection, injects 1 time every 3 d, altogether administration 7 times.By the size of vernier caliper measurement tumor block, according to formula ab
2/ 2 calculate tumor block amasss, and a is major diameter, and b is minor axis.28th d takes off cervical vertebra and puts to death animal, cuts off local skin, blunt separation Chu Liu soma, scales/electronic balance weighing, calculates average tumor and weigh and tumor control rate in units of group.Tumor control rate=(C-T)/C × 100%.The average tumor weight of C=matched group; The average tumor weight of T=administration group.
Result shows, and this tumor control rate of testing siRNA used is 36.01%.Further illustrate, miR-125 inhibits the multiplication capacity of hepatoma carcinoma cell in nude mouse by regulation and control Pokemon.
What finally illustrate is, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although by referring to the preferred embodiments of the present invention, invention has been described, but those of ordinary skill in the art is to be understood that, various change can be made to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.
Claims (2)
1.MiR125 and regulation and control proto-oncogene Pokemon express purposes, it is characterized in that: as the target spot of Hepatoma therapy.
2. the purposes of the proto-oncogene Pokemon expression of the miR125 according to claims 1 and regulation and control thereof, is characterized in that: utilize described target spot to prepare the medicine of Hepatoma therapy.
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