CN109022587A - A kind of miRNA marker and its application of acute myeloid leukemia - Google Patents
A kind of miRNA marker and its application of acute myeloid leukemia Download PDFInfo
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- CN109022587A CN109022587A CN201811065645.8A CN201811065645A CN109022587A CN 109022587 A CN109022587 A CN 109022587A CN 201811065645 A CN201811065645 A CN 201811065645A CN 109022587 A CN109022587 A CN 109022587A
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/178—Oligonucleotides characterized by their use miRNA, siRNA or ncRNA
Abstract
The invention discloses a kind of miRNA marker of acute myeloid leukemia and its applications.MiRNA-146 is preparing the application in acute myeloid leukemia auxiliary diagnostic as the miRNA marker of detection acute myeloid leukemia.Primer, probe or the genetic chip of detection miRNA-146 is preparing the application in acute myeloid leukemia auxiliary diagnostic.Downstream primer shown in the primer of the detection the miRNA-146 preferably upstream primer shown in SEQ ID NO.1 and SEQ ID NO.2 forms.Present invention firstly discovers that the generation of miRNA-146 expression and AML have correlation, by the expression for detecting subject miRNA-146, it may determine that whether subject suffers from AML, to make patient that can take corresponding prevention and treatment measure in illness early stage.
Description
Technical field
The invention belongs to field of biological detection, are related to the miRNA marker and its application of a kind of acute myeloid leukemia.
Background technique
Leukaemia (leukemia) is a kind of candidate stem cell malignant clone disease, can be divided into according to the emergency of onset
Slowly, acute leukemia.Chronic leukemia cell differentiation is preferable, develops slowly, the course of disease several years, and acute leukemia (acute
Leukemia, AL) cell differentiation is stuck in early stage, and disease is quickly grown, the course of disease several months.If acute leukemia without
Special treatment, life cycle are averagely only 3 months, short then dead even after diagnosing a couple of days.By modern treatment, have many suffer from
Person's disease amelioration is so that long-term surviving.AL can be divided into acute myeloid leukemia (acute myeloid leukemia, AML) and
Acute lymphoblastic leukemia (acute lymphocytic leukemia, ALL) two major classes, disease incidence point of the two in China
It Yue Wei 16.2% and 6.9%.AML is a quasi-leukemia most commonly seen in adult, by candidate stem cell in atomization
Proliferation out of control, dysdifferentiation, apoptosis, which are obstructed, to be caused caused by cell development retardance.At present not yet about the pathogenesis of AML
It illustrates completely, it has been found that several microRNA can induce DNA mutation, with the accumulation of mutation candidate stem cell, so as to cause AML
Occur.With progress of research, constantly discover new mechanism and target spot, for AML diagnosis and treatment provide preferably according to and
Scheme.
MicroRNA (miRNA) is the single-stranded microRNA of endogenous that a kind of size is 19-22 nucleotide, by with
Said target mrna 3'-UTR complementary pairing combines, and expresses in post-transcriptional level controlling gene, wide participation cell Proliferation, differentiation, apoptosis
Various physiological processes regulation.MiRNA becomes research hotspot in recent years, in the early clinical diagnosis of tumour, treatment and pre-
It plays an important role in terms of progress assessment afterwards.A large number of studies show that the unconventionality expression of miRNA participates in the generation and development of AML, example
Such as, the promoter region generation methylation of miRNA-370 can be such that its expression lowers in AML, to induce cell Proliferation；
MiRNA-155 activates P13K/AKT signal path so as to cause the generation of AML by targeting SHIPI；MiRNA-126 by with
AML/ETO fusion can play the survival activity that collaboration inhibits and can improve cell to AML Apoptosis；miRNA-
223 be combined with each other with transcription factor E2F 1, are able to suppress the proliferation of Meloid progenitor, and promote its differentiation.
The unconventionality expression of miRNA directly results in some and disease related gene unconventionality expression, thus the hair of induced tumor
It is raw, so the expression of detection miRNA can provide certain reference for the clinical diagnosis of tumour.Proof has been reported
MiRNA can be played an important role in AML by the expression of regulation target gene mRNA.Clinical conditions afterwards
In, miRNA can not only become the new marker of AML early diagnosis, but also can be controlled by changing the expression of certain miRNA
Treat AML.Therefore identify that the relevant miRNA of generation to AML can provide certain basis for the clinical treatment of AML.
In order to make up for the deficiencies of the prior art, the answering in AML diagnosing and treating it is an object of the invention to provide miRNA-146
With.Compared to traditional diagnostic method, AML is diagnosed using miRNA with more timeliness and sensitivity, to make patient in illness
Early stage can take corresponding prevention and treatment measure.
Summary of the invention
The purpose of the present invention is being directed to the above-mentioned deficiency of the prior art, a kind of miRNA mark of acute myeloid leukemia is provided
Will object.
It is a further object of the present invention to provide the reagents for detecting the miRNA.
It is yet another object of the invention to provide the applications of the miRNA marker and its reagent.
The purpose of this law people can be achieved through the following technical solutions:
MiRNA-146 is preparing acute myeloid leukemia auxiliary as the miRNA marker of detection acute myeloid leukemia
Application in diagnostic reagent.
Primer, probe or the genetic chip of miRNA-146 are detected in preparing acute myeloid leukemia auxiliary diagnostic
Application.
The primer preferably upstream primer as shown in SEQ ID NO.1 and SEQ ID NO.2 of the detection miRNA-146
Shown in downstream primer composition.
A kind of primer being used to prepare Diagnosing Acute Myeloid Leukemia reagent, the upstream primer as shown in SEQ ID NO.1
It is formed with downstream primer shown in SEQ ID NO.2.
A kind of acute myeloid leukemia auxiliary diagnostic box, including above-mentioned primer.
The kit further preferably further includes other the routinely examinations for detecting the primer and qPCR of reference gene U6
Agent.
MiRNA-146 as acute myeloid leukemia therapy target preparation treatment acute myeloid leukemia drug in
Application.
The utility model has the advantages that
Present invention firstly discovers that the generation of miRNA-146 expression and AML have correlation, pass through detection subject
The expression of miRNA-146, it can be determined that whether subject suffers from AML, to make patient that can take phase in illness early stage
The prevention and treatment measure answered.MiRNA-146 provided by the invention as AML clinical detection auxiliary diagnosis marker it is superior
Property be that easy to operate, at low cost, detection is accurate, be suitble to Clinical screening.Compared to traditional diagnostic method, examined using miRNA
Disconnected AML has more timeliness and sensitivity, to make patient that can take corresponding prevention and treatment measure in illness early stage.
Detailed description of the invention
The relative expression's situation of Fig. 1 miRNA-146 in blood
Relative expression situation of Fig. 2 miRNA-146 in AML cell line
The inhibiting effect that Fig. 3 anti-miRNA-146 expresses miRNA-146
Specific embodiment
Embodiment 1 screens miRNA relevant to AML
1, sample acquisition
Collect AML blood sample and each 10, healthy human blood's sample.
2, the extraction of sample total serum IgE
Total serum IgE is extracted using BLOG RNA Blood Isolate Kit, according to kit specification concrete operation step
It is as follows:
(1) in the 1.5mL centrifuge tube for taking 200 μ L to RNAase Free of defrosting blood, 1mL combination liquid is added, concussion mixes
Afterwards, it is placed at room temperature for 5min；
(2) 5000rpm is centrifuged 3min, abandons supernatant, and 200 μ L of lysate is added, and mixes, and 200 μ L of digestive juice is added, and concussion is mixed
After even, 56 DEG C of water-bath 10min make cell cracking, are added and 500 μ L of liquid is precipitated, be gently mixed by inversion；
(3) mixed liquor in previous step is transferred in the collecting pipe including being placed with adsorption column, stand 2min, 12000rpm from
Heart 1min outwells the waste liquid in collecting pipe；
(4) adsorption column is put back in collecting pipe, 500 μ L cleaning solutions is added into adsorption column, 12000rpm is centrifuged 1min,
Fall the waste liquid in collecting pipe；
(5) adsorption column is put back in collecting pipe, 12000rpm is centrifuged 2min, outwells the waste liquid in collecting pipe；
(6) adsorption column taking-up is put into the 1.5mL centrifuge tube of new RNAase Free, 30-50 μ L eluent is added,
It is stored at room temperature 3-5min；
(7) 12000rpm is centrifuged 2min, collects RNA solution, saves backup under the conditions of -80 DEG C.
3, the quality testing of RNA sample
The RNA for taking 1 μ L to extract with 1% agarose gel electrophoresis detection, and with Nanodrop2000 (Thermo
Scientific) detectable concentration, when 260/280 ratio is 2.0, RNA purity is 100%, and 260/280 ratio is in 1.8-2.0
Between, RNA purity can be used for reverse transcription close to 80-90%.
4, the extraction of miRNA, label and chip operation
(1) miRNA is obtained using the miRNAs extraction agent box of Ambion company, concrete operations are according to kit specification
It is operated, according to the method for Thomson, sample carries out fluorescent marker with T4RNA connection labelling method, then with anhydrous second
Alcohol precipitating, is used for chip hybridization after drying；
(2) RNA is dissolved in 16 μ L hybridization solutions, 42 DEG C of hybridized overnights；
(3) 4min is cleaned in (containing 2 × SSC, 0.2%SDS) 42 DEG C of mixed liquors；
(4) room temperature cleans 4min in (0.2 × SSC) liquid, dries；
(5) detection miRNA table is carried out with the instruction of miRNA chip of expression spectrum (Boao Biological Co., Ltd) to specifications
Up to spectrum.
5, result:
Analyze the testing result of miRNA chip expression spectrum, it is known that blood and AML patient blood of the miRNA-146 in Healthy People
There are significant differences in liquid, and the level of miRNA-146 is significant compared with the blood of Healthy People, in the blood of AML patient increases (about
6 times)
The differential expression of 2 qPCR of embodiment verifying miRNA-146
1, sample acquisition
According to the testing result of miRNA chip, miRNA-146 is selected to carry out the qPCR verifying of large sample.According to embodiment 1
In sample acquisition mode, collect AML blood sample and each 40, healthy human blood's sample.
2, the extraction of sample total serum IgE
Operating procedure is the same as embodiment 1.
3, the synthesis of cDNA
According toRT reagent Kit (TaKaRa) reverse transcription reagent box is operated, reaction system,
It is as follows:
Reagent in system is added in the centrifuge tube of the RNase Free of 200 μ L, and is placed in PCR instrument and is arranged and starts
Response procedures synthesize cDNA, and response procedures are 70 DEG C of 10min；42℃60min；72℃10min；16 DEG C of 10min, the cDNA of synthesis
It is saved backup under the conditions of -20 DEG C.
4、qPCR
4.1 primer
4.2 reaction system
QPCR reaction solution is configured in eight connecting legs according to the reaction system of upper table, three repetitions are arranged in each sample.By eight
QPCR reaction solution in connecting leg is placed in after uniformly mixing centrifugation and is arranged on real-time fluorescence PCR instrument and starts response procedures.Reaction
Program are as follows:
Pass through 2-△△CtMethod calculate miRNA-146 using U6 as the numerical value of the relative expression levels of internal reference.
5, result
As shown in Figure 1, the expression of miRNA-146 significantly rises in the blood of AML patient compared with the blood of Healthy People
Height, it is consistent with miRNA chip results in embodiment 1.
Expression of 3 miRNA-146 of embodiment in AML cell line
1, cell culture
The bone marrow mononuclear cells and AML cell strain U937, HL-60, NB4 that separate from Healthy People and AML patient are used
RPMI1640 culture medium containing 10% fetal calf serum carries out routine culture, place in 37 DEG C of incubators.
2, the extraction of cell total rna
Cell total rna is extracted using RNA extracts kit (QIAGEN), concrete operation step carries out to specifications.
3, the synthesis of cDNA
Operating procedure is the same as embodiment 2.
4、qPCR
Operating procedure is the same as embodiment 2.
5, result
As shown in Fig. 2, compared with Healthy People bone marrow mononuclear cells, miRNA-146 AML cell strain U937, HL-60,
Expression in the bone marrow mononuclear cells separated in NB4 and AML patient is significantly raised (P < 0.05).
Influence of 4 miRNA-146 of embodiment to AML ability of cell proliferation
1, design synthesis is directed to the antisense oligonucleotides (anti-miRNA-146) of miRNA-146
Go out its specific antisense oligo anti-miRNA-146 and random right according to the sequence design of miRNA-146
According to sequence.
Anti-miRNA-146:5 '-ACGATGACAGAGATATCCC-3 ' (SEQ ID NO.5)
Random controls sequence: 5 '-TCATACTA-3 '
2, cell culture
HL-60 cell culture processes are the same as embodiment 3
3, cell transfecting
HL-60 cell is divided into two groups, miRNA-146 inhibition group (anti-miRNA-146) and inhibits negative control group
(anti-NC).Inhibition group and negative control group are transfected into anti-miRNA-146 and anti-NC respectively, used
Lipofectamine TM2000 (Invitrogen) are referring to specification.The working concentration of anti-miRNA-146 and anti-NC
It is 5 μM.Two groups of cells are collected after 48h, are used for subsequent experimental.
4, the extraction of cell total rna
Operating procedure is the same as embodiment 3.
5, the synthesis of cDNA
Operating procedure is the same as embodiment 2.
6、qPCR
Operating procedure is the same as embodiment 2.
As a result as shown in figure 3, compared with inhibiting negative control group (anti-NC), miRNA-146 inhibition group (anti-
MiRNA-146 the level of miRNA-146) is remarkably decreased, and shows that anti-miRNA-146 can effectively inhibit miRNA-146's
Expression.
7, cell proliferation experiment
The HL-60 cell for transfecting 48h is digested to cell suspension using 0.25% pancreatin, with 5 × 104A/mL is inoculated in
96 porocyte culture plates, after every hole 0.1mL, 1h, mtt assay measures each hole 490nm wavelength absorbance value.With absorbance value size generation
The relative populations of table living cells.
8, result
MiRNA-146 inhibition group (anti-miRNA-146) relative optical density number is 0.325 ± 0.036, inhibits negative right
Relative optical density number according to group (anti-NC) is 1.635 ± 0.113.Compared with inhibiting negative control group (anti-NC),
The absorbance value of miRNA-146 inhibition group (anti-miRNA-146) is remarkably decreased (P < 0.05).It is above-mentioned the experimental results showed that
Anti-miRNA-146 can significantly inhibit HL-60 ability of cell proliferation, while show that miRNA-146 is conducive to HL-60 cell
Proliferation.
Sequence table
<110>Nanjing Qiu Zhen Gene Tech. Company Limited
<120>miRNA marker and its application of a kind of acute myeloid leukemia
<160> 5
<170> SIPOSequenceListing 1.0
<210> 1
<211> 19
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 1
tgagaactga attccatgg 19
<210> 2
<211> 19
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 2
agaactgaat tccatggtt 19
<210> 3
<211> 20
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 3
tgcgggtgct cgcttcggca 20
<210> 4
<211> 20
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 4
aacgcttcac gaatttgcgt 20
<210> 5
<211> 19
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 5
acgatgacag agatatccc 19
Claims (7)
1.miRNA-146 as detection acute myeloid leukemia miRNA marker prepare acute myeloid leukemia auxiliary examine
Application in disconnected reagent.
2. detecting primer, probe or the genetic chip of miRNA-146 in preparing acute myeloid leukemia auxiliary diagnostic
Using.
3. application according to claim 2, it is characterised in that the primer of the detection miRNA-146 is by SEQ ID
The composition of downstream primer shown in upstream primer shown in NO.1 and SEQ ID NO.2.
4. a kind of primer for being used to prepare Diagnosing Acute Myeloid Leukemia reagent, it is characterised in that as shown in SEQ ID NO.1
The composition of downstream primer shown in upstream primer and SEQ ID NO.2.
5. a kind of acute myeloid leukemia auxiliary diagnostic box, it is characterised in that including primer as claimed in claim 4.
6. kit according to claim 5, it is characterised in that further include the primer and qPCR for detecting reference gene U6
Other conventional reagents.
7.miRNA-146 as acute myeloid leukemia therapy target preparation treatment acute myeloid leukemia drug in
Using.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008073915A2 (en) * | 2006-12-08 | 2008-06-19 | Asuragen, Inc. | Micrornas differentially expressed in leukemia and uses thereof |
| CN101842484A (en) * | 2007-09-14 | 2010-09-22 | 俄亥俄州立大学研究基金会 | Mirna expression in human peripheral blood microvesicles and uses thereof |
| CN102007408A (en) * | 2008-02-28 | 2011-04-06 | 俄亥俄州立大学研究基金会 | Microrna signatures associated with cytogenetics and prognosis in acute myeloid leukemia (aml) and uses thereof |
-
2018
- 2018-09-13 CN CN201811065645.8A patent/CN109022587B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008073915A2 (en) * | 2006-12-08 | 2008-06-19 | Asuragen, Inc. | Micrornas differentially expressed in leukemia and uses thereof |
| CN101842484A (en) * | 2007-09-14 | 2010-09-22 | 俄亥俄州立大学研究基金会 | Mirna expression in human peripheral blood microvesicles and uses thereof |
| CN102007408A (en) * | 2008-02-28 | 2011-04-06 | 俄亥俄州立大学研究基金会 | Microrna signatures associated with cytogenetics and prognosis in acute myeloid leukemia (aml) and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| XIN LI ET AL: "Upregulated microRNA-146a expression induced by granulocyte colony-stimulating factor enhanced low-dosage chemotherapy response in aged acute myeloid leukemia patients", 《EXPERIMENTAL HEMATOLOGY》 * |
| 罗学群等: "儿童急性粒细胞白血病及其亚型的微小RNA表达", 《中华肿瘤杂质》 * |
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