CN108085392A - Biomarker of ovarian epithelial carcinoma and application thereof - Google Patents
Biomarker of ovarian epithelial carcinoma and application thereof Download PDFInfo
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Abstract
Biomarker the present invention provides ovarian epithelial carcinoma and application thereof.Combination the present invention provides following miRNA is for studying and detect the method for ovarian epithelial carcinoma：Hsa miR 34b, hsa miR 335, hsa miR 136, hsa let 7e, hsa miR 1297, hsa miR 374b and hsa miR 891b.The present invention also provides the kits and device for the research and the method for detection ovarian epithelial carcinoma.
Description
Technical field
The present invention relates to molecular biology and reagent for disease diagnosis preparation field.Specifically, the present invention relates to epithelial ovum
The biomarker of the miRNA and mRNA groups of nest cancer and its method for being used to study ovarian epithelial carcinoma and the mark
Object prepare for diagnose or detect ovarian epithelial carcinoma kit application.
Background technology
Ovarian epithelial carcinoma (EOC) is the most common gynecologic malignant tumor of women, account for malignant tumor of ovary nearly 90% [1,
2].During diagnosis, there is the late period of disease in Most patients (75%), and almost all of people experienced tumor recurrence [3,4].
About 10% is due to familial/genetic predisposition, mainly due in BRCA1 and BRCA2 in oophoroma case
The mutation of mismatch repair gene, but its genetic mechanism still needs to further study.Several genome-wide association studies (GWAS) have existed
It is carried out in oophoroma, it has been found that some risks and assumptions, such as the rs3814113 on 9p22.2, the rs2072590 on 2q31
It is right, the rs2665390 on 3q25, the rs10088218 on 8q24, rs1516982, rs10098821 and on 19p13
rs2363956[6,7].However, the functional meaning of these risk variables is largely unknown.
Microrna is by hybridizing with mRNA (mRNA) target and triggering to its Translational repression or less typically draw
Its non-coding RNA for controlling one kind of gene expression small of degrading.The discovery and research of miRNA have revealed that in biological development and
The gene tune of the miRNA mediations to play a significant role in various cell processes such as cell differentiation, cell growth and cell death
Control mechanism.Recent studies indicate that the unconventionality expression of specific miRNA may participate in the disease of people, such as neurological disorder and cancer.
The expression variation of microRNA (miRNA) influences the expression of miRNA target genes, and then causes the difference of phenotype, including cancer
Neurological susceptibility [7].The risk allele of oophoroma can be improved to the integration of the analysis of the miRNA and gene expression difference of patient
Functional meaning understanding and innovation analysis method come identify in these miRNA replace traditional standard variance and recurrence
Application in analysis would be possible to improve the accuracy of analysis.
This field is it has been found that hsa-miR-34b (miR-34b) is the tumor inhibiting factor for having p53 dependence regulatory functions
Sub [24,25].Pervious report shows that the downward of the upper reconciliation ING2 of the miR-34b of p53 mediations passes through in human fibroblasts
P53 activation mediated by nutlin-3a induce cell ageing (senescence) [25].In addition, the cluster of miR-34b/34c
(cluster) it is that the direct of TP53 transcribes the target factor, undergos mutation [26] in epithelioma starting.In oophoroma,
MiR-34b is often inactivated in Lynch syndrome related neoplasms.With the situation in sporadic cell tumour on the contrary, Lynch is comprehensive
Lack exception p53 in simulator sickness related neoplasms, this supports miR-34b inactivations and exception p53 to express the effect [27] in canceration.
This field is it has been found that hsa-miR-335 (miR-335) is that have influential miRNA [7] in oophoroma.In ovary
In carninomatosis people, lack the abnormal accumulation of the induced expression Bcl-w of miR-335 and subsequent cellular infiltration [35] out of control.In addition,
MiR-335 [36] related to the prognosis of EOC patient.
In addition, this field it has been found that hsa-miR-136 (miR-136) be also likely to be have in oophoroma it is influential
miRNA.Epithelial-mesenchymal conversion (the epithelial-mesenchymal of the initiation of miR-136 targeting TGF-b/Smad signals
Transition promoter Smad2 and Smad3), and inhibit lung adenocarcinoma cell transfer correlated traits [38].In people's non-small cell
The up-regulation of miR-136 is found in lung cancer (NSCLC) cell, promotes Erk1/2 activation [39] by targeting PPP2R2A.MiR-
136 may also target tumor suppressor PTEN and inhibit the PTEN in breast cancer translation [40].
This field has been diagnosed or has been detected the various various diseases of such as cancer using the method for molecular biology, including adopting
With the high-throughput chip of analysis gene expression or the kit of PCR or non-PCR methods for small amount molecular targets, such as
Taqman sonde method kits etc..However, the screening of ovarian epithelial carcinoma relative specific miRNA express spectras, detection method and
Detecting program, also there are many problems to be solved.Therefore this field also needs to one kind and more rapidly and effectively diagnoses or detect
The method and kit or chip of ovarian epithelial carcinoma.
The content of the invention
The present invention studies and is found that miRNA, and particularly hsa-miR-34b, hsa-miR-335, hsa-miR-136 is upper
Effect and these miRNA in the molecular regulation approach of skin oophoroma are in the upstream and downstream impact factor of biochemical regulation process
And interactively.As a result, the present invention provides it is a kind of for study ovarian epithelial carcinoma more rapidly with effective method.Specifically
, the present invention provides a kind of purposes of combination of miRNA in studying or diagnosing ovarian epithelial carcinoma, in the research or examine
It may also include the combination of mRNA in disconnected.The present invention also provides the combinations of the miRNA and the combination of mRNA to be used to prepare research
Or kit or the purposes of device in diagnosis ovarian epithelial carcinoma.The present invention also provides for studying or diagnose epithelial ovum
Kit or device in nest cancer, such as the base for ovarian epithelial carcinoma to be studied or diagnosed in peripheral blood lymphocytes sample
Because of chip.
Specifically, the present invention provides following miRNA combination for studying or diagnose the method for ovarian epithelial carcinoma, institute
MiRNA combination is stated as hsa-miR-34b, hsa-miR-335, hsa-miR-136, hsa-let-7e, hsa-miR-1297, hsa-
MiR-374b and hsa-miR-891b.
In the wherein another aspect of the present invention, further included in the method for foregoing research or diagnosis ovarian epithelial carcinoma following
The combination of the mRNA of gene：TAOK1、MGEA5、ZBED5、MMP3、DNAJA1、KLHL28、PDCD7、LSM12、SLC9A6、
ATG7、C1orf63。
It is described in the method for foregoing research or diagnosis ovarian epithelial carcinoma in the wherein another aspect of the present invention
MiRNA is divided to for following two groups：
Group (a)：Hsa-miR-34b, Hsa-miR-335 and hsa-miR-136；With
Group (b)：Hsa-let-7e, hsa-miR-1297, hsa-miR-374b and hsa-miR-891b.
In the research of the present invention or the method for diagnosis ovarian epithelial carcinoma, first checked in sample to be tested as core
The miRNA of the group (a) of miRNA, i.e. hsa-miR-34b, hsa-miR-335 and hsa-miR-136, then again in sample to be tested
The miRNA of inspection group (b), including hsa-let-7e, hsa-miR-1297, hsa-miR-374b and hsa-miR-891b.
In the present invention wherein another aspect, the expression for the mRNA that following genes are detected in sample to be tested is additionally included in：
TAOK1、MGEA5、ZBED5、MMP3、DNAJA1、KLHL28、PDCD7、LSM12、SLC9A6、ATG7、C1orf63。
In the research of the present invention or the method for diagnosis ovarian epithelial carcinoma, first inspection is as the group (a) of core miRNA
Then the expression of miRNA, i.e. hsa-miR-34b, hsa-miR-335 and hsa-miR-136 reexamine the miRNA of group (b), bag
Include the expression of hsa-let-7e, hsa-miR-1297, hsa-miR-374b and hsa-miR-891b.In the method for the invention,
If it find that the expression of the miRNA of group (a) does not meet predetermined testing result, for example, hsa-miR-335 expression rise and
The expression of hsa-miR-34b and hsa-miR-136 declines, and can select not continuing following step (2), i.e. inspection group (b)
MiRNA expression.It is possible thereby to increase the efficiency of detection.
The present invention research or diagnose ovarian epithelial carcinoma method in, except in sample to be tested detection group (a) and
The expression of the miRNA of group (b), may also include：
(3) expression of the mRNA of following genes is detected in sample to be tested：TAOK1、MGEA5、ZBED5、MMP3、
DNAJA1、KLHL28、PDCD7、LSM12、SLC9A6、ATG7、C1orf63。
It is similar, if it find that the expression of the miRNA of group (a) and/or group (b) do not meet predetermined testing result (such as
Predetermined testing result be hsa-miR-335 expression rise and hsa-miR-34b, hsa-miR-136, hsa-let-7e,
The expression of hsa-miR-1297, hsa-miR-374b and hsa-miR-891b decline), it can select not continue following step
(3), that is, the expression of the mRNA of following genes is checked：TAOK1、MGEA5、ZBED5、MMP3、DNAJA1、KLHL28、PDCD7、
LSM12、SLC9A6、ATG7、C1orf63.It is possible thereby to increase the efficiency of detection.
In the one aspect of the present invention, the sample to be tested is peripheral blood lymphocytes.
The present invention also provides the kits or dress for the foregoing research of the present invention or the method for diagnosis ovarian epithelial carcinoma
It puts.The kit or device of the present invention includes detecting the reagent of miRNA and mRNA.Wherein described miRNA is
Hsa-miR-34b, Hsa-miR-335, hsa-miR-136, hsa-let-7e, hsa-miR-1297, hsa-miR-374b and
The combination of hsa-miR-891b.Wherein described mRNA for TAOK1, MGEA5, ZBED5, MMP3, DNAJA1, KLHL28, PDCD7,
The combination of the mRNA of LSM12, SLC9A6, ATG7, C1orf63.In the one aspect of the present invention, wherein the miRNA divides
For following two groups：
Group (a)：Hsa-miR-34b, hsa-miR-335 and hsa-miR-136；
Group (b)：Hsa-let-7e, hsa-miR-1297, hsa-miR-374b and hsa-miR-891b.
In the one aspect of the present invention, the kit or device are prepared to implement to study or diagnose epithelial
The method of oophoroma, including following steps：
(1) in sample to be tested the miRNA of detection group (a) expression；
(2) in sample to be tested the miRNA of detection group (b) expression.
(3) expression of following mRNA is detected in sample to be tested：TAOK1、MGEA5、ZBED5、MMP3、DNAJA1、
KLHL28、PDCD7、LSM12、SLC9A6、ATG7、C1orf63。
The present invention also provides miRNA combination be used to prepare research or diagnose ovarian epithelial carcinoma in kit or
The purposes of device, the miRNA combination are hsa-miR-34b, Hsa-miR-335, hsa-miR-136, hsa-let-7e, hsa-
MiR-1297, hsa-miR-374b and hsa-miR-891b.The present invention one aspect, it is described research or diagnosis in
Further include the combination of the mRNA of following genes：TAOK1、MGEA5、ZBED5、MMP3、DNAJA1、KLHL28、PDCD7、LSM12、
SLC9A6、ATG7、C1orf63.In the wherein another aspect of the present invention, the miRNA is divided to for following two groups：Group (a)：hsa-
MiR-34b, hsa-miR-335 and hsa-miR-136；Group (b)：Hsa-let-7e, hsa-miR-1297, hsa-miR-374b and
hsa-miR-891b。
Herein, term " Microrna ", " microRNA ", " miR gene outcomes ", " miR " and " miRNA " exchange make
With referring to the unprocessed or finished RNA transcript from miR genes.Since miR gene outcomes do not translate into albumen,
Term " miR gene outcomes " does not include albumen.Unprocessed miR genetic transcriptions object is also referred to as " miR precursors ", generally comprises length
It is the RNA transcript of about 70-100 nucleotide.MiR precursors can digest the RNA for being processed into active 19-25 nucleotide
Molecule.The RNA molecule of the active 19-25 nucleotide is also referred to as " finished miR genetic transcriptions object " or " ripe
miRNA”.The miRNA of the present invention is primarily referred to as the miRNA of mammal, particularly relates to the miRNA of people.
The miRNA of the present invention is primarily referred to as the miRNA of people.For example, herein, " miR-141 " also represents " hsa-miR-
141”.The miRNA being related in the present invention includes its miRNA family, and family member and sequence are in such as http://
The websites such as www.mirbase.org/ disclose, and are determined by corresponding Accession number.
MiRNA of the present invention includes：
hsa-miR-34b(MI0000742)、Hsa-miR-335(MI0000816)、hsa-miR-136(MI0000475)、
Hsa-let-7e (MI0000066), hsa-miR-1297 (MI0006358), hsa-miR-374b (MI0005566) and hsa-
miR-891b(MI0005534)。
The gene of the present invention is primarily referred to as the gene of people.Herein, albumen symbol does not have to italic, and all Caps；Base
Because symbol uses italic.Such as TAO kinases 1 is written as TAOK1, the gene for encoding the albumen is written as TAOK1.But sometimes herein
Gene symbol is also without using italic.Such as " TAOK1 " also illustrates that the gene TAOK1 for encoding the albumen herein sometimes.Gene
Definition and sequence are in such as https:The websites such as //www.ncbi.nlm.nih.gov/gene/ disclose, by corresponding Gene
ID is determined.In the present invention, the mRNA of gene refers to the mRNA from the genetic transcription.The method for obtaining and checking the mRNA of gene
Or kit is known in this field and common.
Gene of the present invention includes：
TAOK1(Gene ID 57551)、MGEA5(Gene ID 10724)、ZBED5(Gene ID 58486)、MMP3
(Gene ID 4314)、DNAJA1(Gene ID 3301)、KLHL28(Gene ID 66689)、PDCD7(Gene ID
10081)、LSM12(Gene ID 124801)、SLC9A6(Gene ID 10479)、ATG7(Gene ID 74244)、
C1orf63(Gene ID 57035)。
In the present invention, the arbitrary technology of the rna expression level suitable for detection biological sample can be used, to measure
Gene outcome in sample includes the level of miR gene outcomes.For measuring RNA tables in biological sample (for example, cell, tissue)
It is known to the skilled in the art up to horizontal appropriate technology (for example, rna blot analysis, RT-PCR, in situ hybridization).
In the present invention, to gene, the measurement of the expression including miR-96 gene can be by detecting the multinuclear transcribed
The presence of thuja acid or part thereof carries out, wherein the polynucleotides transcribed include the gene or the code area of the miRNA.
Description of the drawings
Fig. 1 is the regulatory pathway network of personal connections of microRNAs and the mRNAs biomarker of the ovarian epithelial carcinoma of the present invention
Network figure.Circle is microRNAs.Triangle is mRNAs.
Specific embodiment
Below in conjunction with substantive content and advantageous effect that embodiment further illustrates the present invention, which is only used for
The bright present invention rather than limitation of the present invention.
1 patient of embodiment and sample
The patient and 47 non-epithelial ovarian patients (control) that subject has family's epithelial ovarian from 74.From
MiRNA and mRNA is obtained in the lymphocyte of the peripheral blood of subject.Between this 74 patients with family's epithelial ovarian
There is no kinship.In the family of these patients, at least two level-ones or two level relatives are detected in its a certain age level
Go out to suffer from science of heredity oophoroma.These patients do not have BRCA1/2 or MLH1/MSH2 and are mutated.
The target gene relation of epithelial ovarian correlation microRNAs and mRNAs that 2 present invention of embodiment studies and make purposes
It analyzes in footpath
Using algorithm as shown in Table 1, i.e. Miranda (microRNA.org), microcode (http://
www.mircode.org/mircode/),MirTarget2[21],Targetscan(http://
Www.targetscan.org/), the microRNAs, especially core microRNAs (hsa- being related to the method for the present invention
MiR-34b, Hsa-miR-335, hsa-miR-136) impact factor (microRNA and mRNA) and interactively analyzed.
The results are shown in Table 1, in the sample of epithelial ovarian patient, find 16 interaction microRNA and
MRNA pairs；The microRNA being related to includes：hsa-miR-34b、hsa-miR-335、hsa-miR-136、hsa-let-7e、hsa-
MiR-1297, hsa-miR-374b and hsa-miR-891b；The gene being related to include TAOK1, MGEA5, ZBED5, MMP3,
DNAJA1、KLHL28、PDCD7、LSM12、SLC9A6、ATG7、C1orf63.In the sample of epithelial ovarian patient, it is related to
Compared with the control group, there is notable difference in expression by microRNA and mRNA.
Table 1
Meanwhile utilize Cytoscape (V 2.8.3, http://www.cytoscape.org/) to provided by the invention
The Effect of Mutual Regulation relation structure regulatory pathway relational network figure of microRNAs and mRNAs.For gene-gene of mapping
The information that interacts (Gene-gene interaction information) is from Biomolecular Interaction
Network Databases (BINDs) are obtained.The results are shown in Figure 1.
Result shown in FIG. 1 is consistent with table 1.Hsa-miR-34b is one of axle center factor of this effect network.hsa-
MiR-34b expression declines, and the expression of its target gene SLC9A6, TAOK1, ATG7 and MGEA5 rise.The table of hsa-miR-34b
Up to amount by the effect of its target gene TAOK1 and MGEA5 and with hsa-miR-1297, hsa-miR-374b, hsa-miR-
The expression quantity of 891b, and hsa-let-7e are related.The expression of the target gene C11orf48 of hsa-miR-374b also rises.
Hsa-miR-136 is one of another axle center factor of this effect network.The expression of hsa-miR-136 declines,
And the expression of its target gene ZBED5 and MMP3 all rises.
Hsa-miR-335 is one of another axle center factor of this effect network.The expression of hsa-miR-335 rises,
And the expression of its target gene DNAJA1, PDCD7, KLHL28 and LSM12 decline.
TAOK1 is the most important target genes of miR-34b.TAOK1 is the upstream activator of MARK, MARK phosphorylation micro-pipe phases
Albumen is closed, it is caused to be separated from micro-pipe and the micro-pipe in interphase cell is caused to be disassembled [28].Members of the TAOK1 as TAO kinases,
The Genome stability of human cell [30-32] is protected by adjusting spindle checkpoint signal.Another important target base
Because being ATG7, it is previously reported related with oophoroma.The silence of ATG7 or BECN1 is significant in human ovarian cancer Caov-3 cells inhibits single
The cell death [33] of Pt inductions.In addition, As2O3Induction does not depend on the autophagy approach of beclin-1 in ovarian cancer cell；
The siRNA of ATG7 targets the significant autophagy [34] for reducing As2O3 inductions together with ATG5 and hVps34.
DNAJA1 is the target gene of miR-335.Evidence shows HDJ2 (also referred to as DNAJA1), enhances in human ovarian cancer
The growth inhibition effect of farnesyl transferase (farnesyltransferase) inhibitor lonafarnib and taxol induced
[37]。
MMP3 is one of target gene of miR-136 disclosed in this research.MMP3 and MMP2 plays key effect, as E2
The downstream media [41] of TC0101441 activity in EOC migrations/infiltration of induction.It is also known that MMP3 can increase chemotherapy to oophoroma
Sensibility [42,43].
3 gene microarray analysis miRNA of embodiment is expressed and mRNA expression
Using passing through Illumina detection of expression chip (Illumina Human v2 MicroRNA expression
Beadchip miRNA expression data (the data number GSE31801, in American National Biotechnology Information center) obtained
The gene expression integrated database of (National Center of Biotechnology Information, NCBI) website
Disclosed in (Gene expression omnibus, GEO)：http://www.ncbi.nlm.nih.gov/geo/
queryacc.cgiAcc=GSE31801) analyzed.The miRNA plates of the chip include 1146 mankind miRNA (>
MiRNA disclosed in 97%miRBase release 12) expression of the miRNA of foregoing subject is analyzed.By chip
MiRNA analyzed areas are divided into 3 regions.What wherein first area was detected includes hsa-miR-34b, hsa-miR-335, hsa-
miR-136；Second area includes hsa-let-7e, hsa-miR-1297, hsa-miR-374b and hsa-miR-891b；3rd area
Domain includes remaining miRNA.
In addition use through Illumina detection of expression chip (llumina HumanHT-12 V3.0expression
Beadchip mRNA expression data (the data number GSE37582) obtained：http://www.ncbi.nlm.nih.gov/geo/
query/acc.cgiAcc=GSE37582) the mRNA expression of foregoing subject is analyzed.By the mRNA plates of the chip
Analyzed area be divided into 2 regions.Wherein first area detection include TAOK1, MGEA5, ZBED5, MMP3, DNAJA1,
The mRNA of KLHL28, PDCD7, LSM12, SLC9A6, ATG7, C1orf63；Second area includes remaining mRNA.
The upper reconciliation down regulation trend analysis for epithelial ovarian correlation miRNA and the mRNA expression that 4 present invention of embodiment studies
One, is by Partial Least Squares (partial least squares, PLS) to the miRNA of the sample of embodiment 2
Expression and mRNA expression data are analyzed
There is the gene [15-19] of differential expression using PLS analysis methods [11] analysis.
In the research of the present invention, PLS analysis method steps include：
1. use NIPALS algorithms【18】Solve following multivariate regression models：
Calculation procedure：
(1) random initializtion (Randomly initialize) u0=Y
(2) w=XTu0, w=w/ | | w | |
(3) t=Xw
(4) c=YTT, c=c/ | | c | |
(5) u=Yc
(6) if u-u0<10-8, then step (7) is carried out；
Otherwise u0=u repeats step (2)-(5).
(7) X=X-ttTX, Y=Y-ttTY.Return to step (2), calculate next latent variable (latent variable) this
Place, Y are classification of diseases matrix of variables, and X is expression matrix (n x p), and n is number of samples, and p is total for mRNA and microRNA variables
Number.
2. the identification of difference expression gene
The identification of difference expression gene calculates the variable drop of each mRNA, microRNA.Variable importance projection
(variable importance on the projection, VIP), defines referring to Gosselin et al., 2010 [20].
Using permutation test, the level of signifiance of each mRNA and microRNA are calculated respectively：
When calculating the mRNA levels of signifiance, the mRNA sums of p=chips detection；When calculating the microRNA levels of signifiance, p
The microRNA sums of=chip detection, h are the latent variable number introduced (i.e. by original p dimension datas dimensionality reduction to h).
False discovery rate (false is reduced using alignment problem (permutation procedure) (carrying out 1000 times)
Discovery rate, FDR).FDR with VIP is less than 0.05 (p<0.05) expression is just with differential expression.
Two, further analyze miRNA expression using Monte Carlo analysis methods and mRNA expresses data
The miRNA and mRNA of differential expression are further analyzed using Monte Carlo analysis methods [12,13].
Monte Carlo analysis methods and step include in the present invention：
According to the computation model of abovementioned steps 2, using the microRNAs of differential expression and mRNAs independent variable, establish more
First regressive prediction model.Calculating regression coefficient θ includes (α and β in model), and the selection of independent variable depends directly on regression coefficient
Stability statistic Sj:
Sj=mean (θj)/std(θj)
Wherein θ is the regression coefficient in linear model.It is sampled by Monte Carlo, calculates each submodule of j-th of variable
The average and standard deviation of type regression coefficient.Highest accuracy based on cross validation determines the threshold value of regression coefficient reliability.Tool
It is the miRNA/ genes with differential expression to have absolute reliability to be more than threshold value and MiRNA/mRNAs of the FDR less than 0.05 of VIP
Group.
Three results
1. the upper reconciliation down regulation trend expressed according to the epithelial ovarian correlation miRNA that the PLS present invention analyzed studies.Knot
Fruit is as shown in table 2.
Table 2
As shown in the result of table 2, hsa-miR-34b, hsa-miR-335, hsa-miR-136, hsa-let-7e, hsa-
In human ovarian cancer patients, relative comparison group has the apparent expression poor by miR-1297, hsa-miR-374b and hsa-miR-891b
Different (with FDR of VIP, p<0.05).Wherein, the expression of hsa-miR-335 rises, hsa-miR-34b, hsa-miR-
136th, the expression of hsa-let-7e, hsa-miR-1297, hsa-miR-374b and hsa-miR-891b decline.
2. the upper reconciliation down regulation trend expressed according to the epithelial ovarian correlation mRNA that the PLS present invention analyzed studies.Knot
Fruit is as shown in table 3.
Table 3
As shown in the result of table 3, TAOK1, MGEA5, ZBED5, MMP3, DNAJA1, KLHL28, PDCD7, LSM12,
In human ovarian cancer patients, relative comparison group has apparent differential expression (with FDR of by SLC9A6, ATG7, C1orf63
VIP, p<0.05).Wherein, the expression of SLC9A6, C1orf63, TAOK1, ATG7 and MGEA5 and ZBED5 and MMP3 rise,
The expression of DNAJA1, PDCD7, KLHL28 and LSM12 decline.
As a result it is consistent with the gene relationship of embodiment 2.
3. it is lowered according to the epithelial ovarian correlation mRNA that the Monte Carlo present invention analyzed the studies upper reconciliations expressed
Trend.The results are shown in Table 4.
Table 4
As shown in the result of table 4, hsa-miR-34b, Hsa-miR-335, hsa-miR-136, hsa-let-7e, hsa-
In human ovarian cancer patients, relative comparison group has the apparent expression poor by miR-1297, hsa-miR-374b and hsa-miR-891b
It is different.Wherein, the expression of Hsa-miR-335 rises, hsa-miR-34b, hsa-miR-136, hsa-let-7e, hsa-miR-
1297th, the expression of hsa-miR-374b and hsa-miR-891b declines.
4. it is lowered according to the epithelial ovarian correlation mRNA that the Monte Carlo present invention analyzed the studies upper reconciliations expressed
Trend.The results are shown in Table 5.
Table 5
As shown in the result of table 5, TAOK1, MGEA5, ZBED5, MMP3, DNAJA1, KLHL28, PDCD7, LSM12,
In human ovarian cancer patients, relative comparison group has apparent differential expression by SLC9A6, ATG7, C1orf63.Wherein, SLC9A6,
The expression of C1orf63, TAOK1, ATG7 and MGEA5 and ZBED5 and MMP3 rises, DNAJA1, PDCD7, KLHL28 and
The expression of LSM12 declines.
As a result the gene action relationship consistency arrived with embodiment 2 and PLS analysis and observations.
Present inventor studies and proposes for the first time the molecular regulation approach network of new ovarian epithelial carcinoma, and
And it is found that particularly hsa-miR-34b, hsa-miR-335, hsa-miR-136 is as this molecular regulation approach by miRNA
Axle center (pivot) effect in network.The present invention is also found that 16 miRNA relevant with these miRNA and mRNA pairs for the first time
With their regulation relationship.Present invention thus provides for studying and detecting ovarian epithelial carcinoma, particularly in periphery blood strangury
The molecular marked compound of ovarian epithelial carcinoma is detected in bar cell sample.Research and detection ovarian epithelial carcinoma provided by the invention
The advantages of method has high specific and faster can carry out and obtain testing result.
The above is the explanation carried out to the present invention, it is impossible to be regarded as the limitation carried out to the present invention.Unless in addition refer to
Go out, practice of the invention will use the routine techniques of organic chemistry, polymer chemistry, biotechnology etc., it is clear that except being stated upper
Outside being particularly described in bright and embodiment, the present invention can also be realized otherwise.Other aspects within the scope of the present invention
It will be apparent to those skilled in the art in the invention with improving.Introduction according to the present invention, many change and variations are
Feasible, therefore it is within the scope of the present invention.
DEG C if without particularly showing, the unit " degree " of herein presented temperature refers to degree Celsius, i.e.,.
Documents below carries out disclosure in a manner of introducing in full in the application.
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Claims (10)
1. the combination of following miRNA is for studying the method for ovarian epithelial carcinoma, the miRNA combination is hsa-miR-34b,
Hsa-miR-335, hsa-miR-136, hsa-let-7e, hsa-miR-1297, hsa-miR-374b and hsa-miR-891b.
2. the method for claim 1 wherein the combinations for the mRNA for further including following genes：TAOK1、MGEA5、ZBED5、MMP3、
DNAJA1、KLHL28、PDCD7、LSM12、SLC9A6、ATG7、C1orf63。
3. the method for claim 1 or 2, which is characterized in that the miRNA is divided to for following two groups：
Group (a)：Hsa-miR-34b, hsa-miR-335 and hsa-miR-136；
Group (b)：Hsa-let-7e, hsa-miR-1297, hsa-miR-374b and hsa-miR-891b；
In the method for the research ovarian epithelial carcinoma, comprise the following steps：
(1) in sample to be tested the miRNA of detection group (a) expression；
(2) in sample to be tested the miRNA of detection group (b) expression；
(3) expression of the mRNA of following genes is detected in sample to be tested：TAOK1、MGEA5、ZBED5、MMP3、DNAJA1、
KLHL28、PDCD7、LSM12、SLC9A6、ATG7、C1orf63。
4. the method for claim 3, which is characterized in that the sample to be tested is peripheral blood lymphocytes.
5. the purposes of kit or device of the combination of following miRNA in being used to prepare research or diagnosing ovarian epithelial carcinoma,
The miRNA combination for hsa-miR-34b, Hsa-miR-335, hsa-miR-136, hsa-let-7e, hsa-miR-1297,
Hsa-miR-374b and hsa-miR-891b.
6. the purposes of claim 5, wherein further including the combination of the mRNA of following genes in the research or diagnosis：TAOK1、
MGEA5、ZBED5、MMP3、DNAJA1、KLHL28、PDCD7、LSM12、SLC9A6、ATG7、C1orf63。
7. the purposes of claim 1 or 2, which is characterized in that the miRNA is divided to for following two groups：
Group (a)：Hsa-miR-34b, hsa-miR-335 and hsa-miR-136；
Group (b)：Hsa-let-7e, hsa-miR-1297, hsa-miR-374b and hsa-miR-891b；
Comprise the following steps in the research or diagnosis：
(1) in sample to be tested the miRNA of detection group (a) expression；
(2) in sample to be tested the miRNA of detection group (b) expression；
(3) expression of following mRNA is detected in sample to be tested：TAOK1、MGEA5、ZBED5、MMP3、DNAJA1、KLHL28、
PDCD7、LSM12、SLC9A6、ATG7、C1orf63。
8. the purposes of claim 7, wherein the kit or device are used to study or examine in peripheral blood lymphocytes sample
Disconnected ovarian epithelial carcinoma.
9. for studying or diagnosing kit or device in ovarian epithelial carcinoma, including for detecting miRNA and mRNA
Reagent, the miRNA be hsa-miR-34b, Hsa-miR-335, hsa-miR-136, hsa-let-7e, hsa-miR-
1297th, the combination of hsa-miR-374b and hsa-miR-891b, the mRNA for TAOK1, MGEA5, ZBED5, MMP3,
The combination of the mRNA of DNAJA1, KLHL28, PDCD7, LSM12, SLC9A6, ATG7, C1orf63,
Preferably, wherein the miRNA is divided to for following two groups：
Group (a)：Hsa-miR-34b, hsa-miR-335 and hsa-miR-136；
Group (b)：Hsa-let-7e, hsa-miR-1297, hsa-miR-374b and hsa-miR-891b；
Comprise the following steps in the research or diagnosis：
(1) in sample to be tested the miRNA of detection group (a) expression；
(2) in sample to be tested the miRNA of detection group (b) expression；
(3) expression of following mRNA is detected in sample to be tested：TAOK1、MGEA5、ZBED5、MMP3、DNAJA1、KLHL28、
PDCD7、LSM12、SLC9A6、ATG7、C1orf63。
10. the kit or device of claim 9, wherein described device be in peripheral blood lymphocytes sample research or
Diagnose the genetic chip of ovarian epithelial carcinoma.
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