CN108949973B - The biomarker of trophocyte invasiveness exception and its application - Google Patents
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Abstract
The present invention relates to the biomarker of trophocyte invasiveness exception and its applications, confirm the universal differential expression of miR-181b in the pregnancy related disorder tissue of trophocyte invasiveness exception, S1PR1 is the direct effect target gene of miR-181b, the discovery of the molecular mechanism of trophocyte invasive ability is influenced by miR-181b-S1PR1 access, the prevention and treatment of the pregnancy related disorder to be caused extremely by trophocyte invasion provides new thread and potential intervention target.
Description
Technical field
The present invention relates to the biomarker of trophocyte invasiveness exception and its mechanism study more particularly to miR-181b
And its downstream target gene S1PR1 is in the application as trophocyte invasiveness abnormality mark object.
Background technique
The invasion of trophocyte are embryo nidation and the essential process of placentation, this invasion and tumour cell
Invasion are shifted surprising similar, but are different from tumour cell, the invasion of trophocyte are had stringent by fine regulation
Space-time limitation.The invasiveness of trophocyte is moderate, is that the success or failure that physiology gestation is established, maintains and terminated in due course are crucial, and invade
It is unbalance to attack power, can cause a variety of pregnancy related disorders, and is related to each stage in pregnancy period: invasiveness crosses weak derivable and causes infertile, stream
The pathological pregnancies such as production, premature labor, fetal growth restriction, preeclampsia；It is too strong and Placenta acrreta and trophoblastic tumor can occur
(such as: suede cancer), these diseases are to threaten one of the arch-criminal of female youngster's life safety.According to statistics, pregnant Early-stage cervical cancer
Incidence be up to 2-4%；To middle pregnant stage in evening, premature labor 9.6%, fetal growth restriction 5%-10%, preeclampsia 3%-5%
Deng incidence all present and rise year by year situation.Therefore, angle is invaded from trophocyte, finds pregnancy related disorder and effectively prevents
It is very urgent to control measure.
It has been found that trophocyte invasiveness is not only related to the factors such as oxidative stress, hypoxemia, hormone, and by S1PR1,
The regulating and controlling effect of the signal paths such as the genes such as CsA, CXCL3 and MEK, ERK, Wnt.With to regulation information research go deep into, one
Class length only 22 bases, post-transcriptional level negative regulation gene expression tiny RNA (microRNA is also known as miRNA) enter grind
The visual field for the person of studying carefully.With the increase that miRNA function recognizes, the effect in pregnancy related disorder is also gradually taken off with mechanism
Show.Research is found: miR-210 is by regulating and controlling the migration of Ephrin-A3a, Homeobox-A9 expression inhibiting trophocyte and invading
It attacks；MiR-29b lowers MCL1, MMP2, VEGFA, ITGB1 expression, influences invasion, apoptosis and the angiogenesis of trophocyte；
MiR-195 low expression can influence ActRIIA expression reduction trophocyte invasiveness in placenta from patients with pre-eclampsia.
However existing research is made a general survey of, it is that (such as: preeclampsia, fetal growth restriction) are assessed from single disease
The correlation of miRNA and trophocyte invasiveness lack comprehensive analysis to such pregnancy related disorder.If can gather a variety of
The disease of trophocyte invasiveness exception, screens relative miRNA comprehensively, can not only increase to embryo nidation, placenta
The understanding of formation can also provide new target for the prevention and treatment of the diseases such as spontaneous abortion, preeclampsia, fetal growth restriction and suede cancer
Mark, therefore become the direction that we study.
Summary of the invention
The present invention provides a kind of miRNA markers in the diagnostic reagent for preparing trophocyte invasiveness exception related disease
In application, it is characterised in that the marker be miR-181b.
The present invention also provides the reagent of the expression for measuring miR-181a in manufacture for predicting object
Application in the kit of a possibility that trophocyte invasiveness exception related disease, wherein if the expression of miR-181a
It significantly increases or reduces relative to normal control, it is considered that trophocyte invasiveness exception related disease occurs for the object
A possibility that increase.
Further, the present invention provides a kind of diagnostic kit of trophocyte invasiveness exception related disease, and feature exists
Contain the reagent of detection miR-181b in the kit.
Preferably, the disease is selected from spontaneous abortion, preeclampsia, suede cancer.
In addition, present invention discover that miR-181b is preparing the application in the reagent for adjusting S1PR1 expression, wherein making
The reagent that miR-181b is overexpressed causes the expression of S1PR1 to decline, and the reagent of miR-181b low expression is made to lead to S1PR1's
Expression rises.
Further, the reagent be used to change trophocyte invasiveness.
Further, the reagent be used to treat trophocyte invasiveness exception related disease.
Preferably, the disease is selected from spontaneous abortion, preeclampsia, fetal growth restriction and suede cancer.
The present invention has the positive effect that:
1.miRNA is a kind of new biomarkers, not only stable, minimally invasive, be easy to detect, and quantitative accurate, will significantly
The abnormality diagnostic sensibility and specificity of trophocyte's invasiveness is improved, the success of such microRNA biomarker is opened
Hair is overturning to the traditional biological marker based on albumen, will start completely new situation for the prevention and treatment of pregnancy related disorder.
2. it is extremely related that miRNA marker miR-181b provided by the invention can be used as Accurate Diagnosis trophocyte invasiveness
The diagnosis marker of disease can avoid invasive diagnosis, and can carry out auxiliary diagnosis in early stage, thus further for clinician
Testing in depth testing provides foundation, quick and precisely to grasp the morbid state of patient and coincident with severity degree of condition, in time taking more individual character
The control prece of change provides support, delays and prevent progression of disease.
3. outer in addition to diagnosing, present invention demonstrates for miR-181b overexpression or the changeable trophocyte of silencing invade
Power is attacked, provides new therapeutic strategy for the treatment of pregnancy related disorder.
4. the present invention further demonstrates miR-181b for the mediating effect+6 of S1PR1, nourished for further further investigation
The relevant molecule mechanism and signal path of cell invasion power provide thinking.
Detailed description of the invention
Fig. 1 is the expression changing rule that miR-181b changes with trophocyte invasiveness.Wherein a:miR-181b and miR-
The expression of 181a, miR-181d in suede cancerous tissue, (* P<0.05vs NP, * * P>0.05vs NP, * * * P>0.05vs NP)；
Expression of the b:miR-181b in the different trophocyte strain of invasiveness, (#P < 0.05vs JAR).
Fig. 2 is miR-181b expression in up-regulation JEG-3 and HTR-8/Svneo cell, and the invasiveness of cell changes situation.a:
Transwell test prompt cell invasion ability changes；B: invasion index, (* P < 0.05vs Scramble)；C: gelatin zymogram
Invasive associated protein MMP-2/MMP-9 activity change is shown in experiment.
Fig. 3 is miR-181b target gene Bioinformatics Prediction.A: software prediction miR-181b possible target gene；b:
The bioinformatics feature of S1PR1 gene.
Fig. 4 is 3 prediction targets such as S1PR1 in the expression being overexpressed on miR-181b trophocyte.A:S1PR1 exists
The expression being overexpressed on JEG-3, HTR-8/Svneo cell strain of miR-181b, (* P < 0.05vs Scramble)；b:CXCL3
Expression on JEG-3, HTR-8/Svneo cell strain for being overexpressed miR-181b；C:PPP3R1 is being overexpressed miR-181b's
Expression on JEG-3, HTR-8/Svneo cell strain.
Fig. 5 is the expression changing rule that S1PR1 changes with trophocyte invasiveness.(*P<0.05vs NP；**P<0.05vs
NV)。
Specific embodiment
Present invention will be described in further detail below with reference to the accompanying drawings, to enable those skilled in the art referring to specification text
Word can be implemented accordingly.
Embodiment 1: the screening of the miRNA of trophocyte invasiveness exception is participated in
The related disease tissue for having selected two kinds of typical trophocyte invasivenesses to weaken: Early-stage cervical cancer villus (takes it
Parent progesterone and Immune Indexes are normal, and exclude chromosome by chromosome karyotype analysis method through our hospital's pre-natal diagnosis center
Abnormal person) and placenta of preeclampsia, it is micro- using μ Paraflo using regions in first-trimester villi and normal placenta tissue as respective control
Fluid chip technology screens the consistent miRNAs of difference between two groups of diseases.
As the result is shown: compared with the control group, the miRNAs in spontaneous abortion villus and human placenta of preeclampsia expresses water
Averagely there is larger difference；But miRNAs expression difference is consistent and in only 25 of 5 times or more between two groups of diseases, wherein
16 expressions increase, 9 expressions decline.Chip results prompt, some miRNA may invade abnormal in trophocyte
Similar effect is played in relevant disease.Further we combine group difference, filter out 10 significant differences (> 5 times)
MiRNAs carry out quantitative PCR verifying.10 miRNAs quantitative results show, difference trend and chip data trend basic one
It causes.In this 10 miRNAs, miR-181b has attracted our attention.MiR-181b group difference is up to 9.4 (tires respectively
Disk) and 8.7 (villus) times.Further with the verifying of Real time round pcr, as a result it is consistent with chip.In figure: NP is normal tire
Disk, PE are placenta of preeclampsia, and NV is regions in first-trimester villi, and SA is spontaneous abortion villus.It is well known that miR-181 family is one
Star molecule extremely conservative in evolution, in a variety of diseases especially in terms of the generation of malignant tumour, development and its clinic diagnosis
Play important role；Existing numerous studies confirm that the migration invasion of miR-181 family and tumour cell are closely related.miR-
Specificity overexpression of the 181b in trophocyte invasiveness deficiency diseased tissue, prompts it may to trophocyte invasiveness
Have the function of similar.
Embodiment 2:miR-181b invades the expression in abnormal related disease in different trophocytes
The correlation of this three and trophocyte invasiveness for further evaluation, we invade too strong in trophocyte
It is verified on suede cancer sample.
50 chorionic villi of spontaneous abortion (trophocyte invasiveness is insufficient) is collected, with Normal villus tissue (trophocyte
Invasiveness is normal) as control；It is collected simultaneously 50 Cases with Preeclampsia placenta tissues (trophocyte invasiveness is insufficient), 50 suede cancers
Tissue specimen (trophocyte invasiveness is excessive), using normal placenta tissue (trophocyte invasiveness is normal) as control.Using
The expression of miR-181b, is commented in Real time PCR or Western Blot technology detection placenta, villus and suede cancerous tissue sample
Relationship between valence and trophocyte invasiveness.
Wherein, the standard in " gynecotokology " (the 7th edition) that 1. the diagnosis reference Le Jie of preeclampsia is edited: gestation 20 weeks
After, blood pressure >=140/90mmHg is spaced 6 hours, and has Urine proteins, Urine proteins >=300mg/24 hour or arbitrarily urinate >=
30mg/dL, interval are surveyed primary for 4 hours again.Preeclampsia group and normal pregnancy group in this research are single tire primipara, are selected a time
Cesarean section delivery, no smoking and pregnancy period high amount of drug take history, no infection history duration of pregnancy and internal disease.
2. suede cancer makes a definite diagnosis the histodiagnosis in main " gynecotokology " (the 7th edition) according to referring to Le Jie chief editor: in son
Transfer stove is shown in that trophocyte in blocks invades profit and necrotic hemorrhage outside palace muscle layer or uterus.Suede carninomatosis involved in this research does not connect per capita
It is transfused blood, immunization therapy.
3. spontaneous abortion refers to unused manual method, what is be discharged due to certain reason embryo or fetus automatically disengage shows
As.Chorionic villi collected is all from the patient that pregnant early stage (gestation is before 12 weeks) miscarries for the first time in this research, and the pregnancy period is without suction
Cigarette and high amount of drug take history, no infection history duration of pregnancy and internal disease, and progesterone and Immune Indexes are normal, and through chromosome core
Type analysis method excludes chromosome abnormality (routinely carrying out this work in our hospital's pre-natal diagnosis center).
As a result, it has been found that invaded in trophocyte on too strong suede cancer sample, miR-181a, miR-181d without significant difference, and
Specific low expression is presented in miR-181b (see Fig. 1 a).On this basis, we have detected miR-181b again and nourish in JAR suede cancer
Cell strain (low invasiveness), JEG-3 suede cancer trophocyte strain (high invasiveness) and HTR-8/Svneo villi trophocyte strain
Expression in (high invasiveness).The results show that miR-181b high is expressed in the jar cell of low invasion, and low expression is in increased resistance invasion
JEG-3 the and HTR-8/Svneo cell of attacking property (see Fig. 1 b).Result above and analysis prompt, miR-181b are not only expressed in taste
It supports in cell, but also extremely related with the trophocyte invasiveness of a variety of pregnancy related disorders.In figure: NP is normal placenta,
CH is suede cancerous tissue, and JEG-3, JAR are the trophocyte strain of suede cancer, and HTR is the trophocyte strain of HTR-8/Svneo villi.
Influence of the embodiment 3:miR-181b to trophocyte invasiveness
Bioinformatic analysis discovery, miR-181b between different plant species (people, rat, mouse, zebra fish) protect by height
It keeps, and homology is in 95% or more (referring to table 1), it is meant that the importance of its potential function.But Literature Material is found, at present simultaneously
The not report about miR-181b and the research of trophocyte invasiveness.
1 miR-181b species conservative Analysis of table
In order to obtain more support foundations, we are thin as tool using two kinds high invasion JEG-3, HTR-8/Svneo cells
Born of the same parents take the strategy of overexpression and silencing to change the expression of miR-181b in cell.
1.miR-181b being overexpressed the influence to trophocyte invasiveness:
MiR-181b Lentiviral is constructed, unloaded slow virus is control, is coated with into lentiviral particle, infects respectively
JEG-3 and HTR-8/SVneo trophocyte, mtt assay exclude influence of the transfection toxicity to cell；Using Real time PCR skill
Art is verified intracellular mature miR-181b and is overexpressed.Main assessment: trophocyte invasiveness: Transwell method detects HTR-8/
SVneo cell invasion function changes.
2.miR-181b influence of the expression silencing to trophocyte invasiveness:
The slow virus carrier of miR-181b expression silencing is constructed, unloaded slow virus is control, and coating is divided at lentiviral particle
Not Gan Ran JEG-3 and HTR-8/SVneo trophocyte, mtt assay excludes influence of the transfection toxicity to cell；Using Real time
Round pcr assesses the silence efficiency of intracellular miR-181b.Main assessment: trophocyte invasiveness: Transwell method detection
HTR-8/SVneo cell invasion function changes.
As a result, it has been found that the invasive ability of two kinds of cells is decreased obviously (Fig. 2 a, 2b) after up-regulation cell miR-181b expression
And the activity of Invasive associated protein MMP-2/MMP-9 also declines (Fig. 2 c).In figure: Blank is blank control group, and Scramble is
Negative control group, miR-181b are miR-181b mimics group, and HTR is the trophocyte strain of HTR-8/Svneo villi.
The analysis of the downstream effects target spot of embodiment 4:miR-181b
The specific mechanism that MiR-181b influences trophocyte invasiveness is still not clear, for this purpose, we believe by biology first
The method of credit analysis is ceased, searching regulates and controls target downstream.Software analysis shows that: CXCL3, S1PR1, PPP3R1 gene are in 3 ' UTR
Containing the core sequence " GAAUGU " (see Fig. 3 a) in conjunction with miR-181b, and CXCL3, S1PR1, PPP3R1 base has been reported
Because both participating in the adjusting of trophocyte function.Therefore we choose these three genes and further investigate, by the miR- of foundation
181b is overexpressed JEG-3, HTR-8/Svneo cell, and detection three expresses variation.As a result, it has been found that CXCL3, PPP3R1 not by
MiR-181b influences (see Fig. 4 b, 4c), and S1PR1 is expressed in two kinds of cells and is remarkably decreased (see Fig. 4 a), prompts S1PR1 can
It can be the direct action target spot of miR-181b.In Fig. 4: Blank is blank control group, and Scramble is negative control group, miR-
181b is miR-181b mimics group, and JEG-3 is the trophocyte strain of suede cancer, and HTR is that HTR-8/Svneo villi nourishes carefully
Born of the same parents' strain.
More direct experimental verification is the target base of miR-181b by UTR luciferase report gene experimental verification S1PR1
Cause: pass through building miR-181b analogies (mimics), the luciferase report gene sequence (wild type) of the UTR Han S1PR13 '
And canonical sequence (saltant type), transfected HEK 293 and HTR-8/SVneo trophocyte；Hybridization in situ detects miR-181b
Expression, Immunohistochemical Method detect the expression of S1PR1；The variation of luciferase activity is detected to verify miR-181b to S1PR1 table
The regulating and controlling effect reached.The result shows that: the overexpression of miR-181b causes the expression of S1PR1 to reduce.
Further to prove S1PR1 and trophocyte invasiveness relationship, the tissue expression rule of S1PR1, Wo Menjian are explored
Its expression in placenta of preeclampsia, spontaneous abortion villus and suede cancerous tissue is surveyed.It was found that the group that S1PR1 is reduced in invasiveness
It knits in (placenta of preeclampsia and spontaneous abortion villus) and lowers (see Fig. 5), in the raised tissue (suede cancer) of invasiveness in expression
It adjusts (see Fig. 5), with miR-181b expression rule on the contrary, meeting its control methods.In Fig. 5: NP is normal placenta, and PE is before eclampsia
Phase placenta, CH are suede cancerous tissue, and SA is spontaneous abortion villus, and NV is regions in first-trimester villi.Knot is analysed and tested in conjunction with above- mentioned information credit
Fruit, we tentatively judge S1PR1 for the downstream effects target spot of miR-181b.
In order to further judge a possibility that S1PR1 influences trophocyte invasiveness as miR-181b downstream target gene,
We are proved from the angle of biological information and gene function again.TargetScan on-line analysis finds S1PR1 and miR-
The binding sequence " GAAUGU " of 181b highly conserved (see Fig. 3 b) in multiple species；Literature Material discovery, S1PR1 full name sheath
Ammonia alcohol kinases receptors (Sphingosine-1-phosphate receptor), can be by activating in conjunction with its ligand S1P
MEK-ERK-MMP-2 signal path influences HepG2 (liver cancer cell lines), MCF10A (galactophore epithelial cell system) and trophocyte
Migration and invasion.So far, it is believed that existing adequate cause thinks that S1PR1 is the target gene in the downstream miR-181b.
Based on above-mentioned analysis and experimental result, it is proposed that " miR-181b regulates and controls S1PR1 expression, influences trophocyte and invades
Power is attacked, the generation of pregnancy related disorder is participated in ".
Although the embodiments of the present invention have been disclosed as above, but its is not only in the description and the implementation listed
With.It can be applied to various suitable the field of the invention completely.It for those skilled in the art, can be easily
Realize other modification.Therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is simultaneously unlimited
In specific details and legend shown and described herein.
Sequence table
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Claims (3)
1. a kind of detection reagent of miRNA marker expression preparation diagnosis trophocyte invasiveness whether Yi Chang reagent
In application, it is characterised in that the marker be miR-181b, the trophocyte invasiveness anomaly occur in spontaneous abortion or
Suede cancer.
2. the reagent of the expression for measuring miR-181b is abnormal in trophocyte invasiveness of the manufacture for predicting object
A possibility that kit in application, wherein if the expression of miR-181b significantly increased relative to normal control or
It reduces, increases it is considered that a possibility that trophocyte invasiveness is abnormal occurs for the object, the trophocyte invasiveness is different
Often occur in spontaneous abortion or suede cancer.
3. change application of the reagent of miR-181b expression in the reagent that preparation changes trophocyte invasiveness, it is described to change
The reagent for becoming miR-181b expression is adjustable S1PR1 expression, wherein the reagent for being overexpressed miR-181b causes
The expression of S1PR1 declines, and the expression for making the reagent of miR-181b low expression lead to S1PR1 rises, described to nourish carefully
Born of the same parents are suede cancer trophocyte or villi trophocyte.
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