CN109828116A - Application of the ESE-1 and mRNA in the diagnostic kit or drug for screening or preparing hepatopathy - Google Patents
Application of the ESE-1 and mRNA in the diagnostic kit or drug for screening or preparing hepatopathy Download PDFInfo
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- CN109828116A CN109828116A CN201910017712.7A CN201910017712A CN109828116A CN 109828116 A CN109828116 A CN 109828116A CN 201910017712 A CN201910017712 A CN 201910017712A CN 109828116 A CN109828116 A CN 109828116A
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Abstract
The invention discloses application of the ESE-1 and mRNA in the diagnostic kit or drug for screening or preparing hepatopathy, belong to biomedicine technical field, present invention combination epicuticle idiosyncratic transcription factor and GP73 can greatly improve the accuracy rate of detection for detecting hepatopathy；In addition, ESE-1 inhibitor can be used for treating hepatopathy.
Description
Technical field
The invention belongs to biomedicine technical fields more particularly to ESE-1 and mRNA in the diagnosis for screening or preparing hepatopathy
Application in kit or drug.
Background technique
Existing research shows that hepatitis, the hepatic tissue of liver cancer and liver cirrhosis patient or blood height expression II type of golgiosome across
Memebrane protein (GOLPH2, GP73).In the diagnosis detection of liver cancer patient, sensibility (63%) that GP73 diagnoses early liver cancer
It is significantly better than alpha-fetoprotein (25%)；Large-scale clinical studies show GP73 to the sensibility of liver cancer considerably beyond AFP, it is reachable
To 74% or so.After operation excision, GP73 is remarkably decreased, and in follow-up when liver cancer recurrence, GP73 can rise again, therefore, it is considered that
GP73 for the early diagnosis of liver cancer and Follow-up After with greater advantage.
However, the accuracy of existing detection hepatopathy (hepatitis, liver cancer and cirrhosis) needs to be further improved；In addition, also
It is necessary to develop the drug for treating hepatopathy.
Summary of the invention
Present invention aims to overcome that the shortcomings of the prior art, and ESE-1 and mRNA are provided and screening or preparing liver
Application in the diagnostic kit or drug of disease, present invention combination epicuticle idiosyncratic transcription factor (ESE-1) and GP73 are used for
Hepatopathy is detected, the accuracy rate of detection can be greatly improved；In addition, ESE-1 inhibitor can be used for treating hepatopathy.
To achieve the above object, the technical scheme adopted by the invention is as follows: epithelium idiosyncratic transcription factor or its mRNA are being sieved
Application in the drug of choosing or preparation for treating hepatopathy, the hepatopathy includes hepatitis, cirrhosis and liver cancer.
In addition, the present invention also provides epithelium idiosyncratic transcription factor or its mRNA are being screened or are being prepared for diagnosis of liver disease
Kit in application, the hepatopathy includes hepatitis, cirrhosis and liver cancer.
In addition, the present invention also provides a kind of kits for diagnosis of liver disease comprising measurement epithelium specific transcriptional because
The specific primer of the mRNA transcription amount of son or the antibody for measuring epithelium idiosyncratic transcription factor translation amount, the kit also wrap
The specific primer or measurement II type transmembrane protein of golgiosome for including measurement II type transmembrane protein mRNA transcription amount of golgiosome turn over
The antibody for the amount of translating, the hepatopathy include hepatitis, cirrhosis and liver cancer.
In addition, the present invention also provides a kind of for treating the drug of hepatopathy comprising epithelium idiosyncratic transcription factor inhibits
Agent, the hepatopathy include hepatitis, cirrhosis and liver cancer.
As an improvement of the above technical solution, the epithelium idiosyncratic transcription factor inhibitor is that epithelium specificity is inhibited to turn
The siRNA of record factor mRNA translation or the antibody specifically bound with epithelium idiosyncratic transcription factor.
As an improvement of the above technical solution, the drug further includes pharmaceutically acceptable auxiliary material.
The invention has the advantages that: the present invention to provide ESE-1 and mRNA in the diagnostic kit or medicine for screening or preparing hepatopathy
Application in object, present invention combination epicuticle idiosyncratic transcription factor (ESE-1) and GP73 can be mentioned significantly for detecting hepatopathy
The accuracy rate of high detection；In addition, ESE-1 inhibitor be inhibit epithelium idiosyncratic transcription factor mRNA translation siRNA or with it is upper
The antibody that skin idiosyncratic transcription factor is specifically bound, ESE-1 inhibitor can be used for treating hepatopathy.
Detailed description of the invention
Fig. 1 shows that IL-1 β can stimulate ESE-1 and GP73 simultaneously；Wherein, 1A shows that IL-1 β expresses ESE-1 and GP73
The influence of amount；Figure 1B is shown in Hep3B cell, influence of the various concentration IL-1 β to ESE-1 and GP73 expression quantity；Fig. 1 C is aobvious
Show in Huh7 cell, influence of the various concentration IL-1 β to ESE-1 and GP73 expression quantity；
Fig. 2 shows that hepatitis induces the expression of ESE-1 and GP73；Wherein, Fig. 2A shows that ALT and AST is at any time in mouse model
Between varied concentration；Fig. 2A shows that the expression quantity of ESE-1 and GP73 in hepatic tissue changes over time；Fig. 2 C shows murine liver tissue
In in 0h and for 24 hours when GP73 expression quantity, arrow is expressed as GP73；
Fig. 3 shows that ESE-1 can raise the expression of GP73；Wherein, Fig. 3 A is shown in Hek293T cell, PCR3.1-ESE-
Influence of 1 plasmid transfection to ESE-1 expression quantity；Fig. 3 B shows in Hep3B cell that PCR3.1-ESE-1 plasmid transfection is to ESE-1
With the influence of GP73 expression quantity；Fig. 3 C shows in Huh7 cell that PCR3.1-ESE-1 plasmid transfection is to ESE-1 and GP73 expression quantity
Influence；Fig. 3 D shows that Δ ESE-1 is constructed successfully；Fig. 3 E shows that Δ ESE-1 makees the up-regulation of GP73 in Hep3B and Huh7 cell
With；Fig. 3 F and 3G show that the transcription and translation level of GP73 can be reduced by striking low ESE-1；Fig. 3 H and 3I, which are shown, strikes low ESE-1 cell
In express ESE-1 again after, GP73 expression restore；
Fig. 4 shows the mechanism of ESE-1 regulation GP73 expression；Wherein, Fig. 4 A and 4B shows that the part containing ESE-1 can be activated
GP73 promoter, but the part containing Δ ESE-1 can not；Fig. 4 C shows that the activation of GP73 promoter has the dosage of ESE-1
Dependence；Fig. 4 D shows that ESE-1 acts on three code areas of GP73 promoter；Scheme E and shows that ESE-1 can be with I, III segment
It is combined in conjunction with generation positive effect and the region IV and generates resistant function.
Specific embodiment
Purposes, technical schemes and advantages in order to better illustrate the present invention, below in conjunction with specific embodiments and the drawings pair
The present invention is described further.
Experimental method
Cell origin
Hep3B, HepG2, H μ h7, HEK 293T cell are stored in Eagle culture medium (Gibco, the beauty of D μ lbecco modification
State), it adds 10% fetal calf serum (FBS, U.S. Hyclone), 100 units per ml penicillin, 0.1% (w/v) streptomysin；
To the cell of cell factor processing, 10% fbsc μ lsh culture medium is removed, in addition 2%FBS-c μ lt μ red and IL-1 β (beauty
State Peprotech) before, it is washed twice with PBS.
Plasmid construction and virus formulation
PCI-ESE1 plasmid with ESE-1Flag label is subcloned into pCR3.1 plasmid with Hind III, EcoR V,
Obtain pCR3.1-ese-1 plasmid.The domain ETS (272~354 amino acid) by removing ESE-1 generates pCR3.1- Δ ESE-
1。
Plasmid pS μ per-shESE-1 is to be inserted into the site pS μ per (Oligoengine, Μ SA) using targeting sequence, with
Bgl II and Hind III are combined, and construct the plasmid pS μ per-shESE-1 that siRNA is generated for ESE-1.Inserting will be infectious
ShESE-1 virion, pS μ per-shESE-1 and packaging plasmid cotransfection enter HEK293T cell.After transfecting 48h, containing disease
The supernatant of poison is added 4 mg/ml polybrenes (Sigma, the U.S.) with target cell and is incubated for after 0.45 μm of filtering.
Quantitative PCR
The total serum IgE of cell or liver organization is prepared according to the agreement of manufacturer using Trizol reagent, Lai Shixian mRNA's
It is quantitative.CDNA is synthesized using Reverse Transcriptase kit (Takara).It is real-time in CFX96 that the real-time PCR of SYBR is carried out with specific primer
Detection system (Bio-rad, Μ SA) and glyceraldehyde 3 phosphate dehydrogenase (GAPDH) or 18S are as standardized internal control in PCR
System；Three multiple holes of all reactions.
Western blot analysis
Radiation Electro-immune precipitation reaction test (RIPA) buffer (Beyotime) the supplement protease suppression of 100 μ l of cell
Preparation cocktail (Roche) is resuspended.Cell pyrolysis liquid is analyzed using 12%SDS-PAGE, is transferred on polyvinylidene fluoride film.
Respectively using 5B12 and ab1392 (Abcam) antibody test GP73 albumen and ESE-1 albumen.GAPDH is the anti-GAPDH Dan Ke of mouse
The house keeping protein (Kang Xiang, Shanghai) that grand antibody test is arrived.
Transfection and reporting system
Cell (2 × 104/ every hole) 96 orifice plates are inoculated in, it is transfected after 12h.GP73 promoter and pCR3.1-ESE-1 plasmid
Or Δ ESE-1 or empty plasmid and pRL-TK plasmid and Lipo2000TMCorotation enters cell (Invitroge n).Cell transfecting 36h
After collect, analyzed with Dual-Luciferase detection kit (Promega).All transfections are in triplicate, at least to repeat
Three times.By the firefly luciferase activity of each sample divided by renilla uciferase activity.
Chromatin imrnunoprecipitation
Progress chromatin imrnunoprecipitation is illustrated according to manufacturer using ChIP kit (P2078, Beyotime)
(ChIP) it detects.Hep3B cell (1 × 107) transfected with Flag-tagged ESE-1 expression vector, then with being with or without
10ng/mL IL-1 β hatches 2h.After 36h, 1% formaldehyde crosslinking 10min at room temperature.Nuclear membrane is impaired, and chromatin is divided by ultrasonic cut 7
Clock generated 250 fragments for arriving 1000bp by 10 minutes.After chromatin is mixed with the Protein G of 50 μ l/A magnetic bead (Life), it was incubated for
Night, then with the non-specific rat immune globulin (Chemicon) of 4 μ l or 4 μ l monoclonal mouse Flag labelled antibodies (F1804,
Sigma) 6h is incubated in 4 DEG C of rotations.DNA is precipitated with 10%Chelex-100, carries out quantitative analysis.
Immunohistochemistry and immunofluorescence analysis
Intraperitoneal injection 35ng/kg LPS and 250mg/kg d- galactosamine establishes mouse liver inflammatory model.The protocol
It has obtained Guangzhou biological medicine Institutes of Health Research, the Chinese Academy of Sciences's (IAC Μ C ID:2013016) animal protection and has used mechanism
The approval of the committee.Hepatic tissue puts collection in different times, is then fixed and is sliced (3 μ m-thick).By using testing
Room prepares 10B4 antibody and anti-mouse HRP- secondary antibody, detects mouse GP73, and be then stored in 3,3 '-fiaminobenzidine liquid
In (ZSGB-BIO, Beijing).Slice is carried out visually with application system (motic VM V1) using the scanning of motic digital slices
Change processing.
Immunofluorescence analysis, full thickness human's liver organization sample are derived from Guangzhou overseas Chinese hospital.These tissue samples it is fixed and
It is sliced (3 μm~4 μ m-thick) and is dyed with hematoxylin-eosin (HE) in a sequence of part.People GP73 is determined using antibody 5B12
Position, and fluorescein isothiocynate (Chemicon, Μ SA) is incubated in conjunction with goat anti-mouse immunoglobulin.ESE-1 ab1392
Antibody (Abcam) label, the goat anti-rabbit antibodies in conjunction with rhodamine are incubated for.Nucleus 4,6- diamino -2- benzene indoles
(DAPI, U.S. KPL).Slice uses confocal microscopy (LSM 710, Zeiss, Germany).
Statistical analysis
Data report is average value ± standard error, and at least there are three independent experiments, and using variance analysis, statistical data is used
(* indicates that p < 0.05, * * indicate that p < 0.01, * * * indicate p < 0.001) shown in ANOVA table.
Experimental result
IL-1 β (proinflammatory cytokine) can stimulate ESE-1 and GP73 simultaneously
First in different HCC cell line (HepG2, Hep3B, Huh7), the basis of ESE-1 and GP73 albumen is compared
Level, discovery Huh7 cell has ESE-1 the and GP73 albumen of high level expression, and HepG2 cell only expresses a small amount of ESE-1,
Hardly express GP73 (as shown in Figure 1A)；In other mankind ESE-1 and GP73 similar with also being observed in mouse liver cell
Expression of results.
Whether the expression in order to confirm GP73 is related to the stimulation of IL-1 β, is then handled respectively with the IL-1 β of various dose
Hep3B and Huh7 cell.QPCR and Western blot analysis shows, and Hep3B (Figure 1B) is untreated in Huh7 (Fig. 1 C)
Control group is compared with cell, and through IL-1 β treated sample, the content of ESE-1 obviously rises, and GP73 is also in that dose-dependant increases
Add.These are the result shows that ESE-1 and GP73 produces respective reaction to the stimulation of IL-1 β.
The expression of hepatitis induction ESE-1 and GP73
Using mouse liver inflammatory model, expression of the ESE-1 and GP73 albumen under inflammatory conditions is detected.In different time
Point intraperitoneal injection LPS (phosphoric acid polysaccharide ester) and d- galactosamine, and real-time monitoring serum alanine aminotransferase (ALT) and day
Aspartic acid aminopherase (AST) is horizontal.Glutamic-pyruvic transaminase and glutamic-oxalacetic transaminease as inflammatory reaction standard are 6 small after injection
When peak, illustrate that mouse liver inflammation is induced success.Curve by observing ALT and AST observes (Fig. 2A), 72h
Inflammation is restored afterwards.The liver organization for collecting mouse different time points detects its ESE-1, GP73mRNA expression water using qPCR method
It is flat；It was found that the expression of ESE-1 reaches peak value in 12h, and the expression of GP73 reaches peak value when for 24 hours, and two kinds of mRNA expression are most
Normal level (Fig. 2 B) is restored in 72 hours eventually.Immunohistochemical analysis result confirms that the expression of GP73 is drawn by liver inflammation
(Fig. 2 C) risen.
Human liver cancer tissue sample carries out immunofluorescence technique
The expression of determination of immunofluorescence method its ESE-1 and GP73, HE dyeing are carried out to serial section human liver cancer tissue sample
Show the pathological change of liver organization, GP73 is located at golgiosome, and ESE-1 is distributed in cytoplasm.ESE-1 expression quantity compared with
High region, GP73 expression quantity is also higher, and in cancer beside organism, the expression quantity of two kinds of albumen is lower.
The above research confirm jointly ESE-1 and GP73 can the stimulation in an in vitro environment to IL-1 β make respective reaction,
Liver inflammation triggering in vivo co-expresses, and the expression of two kinds of albumen increases in liver cancer patient sample.
ESE-1 can raise the expression of GP73 in HCC cell
ESE-1 expression plasmid is constructed, PCR3.1-ESE-1 plasmid transfection 293T cell is confirmed that it expresses (Fig. 3 A), when
When ESE-1 is overexpressed in Hep3B cell, the transcription of GP73 and protein level also increase (Fig. 3 B), and Huh7 cell is also demonstrate,proved
Real similar results (Fig. 3 C).
In order to further confirm that ESE-1 is the reason of causing GP73 expression to increase, we construct ESE-1 and lack ETS structure
The mutant (Δ ESE-1) (Fig. 3 D) in domain；Up-regulation of the Δ ESE-1 to GP73 compared with ESE-1, in Hep3B and Huh7 cell
Effect is obvious to weaken (Fig. 3 E).These results all show that the overexpression of ESE-1 increases GP73 expression quantity.
By construct antiretroviral shRNA carrier, we also have evaluated ESE-1 whether in the presence of IL-1 β on
Adjust GP73 expression quantity.Regardless of the stimulation either with or without IL-1 β, as long as by the Hep3B (Fig. 3 F) and Huh7 that strike low ESE-1 processing
Cell (Fig. 3 G), the transcription of GP73 and protein level can all reduce.ESE- is expressed again in two kinds of cells for striking low ESE-1
After 1, GP73 expression restores (Fig. 3 H and 3I).The result shows that ESE-1 can raise the expression of GP73.
ESE-1 regulates and controls the mechanism of GP73 expression
The action site of ESE-1 is the promoter of GP73.In order to be described in detail ESE-1 is how to regulate and control GP73 expression,
ESE-1 and Δ ESE-1 is transfected into liver cell, Hep3B and Huh7 cell jointly with the promoter of GP73 respectively, and discovery contains ESE-
1 part can activate GP73 promoter, but the part containing Δ ESE-1 can not (Fig. 4 A and 4B)；And GP73 promoter
Activation have the dose dependent (Fig. 4 C) of ESE-1.
Based on the core sequence of GP73 promoter gene segment, the code area of three with ESE-1 effect are predicted.It is respectively
GP73 promoter region I (- 1110/-864), III (- 734/-421) and IV (- 421/-79) (Fig. 4 D).In order to confirm ESE-1
Be to act directly on GP73 promoter, the specific binding of ESE-1 Yu these DNA sequence dnas analyzed using ChIP method, then into
Row qPCR.Compared with the control group, after by IL-1 β stimulation, expression quantity obviously rises.This illustrate IL-1 β stimulate under, ESE-
1 acts on three code areas of GP73 promoter, significantly enhances expression activity.
It, can by deleting adjacent two further to confirm that ESE-1 can be in conjunction with three regions of GP73 promoter
The ESE-1 binding site of energy constructs corresponding deletion mutant in these regions.Δ -989/ -965 and Δ -918/ -869 are mutated
Body is located at region I, and -617/ -583 mutant of Δ is located at region II, and Δ -351/ -365 and -261/ -232 mutant of Δ are located at area
Domain IV.By ESE-1 and GP73 overall length promoter (or deletion mutation promoter) cotransfection into Hep3B cell.Dual-Luciferase
Reporting system the result shows that, the vigor that Δ -918/ -869 compares full length fragment with -617/ -583 deletion fragment of Δ is lower, instead
The deletion fragment vigor of Δ -351/ -365 is also risen (Fig. 4 E).This proves that ESE-1 can be combined with I, III segment and generates
Positive effect and the region IV, which combine, generates resistant function；ESE-1 in multiple binding sites in conjunction with GP73 promoter, with ChIP-
QPCR testing result is consistent.
Above all of result all confirms in HCC cell, ESE-1 be bound directly by the promoter with GP73 come
Raise its expression quantity.
Embodiment 1
The present embodiment provides a kind of kits for diagnosis of liver disease comprising measurement epithelium idiosyncratic transcription factor
The specific primer of mRNA transcription amount or the antibody for measuring epithelium idiosyncratic transcription factor translation amount, kit further include that measurement is high
The specific primer of II type transmembrane protein mRNA transcription amount of dictyosome or resisting for measurement II type transmembrane protein translation amount of golgiosome
Body, hepatopathy include hepatitis, cirrhosis and liver cancer.
Embodiment 2
The present embodiment provides a kind of for treating the drug of hepatopathy comprising carries out with epithelium idiosyncratic transcription factor special
Property combine antibody.
Embodiment 3
The present embodiment provides a kind of drugs, for the siRNA for inhibiting epithelium idiosyncratic transcription factor mRNA translation.
Finally, it should be noted that above embodiments protect the present invention to illustrate technical solution of the present invention
The limitation of range, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should be managed
Solution, can modify to technical solution of the present invention or replace on an equal basis, without departing from technical solution of the present invention essence and
Range.
Claims (6)
1. epithelium idiosyncratic transcription factor or its mRNA are screening or are preparing the application in the drug for treating hepatopathy, feature
It is, the hepatopathy includes hepatitis, cirrhosis and liver cancer.
2. epithelium idiosyncratic transcription factor or its mRNA are screening or are preparing the application in the kit for diagnosis of liver disease, special
Sign is that the hepatopathy includes hepatitis, cirrhosis and liver cancer.
3. a kind of kit for diagnosis of liver disease, which is characterized in that the mRNA including measuring epithelium idiosyncratic transcription factor turns
The specific primer of record amount or the antibody for measuring epithelium idiosyncratic transcription factor translation amount, the kit further include measurement Gao Er
The specific primer of II type transmembrane protein mRNA transcription amount of matrix or the antibody for measuring II type transmembrane protein translation amount of golgiosome,
The hepatopathy includes hepatitis, cirrhosis and liver cancer.
4. a kind of for treating the drug of hepatopathy, which is characterized in that including epithelium idiosyncratic transcription factor inhibitor, the hepatopathy
Including hepatitis, cirrhosis and liver cancer.
5. drug as claimed in claim 4, which is characterized in that the epithelium idiosyncratic transcription factor inhibitor is to inhibit epithelium
The siRNA of idiosyncratic transcription factor mRNA translation or the antibody specifically bound with epithelium idiosyncratic transcription factor.
6. drug as claimed in claim 5, which is characterized in that the drug further includes pharmaceutically acceptable auxiliary material.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101985428A (en) * | 2009-07-29 | 2011-03-16 | 杭州民生药业有限公司 | O-anilino benzoic acid derivatives or pharmaceutically acceptable salts thereof as well as preparation method and application thereof |
-
2019
- 2019-01-08 CN CN201910017712.7A patent/CN109828116A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101985428A (en) * | 2009-07-29 | 2011-03-16 | 杭州民生药业有限公司 | O-anilino benzoic acid derivatives or pharmaceutically acceptable salts thereof as well as preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| WANG, F., LONG, Q., GONG, Y. ET AL.: "Epithelium-Specific ETS (ESE)-1 upregulated GP73 expression in hepatocellular carcinoma cells", 《CELL BIOSCI》 * |
| 聂东雷等: "血清高尔基体蛋白73与肝脏疾病研究进展", 《中华实用诊断与治疗杂志》 * |
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