CN101323876A - Protein disulfide bond isomerase A3 and use of antibody thereof in liver cancer detection - Google Patents
Protein disulfide bond isomerase A3 and use of antibody thereof in liver cancer detection Download PDFInfo
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- CN101323876A CN101323876A CNA2007100419585A CN200710041958A CN101323876A CN 101323876 A CN101323876 A CN 101323876A CN A2007100419585 A CNA2007100419585 A CN A2007100419585A CN 200710041958 A CN200710041958 A CN 200710041958A CN 101323876 A CN101323876 A CN 101323876A
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Abstract
The invention verifies that protein disulfide isomerase A3 expression in the cancer tissues and adjacent tissues of hepatocellular carcinoma is different through screening the protein having differential expression in the cancer tissues and adjacent tissues of hepatocellular carcinoma and carrying out western blot experiment. The invention discloses the application of the protein disulfide isomerase A3 to the detection of liver cancer and/or susceptibility of liver cancer and the application of the antibody of the protein disulfide isomerase A3 to the detection of liver cancer and/or susceptibility of liver cancer. Therefore, as the potential marker of liver cancer, the protein disulfide isomerase A3 can serve as a marker of the prognosis molecule of liver cancer and a target molecule of clinical treatment.
Description
Technical field
The invention belongs to the biotechnology detection range, specifically, the present invention relates to the application in detecting liver cancer of a kind of protein disulfide bond isomerase A 3 and antibody thereof.
Background technology
Liver cancer is a kind of serious harm Human diseases.The sickness rate of western developed country liver cancer is lower, still comparatively weak to the fundamental research of liver cancer in the world, and China country occurred frequently that is liver cancer, M ﹠ M presents ascendant trend, and age of onset constitutes rejuvenation, the medical expense that is used for liver cancer treatment every year greatly increases, liver cancer has become serious harm China people life property safety's dead enemy, and be an important factor that influences socio-economic development, the fundamental research of going into overdrive to carry out China's liver cancer has strategic importance, and separates and identify that new liver cancer related gene is the advanced subject in the present liver cancer fundamental research.
Up to the present, the gene unconventionality expression that does not have 20 kinds is determined relevant with the generation development of liver cancer, but the unconventionality expression rate of fixed liver cancer related gene in liver cancer is not high, and the pathogenesis of liver cancer is not illustrated so far yet, and the early diagnostic rate of liver cancer still remains to be improved.In addition, traditional operation of liver cancer adds chemotherapy and the several genes methods of treatment that is used does not in recent years still have obviously to improve the survival rate of liver cancer patient, thereby especially liver cance high-expression gene is significant for the pathogenesis of inquiring into liver cancer to seek new liver cancer related gene.
Therefore, to research and develop in liver cancer the gene and/or the albumen of high expression level significant for treatment and diagnostic purpose.This area press for new in liver cancer the gene and/or the albumen of high expression level.
Protein disulfide bond isomerase A 3 (Protein disulfide-isomerase A3), becoming the Genebank accession number of endoplasmic reticulum albumen 57 (Endoplasmic Reticulum protein 57) again is gi|2507461|, the accession number of NCBI is P30101, the Swissprot accession number is P30101, is for IPI number: IPI00025252.1.The present protein disulfide bond isomerase A 3 that studies show that is a kind of how localized, multi-functional protein, and its location discovers that in addition it is present in cytolemma and nucleus except the endoplasmic reticulum that original research is found; Its function also not only is confined to the disulfide bond isomerase activity that original research is found, discovers that also it has cell-membrane receptor function and dna binding activity.
The still initial disulfide bond isomerase activity of finding of the present topmost function of protein disulfide bond isomerase A 3, it belongs to the protein disulfide isomerase family of redox enzymes, and the non-natural disulfide linkage in the mammalian cell endoplasmic reticulum in the catalytic proteins ripening process transforms to natural disulfide linkage.Whether so-called natural and non-natural disulfide linkage are to distinguish under the protein active state according to disulfide linkage, and the formation of natural disulfide linkage promotes protein maturation and makes it have normal activity.Studies show that protein disulfide bond isomerase A 3 is the special disulfide bond isomerase of a kind of glycoprotein, also is the key factor of endoplasmic reticulum quality control in the secretory protein ripening process.At least 17 kinds of disulfide bond isomerases are arranged in the mammalian cell endoplasmic reticulum, and they are to be undertaken by the B structural domain that determines substrate specificity to the identification of its substrate.
This function of protein disulfide bond isomerase A 3 and cancer have necessarily gets in touch.Genomic instability that cancer causes or hypoxemia microenvironment can cause that usually a large amount of protein can not normal mature be accumulated in endoplasmic reticulum and cause endoplasmic reticulum pressure; and then cause natural death of cerebral cells; but cancer cells itself can obtain or strengthen its ability of alleviating endoplasmic reticulum pressure again; thereby guarantee its survival, this homeostasis of cancer may become new treatment target spot.
Also have document to show, protein disulfide bond isomerase A 3 also has distribution in nucleus.An A structural domain is contained in his C-terminal zone, has dna binding activity, discovers that it is the key factor of STATA3 signal path kind
Have document to show that it is a kind of membrane receptor simultaneously again, the initial signal path of mediation steroid hormone film discovers that it has two Trx structural domains, can promote dimerization and part combination.
Up to the present, also there is not the Cancer-Related report of protein disulfide bond isomerase A 3 and liver cell.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of protein disulfide bond isomerase A 3 and the application of antibody in detecting liver cancer thereof, to solve defective of the prior art.
Principle of the present invention is: by the protein of screening differential expression in hepatocellular carcinoma cancerous tissue and hepatocellular carcinoma cancer beside organism, the applicant found a kind of in hepatocellular carcinoma cancerous tissue and cancer beside organism in there are differences expressed protein (up-regulated expression in cancerous tissue), be accredited as protein disulfide bond isomerase A 3 through mass spectrum.With non-enzymolysis sample preparation method (nonenzymatic samplepreparation, NESP) cancerous tissue of Zhi Bei hepatocellular carcinoma and cancer beside organism's protein example, with the leucic HepG2 that mixes the C13 mark and the mixture of L02 clone sample is interior mark, by conventional gel electrophoresis technology, in conjunction with screening of polyphone mass-spectrometric technique and evaluation differential expression protein, found that protein disulfide bond isomerase A 3 up-regulated expression in the hepatocellular carcinoma cancerous tissue.Immunoblot experiment confirms that further protein disulfide bond isomerase A 3 there are differences expression really in the cancerous tissue of hepatocellular carcinoma and cancer beside organism.
Based on this dependency of protein disulfide bond isomerase A 3 and hepatocellular carcinoma, the present invention at first provides the application of protein disulfide bond isomerase A 3 in detecting liver cancer and/or liver cancer susceptibility.Reach if protein disulfide bond isomerase A 3 is presented mileometer adjustment in liver cell to be checked, then this liver cell to be checked of prompting is a liver cancer cell.
In addition, the present invention also provides the application of antibody (comprising monoclonal antibody and polyclonal antibody) in detecting liver cancer and/or liver cancer susceptibility of anti-protein disulfide bond isomerase A 3.
The present invention also provides a kind of test kit that is used to detect liver cancer and/or liver cancer susceptibility, and this test kit has comprised protein disulfide bond isomerase A 3 and working instructions.
Put down in writing protein disulfide bond isomerase A 3 on the wherein said specification sheets, merged the antibody that uses protein disulfide bond isomerase A 3.Wherein said antibody comprises monoclonal antibody and polyclonal antibody.
The present invention also provides the method for protein disulfide bond isomerase A 3 in a kind of vitro detection hepatic tissue, and this method may further comprise the steps:
The antibody (monoclonal antibody or polyclonal antibody) of A, usefulness specificity anti-protein disulfide bond isomerase A 3 detects the quantity of protein disulfide bond isomerase A 3 in the liver cell to be measured;
The quantity of B, protein disulfide bond isomerase A 3 that steps A is recorded and the quantity of the protein disulfide bond isomerase A 3 in the normal liver tissue compare.
As the albumen quantity that records is higher than normal value, represents that then the expression of protein disulfide bond isomerase A 3 in the liver cell to be measured exists unusual.
This discovery of the present invention will provide a brand-brand-new way for the diagnosis and/or the treatment of hepatocellular carcinoma.As the potential sign of hepatocellular carcinoma, protein disulfide bond isomerase A 3 is at the prognosis molecule mark that can be used as liver cancer and the target molecule of clinical treatment.
Characteristics such as the employing protein disulfide bond isomerase A 3 detects liver cancer and compares with existing liver cancer detection method, has the reliability height, and specificity is good can reduce the false positive rate in the testing process, improve the accuracy that detects.
Description of drawings
Fig. 1: the immunoblotting assay result of protein disulfide bond isomerase A 3
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.
The experimental technique of unreceipted actual conditions in the following example, usually according to people such as normal condition such as Sambrook, molecular cloning: laboratory manual (New York:Cold Spring HarborLaboratory Press, 1989) condition described in, or the condition of advising according to manufacturer.
Embodiment 1, hepatocellular carcinoma cancerous tissue and cancer beside organism's protein example preparation
Employed urea, 3-[(3-courage amido propyl in the present embodiment)-the diethyl ammonium]-1-propanesulfonic acid (CHAPS), sodium laurylsulfonate (SDS), dithiothreitol (DTT) (DTT) be all available from Sigma company.
Present embodiment with non-enzymolysis sample preparation method (nonenzymatic sample preparation, NESP) preparation hepatocellular carcinoma cancerous tissue and cancer beside organism's protein example, specific as follows:
The flesh tissue piece of excision places rapidly on ice, is cut into fast that several naked eyes are visible, the fritter of no necrotic zone.RPMI1640 substratum (5% foetal calf serum that does not contain glutamine with precooling, 0.2mM PMSF, 1mM EDTA, oxacillin 25mg/mL, gentamicin 50mg/mL, penicillin 100U/mL, Streptomycin sulphate 100mg/mL, amphotericin B 0.25mg/mL, nystatin 50U/mL) after washing organizes fritter for several times, in liquid nitrogen, grind to form cell precipitation fast, cell precipitation is dissolved in an amount of lysate (8mol/L urea respectively, 4%CHAPS, 40mmol/L Tris and 65mmmol/L DTT) in, (Soniprep 150, Britain for the ultrasonic cell disintegration instrument, MSE) ice bath ultrasonic 2min at intermittence, 15000r/min, 4 ℃ of centrifugal 1h.Get supernatant, it is quantitative to carry out gross protein with the Bradford method (seeing Bio-Rad company product description) of improvement, the hepatocellular carcinoma cancerous tissue for preparing and the protein example packing of corresponding adjacent tissues, and-80 ℃ of preservations are standby.
With 16 pairs of hepatocellular carcinoma cancerous tissues of method for preparing and cancer beside organism's protein example.16 routine hepatocellular carcinoma samples clearly are hepatocellular carcinoma all from east hospital of liver and gall surgical department by 2 doctors of Pathology Deparment.Be the male sex, 49.4 years old mean age (31～65 years old), serum detects the hepatitis B virus infection positive, and 16 examples (100%) belong to TNM classification III level.Wherein, AFP is higher than 15 examples (93.75%) of 25 μ g/L; 14 routine tumours are greater than 5cm.The pathological data of 16 routine hepatocellular carcinoma samples sees following table 1 for details.
The pathological data of table 1,16 routine hepatocellular carcinoma samples
The used cancerous tissue of present embodiment and cancer beside organism's sample are the paired samples of taking from same hepatocellular carcinoma patient, all 16 routine hepatocellular carcinoma cases have the case diagnosis index of fairly similar: be the male sex, 49.4 years old mean age (31～65 years old), serum detects the hepatitis B virus infection positive, and 16 examples (100%) belong to TNM classification III level.Wherein, AFP is higher than 15 examples (93.75%) of 25 μ g/L; 14 routine tumours are greater than 5cm.This sampling method helps reducing between individuality difference to the influence of experimental analysis work.
Embodiment 2, the preparation of mixing the leucic HepG2 and the L02 clone sample of C13 mark
The leucine of the C13 mark that uses in the present embodiment is available from Cambridge IsotopeLaboratories, Inc company; The dialysis foetal calf serum is available from hyclone company; The D9785 substratum is available from Sigma company.
Hepatocellular carcinoma cells is that HepG2 and normal liver cell are that the L02 cell is cultivated more than six generations in mixing the leucic D9785 substratum of C13 mark (20% dialysis foetal calf serum), transfer to the 10cm culture dish, when treating that cell covers with 80%, it is inferior to give a baby a bath on the third day after its birth with the phosphoric acid buffer of 4 ℃ of precoolings on ice, with an amount of lysate (8mol/L urea, 4%CHAPS, 40mmol/L Tris and 65mmmol/LDTT) cracking, scrape with cell, (Soniprep 150 for the ultrasonic cell disintegration instrument, Britain, MSE) ice bath ultrasonic 2min at intermittence, 15000r/min, 4 ℃ of centrifugal 1h.Get supernatant, it is quantitative to carry out gross protein with the Bradford method (seeing Bio-Rad company product description) of improvement, the hepatocellular carcinoma cancerous tissue for preparing and the protein example packing of corresponding adjacent tissues, and-80 ℃ of preservations are standby.
Embodiment 3, zymolysis technique and mass-spectrometric technique are carried out the screening of the differentially expressed protein of hepatocellular carcinoma cancerous tissue and cancer beside organism in utilization gel electrophoresis technology, the glue
The urea that uses in the present embodiment, 3-[(3-courage amido propyl)-the diethyl ammonium]-1-propanesulfonic acid (CHAPS), sodium laurylsulfonate (SDS), dithiothreitol (DTT) (DTT) be available from Sigma company; Iodo-acid amide (IAA), acrylamide, N, N-methylene diacrylamide etc. are available from Fluka company.
Ammonium Persulfate 98.5 (IAA), TEMED, PDQuest software etc. are the Bio-Rad product.
LCQ
TMDeca XP system and ProteomeX
TMWorkstation is available from Thermo Finnigan company.
Get the cancerous tissue of 16 pairs of hepatocellular carcinomas that embodiment 1 obtains and 5 couple in cancer beside organism's protein example, other gets leucic HepG2 that mixes the C13 mark and L02 clone sample that embodiment 2 obtains, zymolysis technique and mass-spectrometric technique are carried out the screening of cancerous tissue and cancer beside organism's differential expression protein in attached gel electrophoretic technique, the glue, and be specific as follows:
At first 5 pairs of cancerous tissues and cancer beside organism's sample (f31, f32, f33, f39,320) are respectively got 20 μ g, be mixed into cancerous tissue biased sample 100 μ g and cancer beside organism's biased sample 100 μ g respectively; Also wait quality to be mixed into the clone biased sample in the leucic HepG2 and the L02 clone sample that mix the C13 mark; Be mixed into 200 μ g with quality such as cancerous tissue biased sample and cancer beside organism's biased samples respectively getting 100 μ g clone biased samples respectively.
Then each 200 μ g of two groups of biased samples are mixed with sample-loading buffer, adopt the gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis (that is: SDS-PAGE) of concentration 7.5-17.5% to separate, deposition condition is 15mA/ glue 30min, and 30mA/ glue is retained to tetrabromophenol sulfonphthalein from glue lower edge 0.5cm then.
Enzymolysis and mass spectrum qualification process are as follows in the ensuing glue: the swimming lane that contains the mixed protein quality sample is by manual cutting on the Kao Masi light blue stained gel of mass spectrum compatibility, each swimming lane cuts 23 bands, at 100mM NH4HCO3, decolour in 30% acetonitrile, vacuum lyophilization, (pH 8.3 for 100 μ l50mmol/L NH4HCO3, protein: trypsinase=1: 5, w/w) place 2hr for 4 ℃ in, add 20 μ l 50mmol/L NH4HCO3 (pH 8.3), 37 ℃ of enzymolysis spend the night.Extracting albumen (60% acetonitrile, 0.1% trifluoroacetic acid), vacuum lyophilization.LCQTM Deca XP system (Thermo Finnigan) identifies the good sample of enzymolysis, and Bioworks software carries out database search.
Use zymolysis technique, mass-spectrometric technique in gel electrophoresis technology, the glue, present embodiment has identified 491 kinds of differentially expressed protein.Wherein, in the hepatocellular carcinoma cancerous tissue high expression level be 259 kinds of protein; High expression level is 232 kinds of protein in the hepatocellular carcinoma cancer beside organism.
In the differential expression spectrum, protein disulfide bond isomerase A 3 is expressed in cancerous tissue obviously and is raised, the 1D-LC-MS/MS mass spectrum identifies that getting 9 non-repetition peptide sections (identifying 60 peptide sections altogether) with database search conforms to protein disulfide bond isomerase A 3 and satisfy marking condition (Delta Cn value 〉=0.1, and X corr value: if 1 electric charge 〉=1.9, if 2 electric charge 〉=2.2, if 3 electric charge 〉=3.75), the amino acid fraction of coverage is 37.23%, and concrete outcome sees following table 2 for details:
Table 2, protein disulfide bond isomerase A 3 mass spectrum qualification result
Embodiment 4, the protein disulfide bond isomerase A 3 expressing protein immunoblotting checking
For confirming the differential expression of protein disulfide bond isomerase A 3, get 10 hepatocellular carcinoma patients' cancerous tissue and (the NESP method preparation of corresponding adjacent tissues protein example, f31 in the table 1, f32, f33, f39,3 20,3 17,45,48,4 15,4 24), carry out immunoblotting assay with the anti-protein disulfide bond isomerase A 3 antibody of buying, detailed process is summarized as follows: each sample is got 20 μ g protein examples and is separated with 12%SDS-PAGE, be transferred on the pvdf membrane (available from Amersham Biosciences company), the one anti-mouse-anti human protein disulfide bond isomerase A 3 monoclonal antibody of using is (available from abcam, Inc, 1: 1000), 4 ℃ of overnight incubation, (every liter contains Tris 2.42g with TBST, sodium-chlor 8g, Tween20ml, regulate pH to 7.6 with HCl) wash three times, each 5 minutes, two anti-for anti-mouse antibody (available from Santa Cruz company, 1: 10000), incubated at room 1 hour, with TBST washing three times, each 10 minutes, use ECL plus reagent (Amersham Biosciences) reaction after 5 minutes at last again, with X-mating plate exposure tests, detected result as shown in Figure 1.
The immunoblotting result of Fig. 1 shows, have at least 9 pairs to present such phenomenon in the 10 pairs of cancerous tissues and the cancer beside organism: the concentration of the hybridization band of protein disulfide bond isomerase A 3 is all apparently higher than corresponding cancer beside organism in the cancerous tissue; As seen there is high expression level in protein disulfide bond isomerase A 3 in the cancerous tissue of hepatocellular carcinoma.
In sum, protein disulfide bond isomerase A 3 there are differences expression in the cancerous tissue of hepatocellular carcinoma and cancer beside organism, and obviously the generation development with hepatocellular carcinoma has close dependency, so its expression amount can be used as an index and is used to detect hepatocellular carcinoma.Accordingly, the antibody of specificity anti-protein disulfide bond isomerase A 3, the monoclonal antibody and the polyclonal antibody that comprise various anti-protein disulfide bond isomerase A 3s, because it can be used in the expression amount that detects protein disulfide bond isomerase A 3, thereby can be used to detect liver cancer and/or liver cancer susceptibility, perhaps be used to prepare the preparation that detects the liver cancer liver cancer susceptibility, this is conspicuous for a person skilled in the art.
Though dynamic biological function of protein involved disulfide bond isomerase A 3 and tumour related mechanism are still waiting further research, but be sure as the marker that detects liver cancer or liver cancer susceptibility with it.Protein disulfide bond isomerase A 3 can be used as the potential sign of hepatocellular carcinoma, and its biological function prompting protein disulfide bond isomerase A 3 in born of the same parents may be as the prognosis molecule mark of liver cancer and the target molecule of clinical treatment.
Claims (9)
1, the application of protein disulfide bond isomerase A 3 in detecting liver cancer and/or liver cancer susceptibility.
2, application according to claim 1 is characterized in that protein disulfide bond isomerase A 3 presents mileometer adjustment and reach in the liver cancer cell tissue.
3, the application of the antibody of anti-protein disulfide bond isomerase A 3 in detecting liver cancer and/or liver cancer susceptibility.
4, application according to claim 3 is characterized in that described antibody is monoclonal antibody or polyclonal antibody.
5, a kind of test kit that is used to detect liver cancer and/or liver cancer susceptibility is characterized in that this test kit has comprised protein disulfide bond isomerase A 3 and working instructions.
6, test kit according to claim 5 is characterized in that having put down in writing protein disulfide bond isomerase A 3 on the described specification sheets, merges the antibody that uses protein disulfide bond isomerase A 3.
7, test kit according to claim 6 is characterized in that described antibody is monoclonal antibody or polyclonal antibody.
8, the method for protein disulfide bond isomerase A 3 in a kind of vitro detection liver cell tissue is characterized in that may further comprise the steps:
The quantity of protein disulfide bond isomerase A 3 in the antibody test liver cell to be measured of A, usefulness specificity anti-protein disulfide bond isomerase A 3;
The quantity of B, protein disulfide bond isomerase A 3 that steps A is recorded and the quantity of the protein disulfide bond isomerase A 3 in the normal liver tissue compare.
9, application according to claim 8 is characterized in that described antibody is monoclonal antibody or polyclonal antibody.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103966173A (en) * | 2014-05-04 | 2014-08-06 | 苏州大学 | Hybridoma cell, monoclonal antibody generated by hybridoma cell and application of monoclonal antibody |
| CN110455903A (en) * | 2018-05-07 | 2019-11-15 | 天士力生物医药股份有限公司 | A kind of gradient electrophoresis detection method of injection recombinant human urokinase zymogen impurity analysis |
-
2007
- 2007-06-13 CN CNA2007100419585A patent/CN101323876A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103966173A (en) * | 2014-05-04 | 2014-08-06 | 苏州大学 | Hybridoma cell, monoclonal antibody generated by hybridoma cell and application of monoclonal antibody |
| CN110455903A (en) * | 2018-05-07 | 2019-11-15 | 天士力生物医药股份有限公司 | A kind of gradient electrophoresis detection method of injection recombinant human urokinase zymogen impurity analysis |
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Open date: 20081217 |