CN104360062B - Application of the Peptidylarginine deiminase 1 in clinical tumor diagnostic reagent is prepared - Google Patents
Application of the Peptidylarginine deiminase 1 in clinical tumor diagnostic reagent is prepared Download PDFInfo
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Abstract
The invention discloses application of the Peptidylarginine deiminase 1 in the reagent for clinical diagnosis for preparing diagnosing tumour or detectable substance, the tumour is selected from the cancer of the uterus, liver cancer, cancer of the stomach, the cancer of the esophagus, oophoroma, lung cancer.During concrete application, 1 antibody of anti-Peptidylarginine deiminase is prepared in conventional manner, set up qualitative or quantitative method and the matched reagent box of detection Peptidylarginine deiminase 1.The invention also discloses a kind of Blood diagnosis reagent of diagnosing tumour, including the conventional reagent in 1 antibody of Peptidylarginine deiminase, HRP IgG antibody, and Blood diagnosis reagent.Conventional reagent in the Blood diagnosis reagent includes carbonate buffer solution, PBST washing lotion, confining liquid, nitrite ion and terminate liquid.Present invention firstly discovers that PAD1 can be applied as tumor blood mark, the experiment proved that, PAD1 has feasibility as tumor markers.
Description
Technical field
The present invention relates to Peptidylarginine deiminase 1 is preparing clinical tumor Blood diagnosis as tumor blood mark
Application in reagent.
Background technology
Peptidylarginine deiminase (Peptidylarginine deiminase, PAD or PADI) be in tissue
A kind of middle enzyme, at present, is found that five kinds of PAD enzymes (i.e. PAD/PADIl, 2,3,4 and 6) altogether.These enzymes are by being seated in human chromosome
Cluster coded by said gene on body lp36 region, and with different Tissue distribution.It can be in the presence of calcium ion
Translation modification (post-translational modification) after carrying out to some other histone.This enzyme can be by
The amino of the arginine (arginine) in polypeptide chain is catalyzed into carbonyl, so that conversion of Arginine becomes citrulling
(citrulline).Citrulling is a non-natural amino acid.In this polypeptide being catalyzed by PAD, conversion of Arginine becomes citrulling
Process be referred to as citrullinated (citrullination).As structure changes after albumen generation is citrullinated, cause
Its enzymatic activity, metabolic activity, regulatory function and structure function all change.Therefore, citrullinated it is and phosphorylation, acetyl
Change, glycosylate, methylating, mode is modified after protein translation that ubiquitination is equally important.
In recent years, by the research of immunology, cellular biochemistry and molecular genetics, PAD4 (the de- Asia of peptidyl arginine
Amine enzyme 4, Peptidylarginine deiminase 4, or PADI4) it is proved in people's rheumatoid arthritis pathogenic process
In play very important effect, and can be applied in gland cancer reagent for clinical diagnosis is prepared as adenocarcinoma marker.PAD1
Although (Peptidylarginine deiminase 1, Peptidylarginine deiminase 1, or PADI1) and PAD4 are all peptidyl
Arginine deiminase, but with different Tissue distribution, PAD1 is not related at present as the phase of tumor blood mark
Close report.
Content of the invention
For above-mentioned prior art, the present invention has obtained a kind of new tumor blood mark peptidyl essence by research
Propylhomoserin takes off imines enzyme 1 (PAD1/PADI1), can be used for the clinical diagnosis of tumour.
The present invention is achieved by the following technical solutions：
The present invention had found first by experimental study, with benign tumour patients serum, chronic inflammation patients serum and normal
Human serum is compared, expression of the PAD1 in the sera of patients with malignant tumors such as liver cancer, the knot/carcinoma of the rectum, breast cancer, Esophageal and cardiac cancer
Level substantially increases.PAD1 can be while express, this is in the tumor marker for using at present in Several Kinds of Malignancy patients serum
In be that fewer (current tumor blood label Sensitivity and Specificity is undesirable, and clinical existing tumour serum label reaches
More than 20 plant, but the overwhelming majority is often only used for detecting a kind of tumour that Sensitivity and Specificity is poor, are typically only capable to using joint inspection
Survey and significant data could be provided for clinical diagnosis).The present invention is by PAD1 expression in blood and known cancer mark
Note thing level is compared, it is found that PAD1 lesion detection positive rate and specificity are no less than CEA, broad spectrum activity higher than CA125,
CA199, PSA, CA242 etc..
Found based on above, PAD1 has higher specificity as the application of tumour serum label, for this purpose, the present invention grinds
Diagnostic area is wide, sensitiveness is strong, specificity is high tumor diagnosis kit and detection method is sent out, can be widely used for clinical tumor
Preliminary investigation and health screening, are that clinical diagnosis provides reliable basis.
Specifically, prepare 1 antibody of anti-Peptidylarginine deiminase in conventional manner, set up the de- Asia of detection peptidyl arginine
The qualitative or quantitative method of amine enzyme 1 and matched reagent box.
A kind of Blood diagnosis reagent of diagnosing tumour, including 1 antibody of Peptidylarginine deiminase, HRP-IgG antibody, with
And the conventional reagent in Blood diagnosis reagent.
Conventional reagent in the Blood diagnosis reagent include carbonate buffer solution, PBST washing lotion, confining liquid, nitrite ion and
Terminate liquid.
Further, qualitatively detection method is indirect ELISA method, and its principle is that the antiantibody marked using enzyme is (anti-
Human immunoglobulin(HIg) antibody) with detection combined with solid phase antigen by antibody is examined, concrete mode is as follows：
(1), after blood sample to be detected being diluted 10 times with carbonate buffer solution (pH9.6), add in blank ELISA Plate, 37 DEG C
Incubate 2h；
(2) discard in the hole liquid, PBST washing lotion wash plate three times (the PBST washing lotion refers to PBS solution plus Tween-20,
The pH of PBS solution is 0.1% for the concentration of 7.4, Tween-20, percentage by volume)；
(3) 200 μ L/ hole of confining liquid (0.5%BSA, mass percent), 37 DEG C of incubation 1h are added per hole；
(4) in the hole liquid is discarded, and PBST washing lotion washes plate three times；
(5) per group plus PAD1 antibody diluent (1:2000 dilutions) 100 μ L/ holes, 37 DEG C of incubation 1h；
(6) in the hole liquid is discarded, and PBST washing lotion washes plate three times；
(7) add HRP-IgG antibody diluent (1 per hole:3000 dilutions) 100 μ L, 37 DEG C of incubation 1h；
(8) in the hole liquid is discarded, and PBST washing lotion washes plate five times；
(9) nitrite ion A, B are added per hole【Developer A (containing hydrogen peroxide) is hydrogen donor (DH2), and substrate B is exactly developer B
(containing TMB, 3,3', 5,5'- tetramethyl benzidines)】Each 50 μ L, 37 DEG C of colour developing 10min.
(10) 50 μ L terminate liquid (2M H are added per hole2SO4Solution) color development stopping, shake even, OD is detected with ELIASA450nmValue；
(11) calculate：With negative serum (normal human serum) as control, negative serum OD is detected450nmAverage is (be with many parts
Negative serum is the out average again value of control test)；By OD450nmValue substitutes into formula P/N value=blood sample OD to be measured450nmValue/cloudy
Property serum OD450nmAverage, is calculated the P/N value of blood sample to be detected；
(12) judge：If the P/N value of blood sample to be detected is more than or equal to 2.1, the testing result of the blood sample to be detected is
The positive, the patient belonging to blood sample to be detected are possible to tumour, can be used as one of foundation of clinical diagnosis.
Above-mentioned involved antibody, for being prepared by a conventional method to obtain.Above-mentioned involved various reagents, are existing
Existing conventional reagent in technology.
In the same manner, when quantitative determination is carried out, above-mentioned Cleaning Principle is also adopted by, the standard items of series concentration is prepared, is then drawn
Standard concentration and OD450nmValue or OD630nmThe calibration curve of value, and equation of linear regression is obtained, then by blood sample to be detected
OD450nmValue or OD630nmValue substitutes into calibration curve, tries to achieve the concentration in sample.
Further, during quantitative determination, PAD1 is detected using double-antibody sandwich elisa, step is as follows：
(1) it is coated：The use of PAD1 monoclonal antibody 1 is coated liquid (carbonate buffer solution of pH9.6) 1 μ g/mL is diluted to, plus
To blank ELISA Plate, 100 μ L/ holes, 4 DEG C of saturated humidity left overnight；
(2) plate is washed：In the hole liquid is discarded, and 300 μ L of PBST washing lotion is added per hole, and (the PBST washing lotion refers to that PBS solution adds
Upper Tween-20, the pH of PBS solution are the concentration 0.1% of 7.4, Tween-20, percentage by volume), soak 15 seconds, get rid of and abandon liquid
Body.Plate three time is continuously washed；
(3) close：Add 200 μ L/ hole of confining liquid (0.5%BSA, mass percent), 37 DEG C of incubation 1h per hole；
(4) plate three times, same to step (2) are washed；
(5) set：Stay a hole to make blank, any liquid wouldn't be added；Separately set 7 hole of PAD1 standard items, respectively plus 100 μ L mark
Quasi- product；
(6) it is loaded：After blood sample to be detected is diluted 10 times with PBST, added in reacting hole in order, incubated at room 1.5h；
(7) plate three times, same to step (2) are washed；
(8) enzyme-added：Each hole adds PAD1 monoclonal antibody dilution (1/3000) of 100 μ LHRP mark (not include sky
White control), incubated at room 45min；
(9) plate three times, same to step (2) are washed；
(10) develop the color：Nitrite ion A, B are sequentially added per hole【Developer A (containing hydrogen peroxide) is hydrogen donor (DH2), substrate B
It is exactly developer B (containing TMB, 3,3', 5,5'- tetramethyl benzidines)】Each 50 μ L (including blank), concussion are mixed, room temperature
Lucifuge develops the color 10 minutes；
(11) terminate：Add terminate liquid each 50 μ L (including blank) per hole, concussion mixing terminating reaction；
(12) determine：Returned to zero with blank control wells, and each hole OD was determined with ELIASA Single wavelength 450nm in 30 minutes
Value；Also each hole OD value can be determined with dual wavelength 450nm/630nm；
(13) calculate：Logarithm value with serial standards concentration value (X-axis) as abscissa, with the logarithm value of standard items OD value
For ordinate (Y-axis), (log-log) calibration curve is set up, calculate the PAD1 content of sample to be tested.
In addition, qualitatively detection method is alternatively colloidal gold method, its Cleaning Principle is：Using double antibody sandwich method and colloid
Golden immunological technique, adds anti-PAD1 antibody colloidal gold conjugate in colloidal gold pad in advance, nitrocellulose filter detection line and
Anti- PAD1 antibody is coated with control line respectively.When being detected, it is such as positive sample, the PAD1 in sample can be anti-with gold mark
PAD1 antibody combines to form compound, and as chromatography effect compound is moved forward along test paper then pre-coated with detection line is anti-
Body combines to form " gold labeling antibody-PAD1- antibody " compound and aggegation develops the color.While being coated with a Quality Control on nitrocellulose membrane
Line is used as control, therefore is judged to the positive when there is a red nature controlling line and a red response line.When nothing in sample to be checked
During PAD1 antigen, only there is a red nature controlling line and be judged to feminine gender.As Quality Control, no matter result is positive or negative, can all go out
An existing red nature controlling line.If occurring nothing red line (or only response line), it is invalid to detect.Specifically detection method is：
(1) with a small amount of sample of clean container collection (serum sample venous collection according to a conventional method；The sample of collection is five
In it, detection, need to place 4 DEG C of preservations, need within more than five days to place -20 DEG C of preservations, it is to avoid multigelation；If sample occurs muddy
Or precipitation, detected after should being centrifuged or filtering clarification again)；Inner packing is opened, takes out Test paper.
(2) operated according to product type：
1. detector bar：(note within 30 seconds in one end immersion sample that detector bar is indicated MAX printed words：Liquid level should not have MAX
Line) take out lie against on table top.
2. detection blocks：Indicate in the well of " S " printed words in detection card, sample (about 100 μ l) is dripped with dropper dropping 4.
(3) timing after appearance to be detected to bar nature controlling line (C line), observes result in 20 minutes, observe result later within 20 minutes
Invalid.
The explanation of assay：
(1) negative findings：Only there is nature controlling line (C line).
(2) positive findings：There is two lines, i.e. nature controlling line (C line) and detection line (T line).
(3) null result：Wireless occur, or detection line (T line) only occurs, must detect again.
Present invention firstly discovers that PAD1 can be multiple pernicious in the cancer of the uterus, liver cancer, cancer of the stomach, the cancer of the esophagus, lung cancer and oophoroma etc.
High expression in the cell of tumour and in blood, therefore, PAD1 can be applied as tumor blood mark, through experiment card
Bright, its specificity is no less than CEA, and broad spectrum activity is higher than CA242, CA125, PSA, CA199 etc..Although PAD1 table in kinds of tumors
Reach, do not reach absolute specificity, but, known in one of ordinary skill in the art, clinical detection index specific non-definitely
Can not negate uniquely feasibility of the Testing index as one of the means for diagnosing relevant disease, for example doctor is often by several inspections
Survey index final diagnosis is made with reference to clinical manifestation.Therefore, PAD1 has feasibility as tumor markers；Although PAD1 has
Not exclusive specificity, but PAD1 is also enough to be used in as tumor blood mark with reference to other Testing index and clinical manifestation
Detection tumour (this mode is also normal method at present clinically).In addition, it has also been found that, PAD1 is alternatively arranged as blood
Mark is applied to the detection of the other diseases such as inflammation, and such as hepatitis B, general inflammation (with leucocyte, neutrophilic leukocytosis, drenches
The symptom that bar cells ratio reduces), ephrosis (including nephrotic syndrome, kidney failure, ephritis), uremia is (including uremia and urine
Road feel contaminates), also can be used as one of the clinical diagnosis of the Other diseases such as inflammation foundation.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.
Involved reagent, method etc. in following embodiments, unless otherwise noted, are conventional examination of the prior art
Agent, method.
1 PAD1 of embodiment is used as the detection example 1 of tumor blood mark
Using PAD1 as tumor blood mark, the blood to tumor patient is detected, the number of cases of tumor patient and
The species of suffered from tumour refers to table 1.
Detection method is：
(1), after blood sample to be detected being diluted 10 times with carbonate buffer solution (pH9.6), add in blank ELISA Plate, 37 DEG C
Incubate 2h；
(2) discard in the hole liquid, PBST washing lotion wash plate three times (the PBST washing lotion refers to PBS solution plus Tween-20,
The pH of PBS solution is 0.1% for the concentration of 7.4, Tween-20, percentage by volume)；
(3) 200 μ L/ hole of confining liquid (0.5%BSA, mass percent), 37 DEG C of incubation 1h are added per hole；
(4) in the hole liquid is discarded, and PBST washing lotion washes plate three times；
(5) per group plus PAD1 antibody diluent (1:2000 dilutions) 100 μ L/ holes, 37 DEG C of incubation 1h；
(6) in the hole liquid is discarded, and PBST washing lotion washes plate three times；
(7) add HRP-IgG antibody diluent (1 per hole:3000 dilutions) 100 μ L, 37 DEG C of incubation 1h；
(8) in the hole liquid is discarded, and PBST washing lotion washes plate five times；
(9) nitrite ion A, B are added per hole【Developer A (containing hydrogen peroxide) is hydrogen donor (DH2), and substrate B is exactly developer B
(containing TMB, 3,3', 5,5'- tetramethyl benzidines)】Each 50 μ L, 37 DEG C of colour developing 10min.
(10) 50 μ L terminate liquid (2M H are added per hole2SO4Solution) color development stopping, shake even, OD is detected with ELIASA450nmValue；
(11) calculate：With negative serum (normal human serum) as control, negative serum OD is detected450nmAverage is (be with many parts
Negative serum is the out average again value of control test)；By OD450nmValue substitutes into formula P/N value=blood sample OD to be measured450nmValue/cloudy
Property serum OD450nmAverage, is calculated the P/N value of blood sample to be detected；
(12) judge：If the P/N value of blood sample to be detected is more than or equal to 2.1, the testing result of the blood sample to be detected is
Positive.
As a result：Positive number of cases and positive rate are shown in Table 1, and the positive rate of other tumor markerses is shown in Table 2 (for energy in prior art
Disclosed data), by table 1, table 2 as can be seen that PAD1 is used as tumor blood mark, with good specificity, wide spectrum
Property.
Table 1
| Tumour classification | Total number of cases | Positive number of cases | Positive rate |
| The cancer of the uterus | 654 | 510 | 78.0% |
| Liver cancer | 537 | 399 | 74.3% |
| Cancer of the stomach | 363 | 219 | 60.3% |
| The cancer of the esophagus | 252 | 147 | 58.3% |
| Lung cancer | 387 | 251 | 64.8% |
| Oophoroma | 387 | 195 | 50.4% |
| Amount to | 2580 | 1721 | 66.7% |
Table 2
| Tumour classification | PAD1 | CEA | CA199 | CA125 | CA242 |
| The cancer of the uterus | 78.0% | - | - | - | - |
| Liver cancer | 74.3% | 62%～75% | 65% | - | - |
| Lung cancer | 64.8% | 56%～80% | 44% | 50% | |
| Cancer of the stomach | 60.3% | 60%～90% | 50% | 47% | - |
| The cancer of the esophagus | 58.3% | - | - | - | 62% |
| Oophoroma | 50.4% | - | 35% | 61.4% | - |
2 PAD1 of embodiment is used as the detection example 2 of tumor blood mark
Using PAD1 as tumor blood mark, the blood to patient detects that detection method is with embodiment 1.Meanwhile,
Using CEA, CA199, F/PSA, CA125, PSA, CA242, AFP, HCG, NSE of the prior art as tumor blood mark,
Blood to tumor patient is detected that (detection method is conventional method of the prior art；These tumours of the prior art
The blood examination data of blood markers thing are patient's Outpatient Department data of certain hospital, and whether the data can be suffered from as diagnosis patient
One of foundation of tumour；The present invention brings the blood examination PAD1 of some patientss again).Contrast the positive of each tumor blood mark
Rate, and PAD1 compared with intersecting for each tumor markers.
As a result：The positive number of cases of the number of cases (totally 906) of patient and detection is shown in Table 3.It can be seen from Table 3 that, PAD1
Can be applied as tumor blood mark, its specificity is good.
3 PAD1 of table was compared with intersecting for each tumor markers
3 PAD1 of embodiment is used as the detection example 3 of blood markers thing
Using PAD1 as blood markers thing, to hepatitis B, general inflammation (leucocyte, neutrophilic leukocytosis, lymphocyte ratio
Rate reduce patient), ephrosis (including nephrotic syndrome, kidney failure, ephritis), uremia (including uremia and urinary tract infections) suffer from
The blood of person is detected that the number of cases of patient and the species of illnesses refer to table 4.
Detection method is with embodiment 1.
As a result：Positive number of cases and positive rate are shown in Table 4, it can be seen from Table 4 that, PAD1 is used as blood markers thing, it is also possible to
For detecting hepatitis B, general inflammation (with the symptom that leucocyte, neutrophilic leukocytosis, lymphocyte ratios reduce), ephrosis
The diseases such as (including nephrotic syndrome, kidney failure, ephritis), uremia (including uremia and urinary tract infections), testing result are permissible
As one of clinical diagnosis foundation.
Table 4
| Disease category | Total number of cases | Positive number of cases | Positive rate |
| Hepatitis B | 394 | 34 | 8.6% |
| General inflammation | 225 | 8 | 3.6% |
| Ephrosis | 133 | 8 | 6.0% |
| Uremia | 110 | 20 | 18.2% |
Claims (2)
1. application of the Peptidylarginine deiminase 1 in the clinical blood detectable substance for preparing diagnosing tumour, it is characterised in that：Institute
Tumour is stated selected from the cancer of the uterus, liver cancer, cancer of the stomach or oophoroma.
2. application according to claim 1, it is characterised in that：Anti- Peptidylarginine deiminase 1 is prepared in conventional manner
Antibody, sets up qualitative or quantitative method and the matched reagent box of detection Peptidylarginine deiminase 1.
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| PCT/CN2015/077352 WO2016082444A1 (en) | 2014-11-28 | 2015-04-24 | Application of peptidylarginine deiminase 1 in preparation of reagent for clinical diagnosis of tumors |
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| CN108254558B (en) * | 2018-02-11 | 2021-02-09 | 山东省千佛山医院 | Use of PADI3 in diagnosis and/or treatment of colon cancer |
| CN110927390A (en) * | 2019-12-16 | 2020-03-27 | 广东省农业科学院动物卫生研究所 | ELISA method and kit for detecting African swine fever CD2v protein antibody and application |
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| CN101101290A (en) * | 2006-11-30 | 2008-01-09 | 山东省医药生物技术研究中心 | Tumour serum mark and its uses |
| JP5252339B2 (en) * | 2007-12-25 | 2013-07-31 | 地方独立行政法人東京都健康長寿医療センター | Method for measuring PAD4 and anti-PAD4 antibody and method for detecting rheumatoid arthritis |
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