CN110244057B - Application of ADORA3 in preparation of high-grade serous ovarian cancer diagnosis and prognosis kit - Google Patents
Application of ADORA3 in preparation of high-grade serous ovarian cancer diagnosis and prognosis kit Download PDFInfo
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Abstract
The invention discloses an application of a reagent for detecting ADORA3 protein in preparation of a kit for diagnosis, chemotherapy sensitivity and prognosis judgment of high-grade serous ovarian cancer, belonging to the technical field of molecular biology and biomedicine. The ADORA3 protein is used as a marker for diagnosis, treatment and prognosis judgment, and is expressed as negative or weakly expressed in normal ovarian tissues and ovarian serous cystadenomas but highly expressed in high-grade serous ovarian cancer according to ADORA3, and the expression strength is closely related to drug resistance and prognosis indexes of clinical treatment, so that the high-grade serous ovarian cancer can be assisted to be distinguished and diagnosed, and the treatment effect and prognosis of the high-grade serous ovarian cancer can be judged. Meanwhile, according to the correlation between different expression intensities and the prognosis of high-grade serous ovarian cancer, the patients are subjected to layered treatment, so that a theoretical basis is provided for developing more effective individual chemotherapeutic drugs, and the method has important clinical application and drug development values.
Description
Technical Field
The invention relates to the technical field of molecular biology and biomedicine, in particular to application of a reagent for detecting ADORA3 protein in preparation of a kit for diagnosis, chemotherapy sensitivity and prognosis judgment of high-grade serous ovarian cancer.
Background
About 24 million women worldwide are diagnosed with ovarian cancer each year with a mortality rate nearly three times that of breast cancer, and a 5-year survival rate of less than 25% in stage III or IV patients makes ovarian cancer the most fatal gynecological malignancy. Ovarian cancers fall into three broad categories: epithelial cell cancer, germ cell cancer, and specific stromal cell tumor. The vast majority of ovarian cancers are Epithelial Ovarian Cancers (EOCs), which are largely divided into two major tissue types: type I and type II tumors. Type I tumors include various low-grade serous, mucinous, endometrioid, clear cell carcinomas, and tend to grow slowly, often from identifiable precancerous lesions. In contrast, type II tumors are characterized by a high grade and rapidly progressing disease. High Grade Serous Ovarian Cancer (HGSOC) is the most common type II tumor, accounting for approximately 75% of all ovarian cancers. Unfortunately, it is also the most aggressive. At present, no index or method for early prediction of high-grade serous ovarian cancer with high efficiency and high specificity exists. Even if tumor cells have spread widely in the abdominal cavity, metastasis lacks specific symptoms and cannot be detected and diagnosed early, and therefore, most women have progressed to late stage disease when diagnosed with ovarian cancer for the first time, and the prognosis is poor. Wherein distant metastasis and recurrence after treatment are the fundamental reasons for poor clinical treatment.
Ovarian cancer is a complex disease resulting from a multifactorial polygenic combination, each tissue type having a different molecular-level origin, even within the same tissue type. The molecular and cellular behaviors, clinical manifestations and prognosis are naturally different, but the current clinical treatment can only be used as a treatment scheme and a prognosis judgment basis according to pathological stages, the basis is completely separated from the molecular biological basis, the cytological behavior judgment basis of effective layered personalized treatment cannot be provided, and the diagnosis and treatment effects are not satisfactory. In actual work, more accurate markers are urgently needed to classify patients into high-risk types and low-risk types, so that effective personalized treatment schemes can be adopted, the treatment effect is improved, and the prognosis is improved.
The current molecular markers for ovarian cancer include two levels of molecules, nucleic acids and proteins. The nucleic acid markers comprise gene Copy Number Variation (CNV), microsatellite instability (MSI), base Mutation (Mutation), Single Nucleotide Polymorphism (SNP) and the like, and the recent research also comprises the change of miRNA, but most of the miRNA can only be used as early warning of disease susceptibility and have far correlation with cell behaviors, and the clinical application value is not large. The protein is a final product of gene expression, can directly play a role, changes the biological behavior of cells and the direct response to the surrounding environment, such as the occurrence and development of tumors and the response to treatment means, so the research result of the protein level can directly and effectively provide a molecular marker with clinical guidance value, meet the requirements of classification diagnosis and prognosis judgment of the ovarian cancer molecular level, and have important values on the personalized treatment and prognosis improvement of the ovarian cancer. However, no clear and effective research results exist so far, and the specificity and accuracy of clinical needs cannot be achieved.
The adenosine receptor subtype belongs to the family of G protein-coupled receptors (GPCRs) and is involved in a variety of intracellular signaling pathways and physiological functions. The adenosine a3 receptor (ADORA3) binds to the inhibitory subunit of gpcr (gi), inhibiting adenylate cyclase, reducing cAMP production. Adenosine receptors can be expressed in different tissues, have different physiological and pathological effects, are involved in inhibiting neutrophil degranulation in tissue injury, are involved in protection of nerves and neurodegeneration, and may also mediate cell proliferation and death. The abnormal expression of ADORA3 protein is reported in non-small cell lung cancer, breast cancer and leukemia cells, and the ADORA3 protein is related to the action path of cancer suppressor genes such as p53 and plays an important role in the generation and development of tumors. However, no studies have been found in high-grade serous ovarian cancer.
Disclosure of Invention
The invention aims to research the difference of expression levels of ADORA3 protein in high-grade serous ovarian cancer, distinguish the correlation between different expression levels of ADORA3 and prognosis indexes such as clinical stages, pathological grading and the like of the high-grade serous ovarian cancer and chemotherapy sensitivity, illustrate the role and application value of ADORA3 protein expression in pathogenicity, clinical diagnosis and prognosis judgment of the high-grade serous ovarian cancer, and finally develop the application of the ADORA3 protein in clinical actual kit detection.
In order to achieve the purpose, the invention adopts the following technical route and scheme:
the invention firstly detects the expression of ADORA3 protein in normal ovarian tissues, ovarian serous cystadenomas and high-grade serous ovarian cancers, and finds that the expression level of ADORA3 in the high-grade serous ovarian cancers is obviously higher than that of the normal ovarian tissues and the ovarian serous cystadenomas, and has obvious statistical difference.
The invention simultaneously carries out hierarchical analysis on serum CA125, the ascites volume, the maximum tumor diameter, the FIGO stage, the cell differentiation grade and the chemotherapy sensitivity of the high-grade serous ovarian cancer patient, and the result shows that the patient with higher ADORA3 protein expression is easier to resist chemotherapy and has poorer prognosis.
By combining the analysis results, the invention provides the application value of ADORA3 as a protein marker for clinical auxiliary diagnosis, chemotherapy sensitivity and prognosis judgment of high-grade serous ovarian cancer.
By detecting the expression level of ADORA3 protein in cancer tissues, the diagnosis, chemotherapy sensitivity and prognosis of high-grade serous ovarian cancer can be judged, including: clinical differential diagnosis of high-grade serous ovarian cancer, drug resistance possibly generated by chemotherapy of the high-grade serous ovarian cancer is pre-evaluated, a theoretical basis is provided for a better personalized chemotherapy scheme of a patient with high expression of ADORA3 protein, better layered treatment is performed on the high-grade serous ovarian cancer, and finally prognosis of the patient is improved.
Therefore, the invention provides the application of the reagent for detecting the ADORA3 protein in preparing a kit for differential diagnosis, chemotherapy sensitivity and prognosis judgment of high-grade serous ovarian cancer.
The reagent for detecting ADORA3 protein is an antibody against ADORA3 protein.
Preferably, the reagent for detecting ADORA3 is ADORA3 rabbit anti-human polyclonal antibody.
The differential diagnosis includes: differential diagnosis of high-grade serous ovarian cancer or ovarian serous cystadenoma; the chemotherapy sensitivity and prognosis determination comprises: and (3) evaluating the chemotherapy sensitivity and disease prognosis of high-grade serous ovarian cancer.
As clinical detection application of the protein molecular markers, the invention provides a kit for differential diagnosis, chemotherapy sensitivity and prognosis judgment of high-grade serous ovarian cancer, which is used for detecting the expression level of ADORA3 protein of the high-grade serous ovarian cancer and predicting the clinical differential diagnosis, the chemotherapy drug resistance possibility and the prognosis of the high-grade serous ovarian cancer.
The kit comprises: rabbit anti-human polyclonal antibodies specific for ADORA3 protein and universal secondary antibodies and chromogenic reagents required for immunohistochemical techniques.
Immunohistochemical agents include: goat serum confining liquid, 0.01M citrate antigen repairing liquid and 3% H2O2Peroxidase blocking agent, goat anti-rabbit secondary antibody marked by HRP, DAB color reagent and TBS solution.
Based on the kit, the invention provides an immunohistochemical method and a scoring standard, which comprises the following steps:
and (3) carrying out formalin fixation, dehydration, paraffin embedding and section on the ovarian tissue sample to be detected to obtain a tissue section, and then carrying out immunohistochemical staining, microscopic observation and slide reading, grading and statistical analysis.
Specifically, after a tissue specimen obtained by an operation is subjected to formalin fixation and paraffin embedding slicing, hydration, antigen restoration, hydrogen peroxide inactivation endogenous peroxidase and serum sealing are performed, an ADORA3 rabbit anti-human polyclonal antibody is incubated for 60 minutes at room temperature, TBS is washed for three times and then reacts with a second antibody at room temperature for 15 minutes, horseradish peroxidase labeling is incubated, DAB color development, hematoxylin counterstaining, and finally neutral resin fragmentation is performed after alcohol dehydration and xylene transparency. Score was observed with light microscope.
The semi-quantitative evaluation of ADORA3 protein expression was performed according to the following scoring criteria based on the percentage of positive cells and the intensity of staining (10 random fields at 400-fold). Negative staining is defined as 0 point, light yellow as weak staining 1 point, brown yellow as medium staining 2 points, dark yellow as strong staining 3 points. When the percentage of positive cells was scored, < 5% was defined as score 0, < 25% was defined as score 1, < 75% was defined as score 2, > 75% was defined as score 3. The two scores were added to give a semi-quantitative analysis as follows: negative (score 0), weak positive (score 1-2), moderate positive + + (score 3-4) and strong positive + + + (score 5-6).
According to the experimental results, ADORA3 is basically negative in normal ovarian tissue, is mostly negative in ovarian serous cystadenoma expression, is weakly positive in a few cases, and is mostly moderate and strong positive in high-grade serous ovarian cancer.
The judgment method for the treatment effect and prognosis is as follows, the ADORA3 negative and weak positive patients have better prognosis, good treatment effect and low drug resistance possibility, while the strong positive patients have the worst conventional treatment effect and prognosis and high drug resistance possibility. The therapeutic effect and prognosis for moderately positive patients are intermediate.
The invention has the following beneficial effects:
according to the invention, the expression condition of the ADORA3 protein in high-grade serous ovarian cancer is firstly researched, the ADORA3 is found to be negative or weakly expressed in normal ovarian tissues and ovarian serous cystadenoma, but is highly expressed in the high-grade serous ovarian cancer, the expression strength is closely related to the drug resistance and the prognostic index of clinical treatment, the treatment effect of a patient with high expression of ADORA3 is poor, the drug resistance is easy to appear, and each prognostic index is poor in expression, so that the prognosis is poor. Therefore, the invention provides a kit for differential diagnosis, chemotherapy sensitivity and prognosis judgment of high-grade serous ovarian cancer by taking the ADORA3 protein as a marker for diagnosis, treatment and prognosis judgment, and the kit can assist in differential diagnosis of the high-grade serous ovarian cancer and judge the treatment effect and prognosis of the high-grade serous ovarian cancer. Meanwhile, according to the correlation between different expression intensities and the prognosis of high-grade serous ovarian cancer, the patients are subjected to layered treatment, so that a theoretical basis is provided for developing more effective individual chemotherapeutic drugs, and the method has important clinical application and drug development values.
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FIG. 1 shows the expression of ADORA3 protein in normal ovarian tissue, ovarian serous cystadenoma, and high grade serous ovarian cancer.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which should be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Unless otherwise specified, the specific experimental methods mentioned in the examples are all conventional methods, and the experimental reagents used are all purchased from conventional reagents companies. One of these anti-ADORA 3 rabbit anti-human polyclonal antibodies was purchased from Thermofisoher, Cat.No. PA 5-33326.
Example 1: analysis of differences in expression of ADORA3 protein in Normal ovarian tissue, ovarian serous cystadenoma, and high-grade serous ovarian carcinoma
Firstly, a research object:
241 parts of normal ovarian tissue, ovarian serous cystadenoma and high-grade serous ovarian cancer specimen tissue in the affiliated obstetrical hospital of Zhejiang university medical school in 2004-1-2010-12 are collected. The samples included 41 normal ovarian epithelial tissues, 97 ovarian serous cystadenomas, and 103 high-grade serous ovarian carcinomas (including 6 stages I, 30 stages II, 62 stages III, and 5 stages IV). Patients who received chemotherapy, immunotherapy or radiation therapy prior to surgery were excluded. All patients received initial surgery followed by paclitaxel-based chemotherapy. The following clinical indices were collected for all patients: preoperative serum CA125, ascites volume, maximum tumor diameter, FIGO stage, cell differentiation grade, and chemotherapy sensitivity. Patients who developed progressive disease during chemotherapy or relapsed within 6 months after completion of the primary course of chemotherapy were identified as chemotherapy-resistant. Patients who had relapsed for more than 6 months or no relapse were defined as chemotherapy-sensitive.
The study was conducted in compliance with the ethical committee of the obstetrical hospital affiliated to the university of Zhejiang medical school, and in compliance with the approved guidelines and regulations.
II, an experimental method:
2.1 tissue Paraffin-embedded sections:
1. material taking: after fresh specimen tissue is fixed by 10% formalin, the tissue is taken out from the fixing solution and the tissue of the target part is flattened and placed in a dehydration box.
2. And (3) dehydrating: and (5) sequentially putting the dehydration boxes into gradient alcohol for dehydration. 75% ethanol for 4 hours → 85% ethanol for 2 hours → 90% ethanol for 2 hours → 95% ethanol for 1 hour → absolute ethanol I for 30 minutes → absolute ethanol II for 30 minutes → alkylol for 5 minutes → xylene I for 10 minutes → xylene II for 10 minutes → paraffin I for 1 hour → paraffin II for 1 hour → paraffin III for 1 hour.
3. Embedding: firstly, molten wax is put into an embedding frame, tissues are taken out from a dehydration box and put into the embedding frame before the wax is solidified, and the tissues are taken out and trimmed after the wax is solidified at the temperature of minus 20 ℃.
4. Slicing: the wax block was sliced on a paraffin slicer to a thickness of 4 μm. The slices float on warm water at 40 ℃ of a spreading machine to spread the tissues, the tissues are taken out by a glass slide, and are put into an oven at 60 ℃ to be baked, and the slices are taken out to be stored at normal temperature after being baked by wax.
2.2 tissue dehydration, antigen repair and endogenous peroxidase blockade
1. Paraffin sections were placed in a 67 ℃ oven for 2 hours, dewaxed to water, and washed three times for 3 minutes in TBS (pH 7.4).
2. 0.01M citrate buffer (pH 6.0) was heated to boiling by microwave, and the hydrated tissue slices were put into the boiling buffer, treated by microwave for 10 minutes, cooled naturally with running water, washed twice with distilled water, and finally washed twice with TBS. 3 minutes each time.
3. Adding 1 drop of 3% H into each slice2O2Incubate for 10 min at room temperature, block endogenous peroxidase activity, and wash three times with TBS for 3 min each.
2.3 non-specific site blocking and Primary antibody incubation
1. Blocking of non-specific sites: sucking water on the slices, adding goat serum confining liquid, and reacting in a wet box at room temperature for 10 minutes.
2. The blocking solution was spun off, primary antibody (1:1000) was added dropwise to cover all tissues, and placed in a wet box at room temperature for 60 minutes.
3. TBS was washed three times for three minutes each.
2.4 DAKO EnVision System secondary antibody labeling, visualization and counterstaining:
the kit used was EnVision from DAKOTM+System,Peroxidase(DAKO EnVisionTM+ System "), the specific experimental procedure is as follows:
1. TBS was rinsed for 10 min and EnVision secondary antibody reaction (HRP-labeled) was incubated for 15 min.
2. TBS rinsing is carried out for 10 minutes, two drops (about 100 microliters) of DAB solution are added dropwise, color development is carried out for 5 minutes at room temperature, then observation is carried out under a microscope, dyeing is stopped after proper dyeing, and washing is carried out by tap water.
3. After rinsing with distilled water, hematoxylin counterstaining is carried out for 1-2 minutes, the cell nucleus turns blue, and then the cell nucleus is stopped, and the cell nucleus is rinsed back blue by tap water or TBS (0.5% an water can be used for reversing blue).
4. And (3) dehydrating and drying the slices by gradient alcohol, enabling the slices to be transparent in dimethylbenzene, sealing by neutral gum, airing and observing.
Thirdly, microscopic observation and scoring standard:
the appearance of brownish yellow particles in the tumor cytoplasm and on the cell membrane was considered a positive marker. The semi-quantitative evaluation of ADORA3 protein expression was performed according to the following scoring criteria based on the percentage of positive cells and the intensity of staining (10 random fields at 400-fold). Negative staining is defined as 0 point, light yellow as weak staining 1 point, brown yellow as medium staining 2 points, dark yellow as strong staining 3 points. When the percentage of positive cells was scored, < 5% was defined as score 0, < 25% was defined as score 1, < 75% was defined as score 2, > 75% was defined as score 3. The two scores were added to give a semi-quantitative analysis as follows: negative (score 0), weak positive (score 1-2), moderate positive + + (score 3-4) and strong positive + + + (score 5-6).
Fourth, adrora 3 protein expression and correlation analysis of normal ovarian tissue, ovarian serous cystadenoma, and high-grade serous ovarian cancer:
based on experimental results, we found that the ADORA3 protein is mainly expressed on cell membrane and in cytoplasm, and the ADORA3 protein is basically negative in normal ovarian tissue, is mostly negative in ovarian serous cystadenoma expression, is weakly positive in a few cases, and is mostly moderate positive and strongly positive in high-grade serous ovarian cancer. The data were statistically significantly different after statistical chi-square test. The result can be used for clinically and differentially diagnosing serous carcinoma and serous cystadenoma of ovarian origin. Specific results and analytical data are shown in fig. 1 and table 1.
TABLE 1 expression of ADORA3 protein in Normal ovarian tissue, ovarian serous cystadenoma, and high grade serous ovarian carcinoma
Note: # comparison between three groups; comparison between normal ovarian epithelium and serous cystadenoma; comparison between normal ovarian epithelium and high grade serous carcinoma; comparison between serous cystadenoma and high grade serous carcinoma.
Example 2: hierarchical analysis of clinical prognostic factors and chemotherapy sensitivity of ADORA3 protein expression in high-grade serous ovarian cancer
Based on the results of example 1, the correlation analysis of the clinical prognosis factors and chemotherapy sensitivity of high-grade serous ovarian cancer shows that the expression of ADORA3 protein is stronger and stronger along with the increase of clinical stage and cell differentiation grade, and the more strongly expressed patient has higher possibility of drug resistance, which indicates that ADORA3 negative and weak positive patients have better prognosis, good treatment effect and low drug resistance possibility, while the strong positive patient has the worst conventional treatment effect and prognosis and has high possibility of drug resistance. The therapeutic effect and prognosis for moderately positive patients are intermediate. Specific results and analytical data are shown in table 2.
TABLE 2 relationship between ADORA3 protein expression and clinical prognostic factors and chemotherapy sensitivity in high-grade serous ovarian cancer
Preoperative serum CA125
(U/ml)
The underlined values show significant differences in the statistical data.
Binary correlation analysis was performed using the Kendall's-tau-b correlation coefficient (r).
P values less than 0.05 were considered significant.
The applicant states that: the above embodiments are preferred embodiments of the present invention, and after reading the above description of the present invention, any other changes or modifications made under the theoretical and experimental principles of the present invention should be considered as equivalent to the present invention in the practical implementation of the test, and also fall within the protection scope of the present invention.
Claims (3)
1. Application of a reagent for detecting ADORA3 protein in preparation of a high-grade serous ovarian cancer differential diagnosis kit.
2. The use of claim 1, wherein the agent that detects ADORA3 protein is an antibody against ADORA3 protein.
3. The use of claim 2, wherein the reagent for detecting ADORA3 protein is ADORA3 rabbit anti-human polyclonal antibody.
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| WO2004086034A2 (en) * | 2003-03-28 | 2004-10-07 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with g-protein-coupled receptor adenosine a3(adora3) |
| CN106771248A (en) * | 2016-12-30 | 2017-05-31 | 山东大学齐鲁医院 | High-level serous ovarian cancer diagnosis and/or the mark of Index for diagnosis |
| CN108508212A (en) * | 2018-04-19 | 2018-09-07 | 山东大学齐鲁医院 | The marker of high-level serous ovarian cancer targeted therapy and Index for diagnosis |
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| WO2004086034A2 (en) * | 2003-03-28 | 2004-10-07 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with g-protein-coupled receptor adenosine a3(adora3) |
| CN106771248A (en) * | 2016-12-30 | 2017-05-31 | 山东大学齐鲁医院 | High-level serous ovarian cancer diagnosis and/or the mark of Index for diagnosis |
| CN106771248B (en) * | 2016-12-30 | 2018-05-15 | 山东大学齐鲁医院 | High-level serous ovarian cancer diagnosis and/or the marker of Index for diagnosis |
| CN108508212A (en) * | 2018-04-19 | 2018-09-07 | 山东大学齐鲁医院 | The marker of high-level serous ovarian cancer targeted therapy and Index for diagnosis |
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| The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB/Akt and NF-kB signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats;A Ochaion等;《Biochemical Pharmacology》;20081231;第76卷;第483页第2.1节，第485页第2.7节 * |
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