CN117589989A - Endometrial cancer nursing treatment drug-resistant marker, product and application - Google Patents
Endometrial cancer nursing treatment drug-resistant marker, product and application Download PDFInfo
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- CN117589989A CN117589989A CN202311320552.6A CN202311320552A CN117589989A CN 117589989 A CN117589989 A CN 117589989A CN 202311320552 A CN202311320552 A CN 202311320552A CN 117589989 A CN117589989 A CN 117589989A
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57442—Specifically defined cancers of the uterus and endometrial
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
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Abstract
The invention relates to an endometrial cancer conservation treatment drug-resistant marker, a product and application thereof, and relates to the technical field of endometrial cancer conservation function treatment, wherein the endometrial cancer conservation treatment drug-resistant marker comprises at least 4 of DYLLT 1 protein, HSD17B12 protein, EEF1E1 protein, ILVBL protein, SRPK1 protein and NUDT5 protein. According to the invention, the endometrial cancer nursing treatment drug-resistant protein markers are obtained through screening, and the treatment response of a patient can be predicted before the endometrial cancer patient is subjected to nursing treatment by detecting the expression level of the 6 protein markers, so that drug-resistant people can be effectively screened, the treatment scheme is optimized pertinently, and the benefit rate of the patient is provided.
Description
Technical Field
The invention relates to the technical field of endometrial cancer fertility maintenance treatment, in particular to an endometrial cancer nursing treatment drug-resistant marker, a endometrial cancer nursing treatment drug-resistant product and application of endometrial cancer fertility maintenance treatment drug-resistant marker.
Background
Endometrial cancer (Endometrial carcinoma, EC) is one of the three most common malignant tumors of the female reproductive system. Endometrial cancer is closely related to obesity, diabetes and other risk factors, and in recent years, the incidence of endometrial cancer is in a trend of rising and younger year by year, accounting for about 7% of the total number of female cancers, accounting for more than 30% of malignant tumors of female reproductive systems, and approaching or even exceeding the incidence of cervical cancer.
In recent years, patients with early onset endometrial cancer have increased, and these women at their gestation age often have a strong fertility demand, and preserved fertility treatments based on medroxyprogesterone acetate (MPA) have been chosen to preserve the fertility of the patient. Thus, there is an increasing interest in conservation therapy, and despite satisfactory results achieved by potent progestogen-based regimens, more than 30% of patients are insensitive to progestogen therapy and become refractory. The clinical problem with progestogen-insensitive patients is urgently addressed: i.e. how to screen out patients insensitive to progestogen therapy before the start of the treatment in order to formulate a treatment regimen for these patients.
In the past decades, researchers find that endometrial cancer has great consistency in morphology and molecular characteristics, and along with the deep research of tumor pathogenesis molecular mechanisms and the maturation of bioinformatics technologies such as second generation sequencing, molecular typing of endometrial cancer is proposed to assist clinicians in predicting prognosis and targeting drugs of patients. However, previous studies have included only patients with endometrial cancer treated by surgery, and the molecular landscape for patients receiving care treatment remains blank, and the molecular characteristics of care patients responding to different treatments are not clear. In view of this, the present invention provides endometrial cancer care drug-resistant markers, products and uses.
Disclosure of Invention
The invention aims to solve the technical problem of providing endometrial cancer nursing treatment drug-resistant markers, products and applications. The method aims at using the DYNLT1, HSD17B12, EEF1E1, ILVBL, SRPK1 and NUDT5 protein markers obtained by screening in the preparation of products for predicting the response of endometrial cancer care treatment so as to judge the drug resistance of patients with endometrial cancer care treatment.
The present invention solves the above technical problems, and a first aspect provides an endometrial cancer conservation treatment drug-resistant marker, which comprises at least 4 of DYNLT1 protein, HSD17B12 protein, EEF1E1 protein, ILVBL protein, SRPK1 protein and NUDT5 protein.
The invention screens endometrial cancer conservation treatment drug resistance markers based on mass spectrum proteome technology, adopts immunohistochemical staining for verification, and constructs 6 protein molecules (DYLLT 1, HSD17B12, EEF1E1, ILVBL, SRPK1 and NUDT 5) for predicting the conservation treatment drug resistance of endometrial cancer patients.
The beneficial effects of the invention are as follows:
(1) According to the invention, the endometrial cancer nursing treatment drug-resistant protein markers are obtained through screening, and the treatment response of a patient can be predicted before the endometrial cancer patient is subjected to nursing treatment by detecting the expression level of the 6 protein markers, so that drug-resistant people can be effectively screened, the treatment scheme is optimized pertinently, and the benefit rate of the patient is provided.
(2) The biological markers explored by the invention suggest that the use of DYNLT1, HSD17B12, EEF1E1, ILVBL, SRPK1 and NUDT5 proteins as targets can reverse the drug resistance of progestogen treatment, so the biological markers have wide clinical application prospect.
The second aspect of the present invention provides the use of an endometrial cancer conservation therapy drug-resistant marker, wherein the agent for detecting the endometrial cancer conservation therapy drug-resistant marker is used for preparing endometrial cancer conservation therapy drug-resistant products.
The beneficial effects of adopting above-mentioned scheme are: the reagent for detecting the expression level of the 6 protein markers (DYNLT 1, HSD17B12, EEF1E1, ILVBL, SRPK1 and NUDT 5) is used for preparing endometrial cancer conservation therapy drug resistant products, so that a prediction system based on 6 proteins for the conservation therapy drug resistance of endometrial cancer patients is successfully constructed, the treatment response of the endometrial cancer patients can be predicted before the conservation therapy is carried out, and drug resistant people can be effectively screened.
Further, the drug resistance condition of the endometrial cancer conservation treatment patient is judged by quantitatively detecting the drug resistance marker of the endometrial cancer conservation treatment.
Further, the medicine for endometrial cancer conservation treatment is a progestogen.
Further, the medicine for the endometrial cancer nursing treatment is medroxyprogesterone acetate.
In the present invention, "conservation therapy" is a therapeutic strategy for patients with early endometrial cancer. The goal of conservation therapy is to preserve as much as possible the uterine and fertility functions of the patient while effectively controlling the development and spread of cancer. The main mode is based on progestogen treatment: oral administration of high-potency progesterone is currently the most commonly used method of care treatment. Progestogen inhibits proliferation of cancer cells by altering cell growth and differentiation of endometrium, thereby achieving therapeutic effect. Whereas, the drug resistance of the nursing treatment refers to whether the patient has developed disease within 6 months or is still not relieved within 12 months after receiving the oral medroxyprogesterone acetate (Medroxyprogesterone acetate, MPA) treatment. The state of resistance of endometrial cancer to conservation therapy can be predicted by the expression level of a marker protein in tumor tissue prior to treatment of the patient.
Further, the reagent for detecting the endometrial cancer conservation therapy drug resistance marker comprises a substance specifically binding to the DYNLT1 protein, the HSD17B12 protein, the EEF1E1 protein, the ILVBL protein, the SRPK1 protein and the NUDT5 protein.
Further, the substance is an antibody or antibody fragment.
The substances for detecting DYNLT1, HSD17B12, EEF1E1, ILVBL, SRPK1 and NUDT5 according to the present invention include antibodies or fragments thereof that specifically bind to the target protein. Antibodies or fragments thereof of any structure, size, immunoglobulin class, origin, etc. may be used as long as it binds to the target protein. Antibodies of the invention or a variant thereofFragments may be monoclonal or polyclonal. An antibody fragment refers to a portion of an antibody (a fragment of a portion) or a peptide containing a portion of an antibody that retains the binding activity of the antibody to an antigen. Antibody fragments may include F (ab') 2 Fab', fab, single chain Fv (scFv), disulfide bonded Fv (dsFv) or polymers thereof, dimerized V region (diabody), or CDR-containing peptides. The substances for detecting DYNLT1, HSD17B12, EEF1E1, ILVBL, SRPK1 and NUDT5 proteins of the present invention may include isolated nucleic acids encoding amino acid sequences of antibodies or encoding antibody fragments, vectors comprising the nucleic acids, and cells carrying the vectors.
The above antibodies may be obtained by methods well known to those skilled in the art. For example, a polypeptide or mammalian cell expression vector incorporating a polynucleotide encoding a protein of interest may be prepared as an antigen, retaining all or part of the protein of interest. After immunization of the animal with the antigen, the immune cells may be collected and fused with myeloma cells to obtain hybridomas. Antibodies can then be collected from the hybridoma culture. Finally, antigen-specific purification can be performed using DYNLT1, HSD17B12, EEF1E1, ILVBL, SRPK1 and NUDT5 proteins or portions thereof as antigens, thereby obtaining monoclonal antibodies against these proteins. The method for preparing the polyclonal antibody is as follows: the animals were immunized with the same antigen as described above, blood samples of the immunized animals were collected, serum was isolated, and then antigen-specific purification of serum was performed using the above antigen. The antibody fragment may be obtained by enzymatic treatment of the obtained antibody or by using the obtained antibody sequence information.
In a third aspect, the present invention provides a product for detecting an endometrial cancer conservation therapy drug resistance marker, the product comprising a reagent for detecting the endometrial cancer conservation therapy drug resistance marker.
The products of the invention for detecting DYNLT1, HSD17B12, EEF1E1, ILVBL, SRPK1 and NUDT5 proteins may function and function based on known methods using the above antibodies or antibody fragments, including ELISA, western blotting, immunohistochemical staining, and the like. Products of DYNLT1, HSD17B12, EEF1E1, ILVBL, SRPK1 and NUDT5 proteins can also be quantified based on mass spectrometry techniques, such as the non-labeled protein quantification technique (4D-Label Free) and the TMT (Tandem Mass Tag) labeled quantification technique.
The beneficial effects of adopting above-mentioned scheme are: the invention constructs a detection product for predicting the conservation drug resistance, only needs to collect tumor tissues of a patient to carry out experiments according to a manual, evaluates whether the drug resistance of the patient occurs according to a staining result, and has the advantages of clinical accessibility and accuracy.
Further, the product comprises a detection reagent, a kit, a chip, a test paper or a high throughput sequencing platform.
Further, the high throughput sequencing platform comprises a Tims-TOF mass spectrometer.
The fourth aspect of the present invention provides a method for screening a drug-resistant marker for endometrial cancer care, comprising the steps of:
(1) Obtaining a tumor tissue sample of a patient who is undergoing a maintenance therapy;
(2) Lysing the tissue of the patient, extracting proteins therein, and performing pancreatin digestion to obtain lysed peptide fragments;
(3) Performing high-throughput sequencing on the peptide fragment based on a Tims-TOF platform by using a label-free technology to obtain a sequencing result of the peptide fragment;
(4) Searching a library of the obtained peptide sequencing results by using MaxQuant software to obtain high-throughput quantitative results of each protein;
(5) Grouping patients with different treatment responses, performing differential analysis on quantitative levels of each protein between groups, and checking statistical significance by using a Wilcoxon method;
(6) Proteins significantly up-regulated in the incubator resistant group can be considered to be associated with incubator resistance.
The samples were derived from tumor tissue prior to treatment of patients undergoing conservation treatment.
Drawings
FIG. 1 is a screening process of the invention for a protein group-based protection-related marker for endometrial cancer; wherein a is a protein volcanic map of an conservation treatment-related group; b is a mesenchymal transition pathway for obviously enriching protein of a patient with drug resistance in conservation treatment; c, D is survival analysis of 33 drug resistance related proteins in 6 external data sets; p <0.1 for Log-rank test in at least three data sets; risk ratio >2;
FIG. 2 is a schematic diagram showing the verification of endometrial cancer conservation drug resistance related markers and the construction of a conservation drug resistance system according to the invention; wherein A is a representative image of EEF1E1, ILVBL, SRPK1 and NUDT5 immunohistochemical staining in a patient with susceptibility to and resistance to maintenance; b is the immunohistochemical staining score of EEF1E1, ILVBL, SRPK1, NUDT5 in care sensitive and insensitive patients; c is the correlation of EEF1E1, ILVBL, SRPK1 with NUDT5, P <0.05; * P <0.01, P <0.001.
Detailed Description
The principles and features of the present invention are described below with examples given for the purpose of illustration only and are not intended to limit the scope of the invention. The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or apparatus used were conventional products commercially available through regular channels, with no manufacturer noted.
Example 1
The screening method of the drug-resistance related markers provided by the invention comprises the following steps:
a) Sample collection
The study meets the ethical standard of the declaration of Helsinki, and ethical lot numbers are TJ-IRB20211005 and 2021-181, respectively. Written informed consent was obtained for each patient prior to conducting any specific study investigation.
The invention screens 62 endometrial cancer patients who receive conservation treatment from 1 month in 2015 to 7 months in 2020. Histological sections of tumor/adjacent tissue were taken, hematoxylin and eosin staining (HE) to determine pathological grading of tumor tissue and tumor cancer occupancy. Each tumor/adjacent sample was examined by 2 pathologists and sample quality was confirmed according to the following criteria: (1) histopathologically defining an endometrium-like endometrial cancer; (2) Tumor cell rate (tumor purity) >90% after removing tumor tissue on slice under the naked eye; (3) no tumor cells in adjacent paracancerous tissue. All cases were staged according to international union of gynaecology and obstetrics (International Federation of Gynecology and Obstetrics, FIGO) diagnostic criteria (2018). Other group entry criteria were: the patient received no treatment prior to admission, did not incorporate other malignancies, did not incorporate other hormone-related diseases, and had complete clinical information.
b) FFPE sample protein extraction and trypsin digestion
FFPE specimens were scraped from tissue sections and transferred to 1.5mL conical tubes and paraffin was removed using a dilution of ethanol and water. The method comprises the following steps: first dewaxed with xylene and then four volumes of lysis buffer, which is a mixture of 1% SDC (sodium deoxycholate, purchased from Sigma-Aldrich, cat# D5670) and 1% protease inhibitor (purchased from ServiceBio, cat# G2006-250 UL), were added to the tissue and sonicated on ice for 3 minutes. The remaining debris was removed by centrifugation at 12000g for 10min at 4℃and finally the supernatant was collected and the protein concentration was determined using the BCA kit (purchased from Beyotime, cat. P0009).
The extracted protein samples were added to 1% SDC buffer, incubated with 5mM dithiothreitol (purchased from Sigma, cat. No. 43816) at 56℃for 30 min, and alkylated with 11mM iodoacetamide (purchased from Sigma, cat. A3221) in the dark at room temperature for 15 min. Next, the first overnight digestion was performed at a trypsin (purchased from Sigma, cat# T6567)/protein mass ratio of 1:50, and the second 4 hours digestion was performed at a trypsin/protein mass ratio of 1:100. The digested peptide fragment was acidified with 10% TFA (trifluoroacetic acid, purchased from Sigma, cat# T6508) to pH 2-3, centrifuged at 12000g for 10min at room temperature and the supernatant was transferred to a new EP tube. After methanol activation of the SPE column, the column was equilibrated with 0.1% TFA, and the acidified peptide solution was applied to the SPE column, then desalted with 0.1% TFA, and finally the peptide eluted with 80% ACN (acetonitrile, purchased from Sigma, cat. No. 34851) and concentrated in vacuo before storage to-80 ℃.
c) Liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) analysis and protein quantification
The peptide fragments were dissolved in liquid chromatography mobile phase a and then separated using a NanoElute ultra high performance liquid system. Mobile phase a was an aqueous solution containing 0.1% formic acid and 2% acetonitrile; mobile phase B was a solution containing 0.1% formic acid and 100% acetonitrile. The flow rate was maintained at 450nL/min using a liquid phase gradient set for 90 minutes.
Peptide fragments were isolated by ultra-high performance liquid chromatography and injected into a Capilliry ion source for ionization and then analyzed by timsTOF Pro mass spectrometry. The ion source voltage was set at 1.65kV and both the peptide fragment parent ion and its secondary fragments were detected and analyzed using high resolution TOF. The secondary mass spectrum scan range was set to 100-1700. The data acquisition mode uses a parallel cumulative serial fragmentation (PASEF) mode. And a primary mass spectrum is acquired, and then a secondary spectrogram is acquired by a PASEF mode for 10 times.
Secondary mass spectrometry data were retrieved using maxquat (v1.6.15.0). And (5) searching parameter settings: the database is homosapiens_9606_sp_20210721. Fasta (20387 sequences), an inverse database is added to calculate false positive rate (FDR) caused by random matching, and a common pollution database is added to the database to eliminate the influence of pollution proteins in the identification result; the enzyme cutting mode is set as Trypsin/P; the number of the missed cut sites is set to 2; the mass error tolerance of the secondary fragment ions was 20ppm. Cysteine alkylation Carbamidomethyl (C) was set as an immobilization modification, a variable modification to oxidation of methionine, acetylation of the N-terminus of the protein. FDR was set to 1% for both protein identification and PSM identification.
The multiple hypothesis test was corrected with a substitution-based error discovery rate (FDR < 1%) to fix 95292 peptide fragments together with 7409 proteins, the data were K-nearest neighbor (KNN) algorithm filled with null values, and log-transformed as data for subsequent analysis.
d) Proteome data preprocessing and normalization
Proteomic analysis multiple hypothesis testing (FDR <1%; FIG. 2) was corrected using a permutation-based error discovery rate (False discovery rate, FDR) in a MaxQuant environment. Further analysis of peptide fragment length, number of peptide fragments, protein molecular weight and protein coverage ensured the quality of proteomic data. Log2 conversion was performed on the proteomic data, and at least half of the samples were filled with missing values for the quantified protein using the k-Nearest Neighbor (KNN) algorithm. The calculation method is implemented in the streamai R packet.
e) Screening process of protein related to conservation and drug resistance
Patients are divided into two groups of drug resistance (n=30) and sensitivity (n=32) based on the response of the nursing treatment, and the protein group data obtained after filling are used for standardization and normalization, so that the accuracy and comparability of the data are ensured. In order to identify proteins with significant differences between the different groups, the present invention uses the Wilcoxon statistical test to explore proteins with statistically significant differences.
f) Screening result of protein related to conservation drug resistance
The results of the differential analysis showed that there was a significant up-regulation of 33 proteins in the drug-resistant patients of the maintenance treatment (Wilcoxon's p <0.05,Fold Change>1.5) (results shown in fig. 1A-B).
To further screen and verify the association of these molecules with the response to the conservation treatment, the present invention performed Log Rank test on the association of 33 candidate proteins with the endocrine treatment response in a common dataset (GSE 1378, GSE1379, GSE6532, GSE9195, GSE12093, GSE 17705) of 6 breast cancers treated with tamoxifen. The present invention found that 6 genes (EEF 1E1, DYNLT1, ILVBL, HSD17B12, NUDT5, and SRPK 1) out of the 33 candidate genes were associated with endocrine therapy resistance (Log Rank's p <0.1;Hazard Ratio>2). The 6 proteins obtained were proteins associated with endometrial cancer resistance (results shown in FIGS. 1C-D).
Example 2
The drug resistance related marker verification and conservation drug resistance prediction system construction process provided by the invention comprises the following steps:
a) Sample collection
The method of collecting the samples is the same as in example 1.
b) Immunohistochemical (IHC) staining
1. Selecting paraffin tissue sections to be subjected to immunohistochemical staining, soaking in an environment-friendly tissue dewaxing solution (environment-friendly dewaxing transparent solution purchased from Sivel organisms, cat No. G1128-1L) for 2 hours
2. The tissue sections were removed and immersed in the new environmental tissue dewaxing solution for 20 minutes.
3. Taking out the tissue slices, and hydrating the tissue slices by using ethanol with different gradient concentrations, wherein the ethanol concentration is 95%, 85% and 75% in sequence. Tissue sections were soaked in ethanol at each concentration for 10 minutes.
4. Tissue sections were removed and rinsed with phosphate buffer (Phosphate buffered saline, PBS). The cassette containing the tissue sections and PBS was placed on the shaker, rinsed 5 minutes each, and rinsed 3 times.
5. After the slicing is rinsed, the slices are put into antigen retrieval liquid at 100 ℃ and heated in a microwave oven. The antigen retrieval mode used in the invention is EDTA sodium solution (PH is 9, purchased from Sivel organism, cat No. G1203-250 ML), fire power is 30, and time is 10 minutes. And taking out the antigen retrieval liquid box after finishing, standing, and naturally cooling to room temperature. During which the antigen retrieval level is guaranteed to completely bypass the tissue.
6. The sections were placed in 5% polysorbate-20 in PBS (Phosphate buffered saline-Tween, abbreviated as PBST), and rinsed on a shaker in PBST for 5 minutes each for a total of 3 washes.
7. The tissue sections were placed flat into a wet box. The surface of the slide was blotted with toilet paper. A pencil was then used to draw a circle around the tissue edge of 2 mm. And then 3% hydrogen peroxide solution is dripped on the surface of the tissue, and the tissue is completely covered by the hydrogen peroxide solution. After the completion, the wet box cover is covered, and the wet box cover is placed in a biochemical incubator at 37 ℃ for incubation for 20 minutes.
8. The wet cassette was removed and the tissue sections rinsed with PBST. Each time for 5 minutes was rinsed 3 times.
9. After the rinsing is finished, the water on the surface of the tissue slice is washed by toilet paper and then placed in a wet box. Approximately 50. Mu.L of 3% goat serum (i.e., goat serum type, available from Boschia, cat. No. AR0009-12 ML) was added dropwise to the surface of the tissue to completely cover the tissue with goat serum. The wet box was covered and then incubated in a 37℃biochemical incubator for 20 minutes.
10. The primary antibody was diluted with PBS at the following antibody dilution ratio: EEF1E1,1:200; the ILVBL is used to determine the level of the buffer,
1:200; SRPK1,1:100; NUDT5:1, a step of; 200. the prepared antibody diluent is placed on ice for standby.
11. The wet cartridge was removed, the tissue surface was blotted with toilet paper to remove goat serum liquid, and then approximately 50 μl of primary anti-dilution was directly added dropwise to the tissue surface. The antibody should cover the tissue surface completely. The lid was then wet covered and incubated overnight at 4 ℃.
12. After incubation for more than 12 hours with primary antibody, the wet cassette was removed and the tissue sections were rinsed on a shaker with PBST. Each rinse was performed for 10 minutes and 3 times.
13. After the rinsing, the surface of the slide was blotted with toilet paper, and then secondary antibodies (anti-rabbit secondary antibodies for immunohistochemical goat, purchased from Sivel, cat No. G1213-100 UL) were added dropwise to the tissue surface. Ensuring that the secondary antibody completely covers the tissue. Tissue sections were placed in wet boxes and incubated for 30 minutes at room temperature.
14. Tissue sections were removed after the end of secondary antibody incubation and rinsed with PBST. Each rinse was performed for 10 minutes and 3 times.
15. DAB color development working solution (DAB color development kit, purchased from Saiweier, cat# G1212-200T) was prepared, and 50. Mu.L of DAB color development solution was added dropwise to the tissue surface. The staining of the cells was observed under a microscope. After the slide was sufficiently colored, the slide was immersed in tap water to terminate the color development.
16. Hematoxylin staining of nuclei was performed for 5 minutes after all slides were developed. And then washed once with tap water. The slide was then differentiated in ethanol hydrochloride for about 5 seconds, washed again with tap water, and then blue-turned by immersing the slide in ammonia water. The nuclear staining was observed under a microscope. The nuclei staining was rinsed by immersing the slides in tap water.
17. The slides are dehydrated by gradient alcohol with the alcohol concentration of 75%, 85% and 95% in sequence. The slide was then immersed in the environmental dewaxing solution for 5 minutes of transparency. Finally taking out the glass slide and airing in a fume hood
18. And sealing the aired glass slide by using neutral resin. The slide after the completion of the sealing is dried, and then is taken for observation and photographing by a microscope.
Tumor cell staining was scored using a semi-quantitative five-class grading system: 0, no tumor cell staining; 1,1-10% tumor cell staining; staining 2,11-25% of tumor cells; 3,26-50% tumor cell staining; 4,51-75% tumor cell staining; 5, >75% tumor cells were stained. Staining intensity was scored using a semi-quantitative four-class grading system: 0. no dyeing; 1. weak staining; 2. medium dyeing; 3. and (5) strong dyeing. Tumor cell staining scores were stained simultaneously by two independent experts under the same conditions. In the event of inconsistent scores, the slice is re-evaluated.
c) Immunohistochemical staining results
IHC demonstrated a significant elevation in tissue of endometrial cancer patients resistant to the maintenance therapy for 4 hormone-insensitive related proteins (EEF 1E1, ILVBL, SRPK1 and NUDT5 with available antibodies), further supporting the results of these proteins predicting the progestin treatment response. And correlation analysis showed positive correlation between the 4 proteins (FIGS. 2A-C).
In conclusion, the 6 protein markers for resisting the endometrial cancer nursing treatment obtained by screening can be used for predicting the treatment response of a patient before the endometrial cancer patient is subjected to the nursing treatment by detecting the expression level of the 6 protein markers, so that drug-resistant people can be effectively screened, the treatment scheme is optimized in a targeted manner, and the benefit rate of the patient is provided. The invention constructs a detection product for predicting the conservation drug resistance, only needs to collect tumor tissues of a patient to carry out experiments according to a manual, evaluates whether the drug resistance of the patient occurs according to a staining result, and has the advantages of clinical accessibility and accuracy.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (10)
1. An endometrial cancer care drug resistance marker comprising at least 4 of DYNLT1 protein, HSD17B12 protein, EEF1E1 protein, ILVBL protein, SRPK1 protein and NUDT5 protein.
2. The use of an endometrial cancer conservation therapy drug-resistant marker, characterized in that a reagent for detecting the endometrial cancer conservation therapy drug-resistant marker according to claim 1 is used for preparing an endometrial cancer conservation therapy drug-resistant product.
3. The use of the endometrial cancer care treatment resistance marker according to claim 2, wherein the endometrial cancer care treatment resistance condition of the patient is judged by quantitatively detecting the endometrial cancer care treatment resistance marker.
4. The use of a marker for endometrial cancer conservation therapy according to claim 2, wherein the drug for endometrial cancer conservation therapy is a progestin.
5. The use of a marker for endometrial cancer care treatment according to claim 2, wherein said drug for endometrial cancer care treatment is medroxyprogesterone acetate.
6. The use of an endometrial cancer conservation therapy drug-resistant marker according to claim 2, wherein the agent for detecting the endometrial cancer conservation therapy drug-resistant marker comprises a substance that specifically binds to the DYNLT1 protein, the HSD17B12 protein, the EEF1E1 protein, the ILVBL protein, the SRPK1 protein and the NUDT5 protein.
7. The use of an endometrial cancer care treatment drug resistance marker of claim 6, wherein the substance is an antibody or antibody fragment.
8. A product for detecting an endometrial cancer conservation therapy drug resistance marker, characterized in that the product comprises a reagent for detecting an endometrial cancer conservation therapy drug resistance marker according to claim 1.
9. The product for detecting endometrial cancer conservation therapy drug-resistant markers of claim 8, wherein the product comprises a detection reagent, a kit, a chip, a test paper or a high throughput sequencing platform.
10. The product for detecting endometrial cancer conservation therapy drug resistant markers of claim 9, wherein the high throughput sequencing platform comprises a Tims-TOF mass spectrometer.
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