CN111781358A - XAB2 protein as ovarian cancer prognosis and/or prediction platinum drug resistance marker - Google Patents
XAB2 protein as ovarian cancer prognosis and/or prediction platinum drug resistance marker Download PDFInfo
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Abstract
The invention belongs to the technical field of biomedicine, and particularly discloses application of XAB2 protein as an ovarian cancer prognosis and/or prediction platinum drug resistance marker. The invention discloses a protein XAB2 closely related to platinum drug resistance generation of ovarian cancer cells, detects XAB2 protein expression in ovarian cancer tissues by an immunohistochemical method, and judges the prognosis of ovarian cancer and/or predicts platinum drug resistance. The expression level of the XAB2 protein in ovarian cancer is related to the survival rate of patients, the prognosis of patients with high XAB2 protein expression is poor, and the overall survival rate and the progression-free survival rate are reduced. The expression level of XAB2 protein is not only related to patient prognosis, but also high expression level of XAB2 protein is related to platinum resistance of ovarian cancer patients, and the risk of platinum resistance of the patients with high expression level of XAB2 protein is increased. The XAB2 protein is used as a biomarker for ovarian cancer prognosis and/or platinum drug resistance prediction, and has wide application prospect and great potential social benefit.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to XAB2 protein serving as an ovarian cancer prognosis and/or platinum drug resistance prediction marker, and particularly to XAB2 protein serving as a high-grade serous ovarian cancer prognosis and/or platinum drug resistance prediction marker, and a reagent and a kit for detecting the marker.
Background
Ovarian Cancer (Ovarian Cancer) is currently the worst-prognosis gynecological malignancy, the main pathological type of which is high-grade serous Ovarian Cancer (HGSOC), and its five-year survival rate is only 47%. Current standard ovarian cancer treatment regimens include tumor cell debulking and platinum-based combination chemotherapy. Even after ideal tumor cytoreductive surgery and sufficient chemotherapy, 70% of patients experience relapse and metastasis.
Platinum resistance (Platinum resistance): patients with ovarian cancer who are sensitive to platinum drugs in the initial treatment stage still relapse in about 2-3 years, and the patients with the relapse almost all suffer from platinum drug resistance. And about 20% of ovarian cancer patients are inherently resistant to platinum, eventually leading to treatment failure. The phenomenon of platinum drug resistance is the most important factor for restricting the improvement of the survival rate of ovarian cancer patients. At present, no good biomarker is used for predicting platinum treatment sensitivity of ovarian cancer patients, research which can be applied to clinical prediction of platinum drug resistance markers of ovarian cancer is found, and the method has great significance for improving prognosis of ovarian cancer patients.
XAB2(XPA-binding protein 2) is a protein molecule involved in the process of repairing cellular DNA damage, and has multiple biological functions, such as: regulates the selective shearing process of cellular precursor mRNA, regulates the transcription of cellular mRNA, and can influence the nuclear output of mRNA and other cell biological functions.
However, the relation between XAB2 protein and ovarian cancer, particularly high-grade serous ovarian cancer, prognosis and platinum resistance is not reported in the literature.
Disclosure of Invention
According to the invention, the expression condition of the XAB2 protein in ovarian cancer tissues, especially high-grade serous ovarian cancer tissues is researched for the first time, the relation between the XAB2 protein and the clinical pathological characteristics, survival prognosis and platinum drug treatment tolerance of the high-grade serous ovarian cancer is analyzed, and the XAB2 protein is found to be a marker for prognosis and/or prediction of platinum drug resistance of the high-grade serous ovarian cancer, so that an experimental basis is provided for the molecular mechanism and prognosis judgment of the occurrence and development of the ovarian cancer, especially the high-grade serous ovarian cancer, and a basis is provided for clinical application.
In order to achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the invention provides the use of a reagent for detecting XAB2 protein in the preparation of a diagnostic reagent or kit for ovarian cancer. Wherein the ovarian cancer is high grade serous ovarian cancer. Further, the ovarian cancer diagnostic reagent or kit comprises an antibody or antibody fragment specifically recognizing XAB2 protein. The ovarian cancer diagnostic reagent or the kit is used for judging by detecting the expression condition of XAB2 protein in the surgical resection tissue of an ovarian cancer patient through an immunohistochemical technology; the high expression of the XAB2 protein in the tissues is positively correlated with the occurrence of ovarian cancer; the positive rate of the XAB2 protein expressed in the tissues is inversely related to the prognostic survival of ovarian cancer patients; the high expression of the XAB2 protein in tissues is positively correlated with the incidence rate of platinum drug resistance of ovarian cancer patients.
In one aspect, the invention provides the use of a reagent for detecting XAB2 protein in the preparation of a diagnostic reagent or kit for the prognostic evaluation of ovarian cancer. Wherein the ovarian cancer is high grade serous ovarian cancer. Further, the diagnostic reagent or the kit for the prognosis evaluation of ovarian cancer comprises an antibody or an antibody fragment specifically recognizing XAB2 protein. The reagent or the kit for prognosis evaluation and diagnosis of ovarian cancer is used for judging by detecting the expression condition of XAB2 protein in the surgical resection tissue of an ovarian cancer patient through an immunohistochemical technology; the high expression of the XAB2 protein in the tissues is positively correlated with the occurrence of ovarian cancer; the positive rate of expression of the XAB2 protein in tissues is inversely correlated with the prognostic survival of ovarian cancer patients.
In one aspect, the invention provides application of a reagent for detecting XAB2 protein in preparing a platinum-based drug resistance prognosis screening diagnostic reagent or kit for ovarian cancer. Wherein the ovarian cancer is high grade serous ovarian cancer. Further, the platinum-based drug resistance prognostic screening diagnostic reagent or kit for ovarian cancer comprises an antibody or an antibody fragment specifically recognizing XAB2 protein. The reagent or the kit for prognosis evaluation and diagnosis of ovarian cancer is used for judging by detecting the expression condition of XAB2 protein in the surgical resection tissue of an ovarian cancer patient through an immunohistochemical technology; the high expression of the XAB2 protein in the tissues is positively correlated with the occurrence of ovarian cancer; the high expression of the XAB2 protein in tissues is positively correlated with the incidence rate of platinum drug resistance of ovarian cancer patients.
In one aspect, the invention provides application of a reagent for detecting XAB2 protein in preparing a platinum-based drug resistance prediction screening diagnostic reagent or kit for ovarian cancer. Wherein the ovarian cancer is high grade serous ovarian cancer. Further, the platinum-based drug resistance prediction screening diagnostic reagent or kit for ovarian cancer comprises an antibody or an antibody fragment specifically recognizing XAB2 protein. The reagent or the kit for prognosis evaluation and diagnosis of ovarian cancer is used for judging by detecting the expression condition of XAB2 protein in the surgical resection tissue of an ovarian cancer patient through an immunohistochemical technology; the high expression of the XAB2 protein in the tissues is positively correlated with the occurrence of ovarian cancer; the high expression of the XAB2 protein in tissues is positively correlated with the incidence rate of platinum drug resistance of ovarian cancer patients.
Further, the reagent for detecting XAB2 protein also comprises: goat serum, EDTA antigen retrieval solution (pH 9.0), 3% H2O2The kit comprises a biotin-labeled goat anti-mouse/rabbit IgG, an alkaline phosphatase-labeled streptavidin or horseradish enzyme-labeled streptavidin working solution, a DAB color reagent and a PBS solution.
In one aspect, the invention provides application of a protein coded by XAB2 gene in preparation of an ovarian cancer personalized treatment screening kit. Wherein, the individualized treatment screening kit detects the expression of XAB2 protein in the surgical excision tissue of the ovarian cancer patient by an immunohistochemical technology. Further, high expression of the XAB2 protein in ovarian cancer tissues can direct clinical treatment. Wherein the ovarian cancer is high grade serous ovarian cancer.
According to the invention, the expression level of XAB2 protein in high-grade serous ovarian cancer tissues is firstly detected, the postoperative 5-year survival conditions of high-grade serous ovarian cancer in different stages are compared, and the result shows that the postoperative total survival rate and the non-progression survival rate of a patient with high XAB2 protein expression are both significantly lower than those of a patient with low XAB2 protein expression.
The invention also compares high-grade serous ovarian cancer patients with different response effects on treatment of platinum drugs, and finds that the platinum drug resistance response of the XAB2 protein high-expression patient is more obvious than that of the XAB2 protein low-expression patient, and the risk of platinum drug resistance is obviously increased. In combination with the above research results, the present invention provides the use of XAB2 as a marker for prognosis and/or prediction of platinum resistance in high-grade serous ovarian cancer.
The detection reagent and the related kit for the marker are further researched for determining the expression level of the XAB2 marker, so that the detection reagent and the related kit can be used for prognosis judgment and/or prediction of platinum-based drug resistance of high-grade serous ovarian cancer.
In one aspect, the invention provides a method for detecting XAB2 gene, comprising the following steps:
the high-grade serous ovarian cancer tumor fresh tissue is fixed by 10% neutral formalin conventionally, then paraffin embedding is carried out, tissue sections are manufactured, immunohistochemical staining is carried out, a microscope and imaging equipment are scanned to be electronic pictures, and the pictures are read and subjected to statistical analysis.
The specific detection method comprises the following steps:
dewaxing and hydrating a high-grade serous ovarian cancer tissue section by using dimethylbenzene and ethanol with gradient concentration, repairing a microwave antigen, inactivating endogenous peroxidase and goat serum, respectively incubating the high-grade serous ovarian cancer tissue section with primary anti-XAB 2 in a moisture preservation box at 4 ℃ overnight, washing the high-grade serous ovarian cancer tissue section with TBS (TBS), respectively incubating the high-grade serous ovarian cancer tissue section with biotin-labeled goat anti-mouse/rabbit IgG and alkaline phosphatase-labeled streptavidin, performing DAB (digital amplification) color development, and performing hematoxylin counterstaining; and finally, sealing the slices by neutral gum after gradient ethanol dehydration and xylene transparency, scanning the slices into digital photos by using a microscope and imaging equipment, and scoring each immunohistochemical staining slice.
The method for prognosis judgment or prediction of platinum drug resistance comprises the following steps: the XAB2 protein is expressed positively, so that the life cycle of the ovarian cancer patient is short, and the risk of platinum drug resistance reaction is high; when the XAB2 protein expression is negative, the ovarian cancer patient has long survival time and low risk of platinum drug resistance reaction.
Advantageous effects
According to the invention, the first research discovers that the XAB2 protein expression level in high-grade serous ovarian cancer is closely related to the prognosis of ovarian cancer patients, and the risk of platinum drug resistance of patients with high XAB2 protein expression level is obviously increased. The invention takes XAB2 protein as a marker, detects the expression of XAB2 protein in tumor tissues by an immunohistochemical method, and judges the prognosis of patients with high-grade serous ovarian cancer and/or predicts the risk of platinum drug resistance. The expression level of XAB2 protein in high-grade serous ovarian cancer is related to the survival rate of patients, the prognosis of patients with high XAB2 protein expression is poor, the overall survival rate (OS) and the Progression free survival rate (PFS) are reduced, and the survival rate is short. The XAB2 protein expression level is not only related to patient prognosis, but also the high XAB2 protein expression level is related to the platinum resistance of patients with high-grade serous ovarian cancer, and the patients with the high XAB2 protein expression level have increased risk of platinum resistance. The XAB2 protein is used as a biomarker for prognosis and/or prediction of platinum drug resistance of high-grade serous ovarian cancer, and has wide application prospect and great potential social benefit. The expression level of the XAB2 protein is not only related to the overall survival time of the patient, but also can be used as a marker for predicting the drug resistance of the ovarian cancer patient to platinum treatment, and the detection of the expression level of the XAB2 protein has wide application prospect and great potential social benefit.
Drawings
FIG. 1: the expression of XAB2 protein in high-grade serous ovarian cancer tissues; in the figure, A: HE staining of the same patient tissue, B: immunohistochemical staining of XAB2 protein in high-grade serous ovarian cancer patient tissue:
FIG. 2: the Kaplan-Meier survival curve of XAB2 protein in different expression populations; in the figure, A: relationship between the expression level of XAB2 protein and overall survival of high-grade serous ovarian cancer (p ═ 0.031) (median survival time of patients with negative XAB2 expression was 51.5 months, median survival time of patients with positive XAB2 protein expression was 46.4 months), B: relationship between the expression level of XAB2 protein and progression-free survival of high-grade serous ovarian cancer (p ═ 0.01) (median progression-free survival time for patients with negative expression of XAB2 was 22.7 months, and median progression-free survival time for patients with positive expression of XAB2 protein was 10.5 months);
FIG. 3: the expression of XAB2 protein in high-grade serous ovarian cancer tissues sensitive and resistant to platinum treatment; in the figure, A: high-grade serous ovarian cancer XAB2 protein staining resistant to platinum-based treatments, B: high grade serous ovarian carcinoma XAB2 protein staining sensitive to platinum based treatment.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.
Example 1
1. The test method comprises the following steps:
we collected wax blocks from surgical specimens of 56 patients with high-grade serous ovarian cancer during 2014-2018, and the specimens were serially sliced into paraffin sections. After xylene dewaxing and gradient ethanol hydration, the expression of the target protein is detected by a biotin method, which comprises the following steps:
(1) paraffin section of ovarian cancer tumor tissue is subjected to baking at 65 ℃, xylene dewaxing and gradient ethanol hydration.
(2) Sections were antigen-repaired with EDTA antigen-repair solution (pH 9.0), 3% H2O2Endogenous peroxidase was inactivated, followed by blocking by goat serum.
(3) The XAB 2-moisture resistant box was incubated overnight at 4 ℃.
(4) The sections were washed three times with PBS solution after immunohistochemistry, added dropwise with biotin-labeled goat anti-mouse/rabbit IgG polymer (reagent 3), incubated at room temperature for 15min, washed three times with PBS, added dropwise with horseradish enzyme-labeled streptavidin working solution (reagent 4), incubated at room temperature for 15min, and washed three times with PBS.
(5) Sections were visualized with DAB.
(6) The sections are re-stained with hematoxylin, dehydrated by gradient ethanol, transparent by xylene and sealed by neutral gum.
And (4) evaluating the results: after the neutral gum is dried, the sections are scanned in full slices using a full automatic slide scanning system with the scanning parameters set to a monolayer multiple of 20 ×. And (3) intercepting three fields with highest positive expression in each section at a magnification of 200 times, and selecting to reduce non-tumor cell components such as blood vessels, fibers and the like in the fields as much as possible. And analyzing the dyeing result by using ImageJ 1.52a image analysis software, wherein the operation method is carried out by referring to the standard flow of IHC Profile, and the scoring calculation formula is as follows:
the analysis mode was set to nuclear stained image (nuclear stained image) and the software scored positive or negative for the results according to the staining score of the picture.
Statistical processing of data: statistical analysis was performed using IBM SPSS Statistics 26.0 software. Statistical analysis is carried out on the relationship between the expression level of XAB2 protein and clinical characteristics of patient age, FIGO stage, surgical residual focus, platinum treatment reaction and the like by using chi-square test; the expression of XAB2 protein was plotted against patient survival using the Kaplan-Meier method and subjected to hypothesis testing using the Log-rank method. Both statistical tests used a two-sided test, and P.ltoreq.0.05 was considered statistically significant.
2. And (3) test results:
(1) the XAB2 protein is expressed in high-grade serous ovarian cancer, and the result is shown in figure 1;
(2) the Kaplan-Meier survival curve (P ═ 0.021; P ═ 0.01) of XAB2 protein in different expression populations is shown in FIG. 2; as can be seen from fig. 2: the mean Overall survival (Overall survival: OS) of patients positive for XAB2 protein was 46.4 months, less than 51.5 months for negative patients (χ 2 ═ 4.659, P ═ 0.031); median Progression-free survival (PFS) for patients positive for XAB2 protein was 10.5 months, less than 22.7 months for negative patients (χ 2 ═ 6.651, P ═ 0.01). The results show that the overall survival rate and the progression-free survival rate of the XAB2 protein high-expression patient after operation are both obviously lower than those of the low-expression patient;
(3) the relationship between clinical characteristics of FIGO stages, residual focus, platinum treatment response and the like of a patient and the expression condition of XAB2 protein. The results are shown in Table 1.
Table 1: clinical characteristics of patients including FIGO stages, residual focus, platinum treatment response and the like and XAB2 protein expression conditions.
As can be seen from Table 1, there is a significant correlation between positive expression of XAB2 protein and patient development of platinum-based drug resistance (P < 0.001). It is found that the platinum-based drug resistance reaction of patients with high XAB2 protein expression is more obvious, and the risk of platinum-based drug resistance is obviously increased.
(4) The expression of XAB2 protein in patients responding to different platinum-based treatments is shown in figure 3 and table 2.
Table 2: expression of XAB2 protein in patients with different response to platinum therapy
As can be seen from fig. 3 and table 2, positive expression of XAB2 protein was significantly increased in platinum-resistant patients, with a significant difference from positive expression of XAB2 protein in platinum-sensitive patients (OR ═ 13.80, 95% CI: 3.247-58.645, P < 0.001).
In conclusion, the XAB2 protein can be used as an index for prognosis and/or prediction of platinum drug resistance evaluation of high-grade serous ovarian cancer, particularly can predict the sensitivity of a patient to platinum drug treatment, and provides suggestions and references for selection of treatment schemes and judgment of curative effect for clinicians.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Use of a reagent for detecting XAB2 protein in the preparation of a diagnostic reagent or kit for ovarian cancer.
2. The use according to claim 1, wherein the ovarian cancer diagnostic reagent or kit comprises an antibody or antibody fragment specifically recognizing XAB2 protein.
3. The use according to claim 1, wherein the ovarian cancer diagnostic reagent or kit is used for diagnosis by detecting the expression of XAB2 protein in the surgically excised tissue of an ovarian cancer patient by immunohistochemical technique; the high expression of the XAB2 protein in the tissues is positively correlated with the occurrence of ovarian cancer; the positive rate of the XAB2 protein expressed in the tissues is inversely related to the prognostic survival of ovarian cancer patients; the high expression of the XAB2 protein in tissues is positively correlated with the incidence rate of platinum drug resistance of ovarian cancer patients.
4. Use of a reagent for detecting XAB2 protein in preparation of a diagnostic reagent or kit for ovarian cancer prognosis evaluation.
5. The use according to claim 4, wherein the diagnostic reagent or kit for the prognostic assessment of ovarian cancer comprises an antibody or antibody fragment that specifically recognizes XAB2 protein.
6. The use according to claim 4, wherein the diagnostic reagent or kit for the prognosis evaluation of ovarian cancer is judged by detecting the expression of XAB2 protein in the surgically excised tissue of an ovarian cancer patient by immunohistochemical technique; the high expression of the XAB2 protein in the tissues is positively correlated with the occurrence of ovarian cancer; the positive rate of expression of the XAB2 protein in tissues is inversely correlated with the prognostic survival of ovarian cancer patients.
7. An application of a reagent for detecting XAB2 protein in preparing a platinum-based drug-resistant prognosis screening diagnostic reagent or kit for ovarian cancer.
8. Application of a reagent for detecting XAB2 protein in preparing a platinum-based drug resistance prediction screening diagnostic reagent or kit for ovarian cancer.
9. The use according to any one of claims 1 to 8, wherein the reagent for detecting XAB2 protein further comprises: goat serum, EDTA antigen retrieval solution (pH 9.0), 3% H2O2The kit comprises a biotin-labeled goat anti-mouse/rabbit IgG, an alkaline phosphatase-labeled streptavidin or horseradish enzyme-labeled streptavidin working solution, a DAB color reagent and a PBS solution.
10. The application of a protein coded by XAB2 gene in preparing an ovarian cancer individualized treatment screening kit is characterized in that the individualized treatment screening kit detects the expression of XAB2 protein in the surgical resection tissues of ovarian cancer patients through an immunohistochemical technology; the high expression of the XAB2 protein in ovarian cancer tissues can direct clinical treatment.
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