CN112881704A - Application of detection reagent of CIT-H3 protein in preparation of liver cancer prognosis and/or recurrence prediction reagent - Google Patents
Application of detection reagent of CIT-H3 protein in preparation of liver cancer prognosis and/or recurrence prediction reagent Download PDFInfo
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Abstract
The invention discloses an application of a detection reagent of CIT-H3 protein in preparing a liver cancer prognosis and/or recurrence prediction reagent, and provides an immunohistochemical detection kit for evaluating prognosis and recurrence risk of a liver cancer patient, wherein the kit detects a marker CIT-H3 (citrullinated histone H3) of a 'neutrophil extracellular trapping net' by using an immunohistochemical principle, has the characteristics of objectivity, accuracy, simplicity, convenience, intuition, easiness in operation and the like, can be operated in a pathological room of a hospital by common technicians without the aid of complex instruments; the method can effectively evaluate the prognosis and the recurrence risk of the liver cancer patient, thereby better helping a doctor to monitor the state of the patient, adjusting a proper treatment means in time, helping to improve the treatment effect and prolonging the survival time of the patient.
Description
Technical Field
The invention relates to the technical field of life science, in particular to an application of a detection reagent of CIT-H3 protein in preparation of a liver cancer prognosis and/or recurrence prediction reagent.
Background
Primary hepatocellular carcinoma (liver cancer for short) is one of common malignant tumors in China, and the incidence and the fatality rate of the primary hepatocellular carcinoma are the fifth and the second place of the malignant tumors in China. Currently, the most common treatment for liver cancer is surgical resection and liver transplantation. However, the liver cancer is high in malignancy degree, has the characteristics of rapid development, easy transfer and the like, and causes poor prognosis effect and quick overall recurrence of liver cancer patients, so that the overall five-year survival rate of the liver cancer is still at a lower level. Therefore, by searching for relevant markers for evaluating prognosis and recurrence risk of liver cancer patients, important references and help can be provided for clinical postoperative risk judgment and adjustment of appropriate treatment means, and the method is also one of key steps for realizing individual accurate treatment of tumors.
At present, two types of tumor markers are actually applied in the process of liver cancer diagnosis and treatment, and one type is a marker for clinical diagnosis, such as alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and the like. Besides being used for diagnosing liver cancer, the markers can also evaluate the prognosis condition of a patient to a certain extent. However, these markers have low sensitivity, poor correlation, and low reference value for patient prognosis and relapse assessment. And the other is a marker for targeted drug screening, such as vascular endothelial cell growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), etc. The expression of the markers has good correlation with the prognosis of patients, but the markers need to be detected by means of gene detection and the like, so that the detection cost is high, and certain technical thresholds are provided.
At present, no marker detection scheme specially used for patient prognosis and recurrence evaluation exists in the clinical diagnosis and treatment process of liver cancer, and the defects of low sensitivity, high cost and technical threshold and the like exist in the detection of common diagnosis and targeted drug screening markers respectively. Therefore, the search for liver cancer prognosis markers with high sensitivity, low cost and easy detection and detection methods is imperative,
there are many factors affecting prognosis and recurrence of liver cancer, and a large number of documents report that neutrophils play an important role in promoting tumor metastasis and recurrence. Citrullinated histones H3, a biomarker of neutral extracellular trap formation, predictions of venous thrombosis in cancer patients, discloses a biological marker of Citrullinated histone H3(H3Cit) -NET formation, whose content in peripheral blood can be used to predict the risk of venous thromboembolism in cancer patients, and cannot directly predict the prognosis and recurrence of the associated cancer.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides the application of a detection reagent of CIT-H3 protein in preparing a liver cancer prognosis and/or recurrence prediction reagent. The CIT-H3 protein specifically expressed by the neutrophil extracellular trapping net in the liver cancer has higher correlation with the prognosis and the recurrence risk of a patient, and the prognosis and the recurrence risk of the patient are predicted by monitoring the expression level of the CIT-H3 protein, so that the CIT-H3 protein is superior to the conventional molecular such as a diagnostic tumor marker AFP and the like for predicting the prognosis and the recurrence risk of the patient.
The invention aims to provide an application of a detection reagent of CIT-H3 protein in preparing a liver cancer prognosis and/or recurrence prediction reagent.
The second purpose of the invention is to provide the application of the detection reagent of CIT-H3 protein in the preparation of a kit for predicting the prognosis and/or recurrence of liver cancer.
The third purpose of the invention is to provide a kit for predicting prognosis and/or recurrence of liver cancer.
In order to achieve the purpose, the invention is realized by the following scheme:
the inventor researches and discovers that the neutrophil can promote malignant progression of the liver cancer together in a mode of promoting the enhancement of tumor invasion capacity by producing a 'neutrophil extracellular trapping net'. Meanwhile, the production of the neutrophil extracellular trapping net can specifically express CIT-H3 protein, and the production condition (the amount of the CIT-H3 protein) of the neutrophil extracellular trapping net in liver cancer tumor tissue and the poorer prognosis and higher recurrence rate of patients have a remarkable positive correlation: the generation condition (the amount of CIT-H3 protein) of the 'neutrophil extracellular trap' in the liver cancer tumor has stronger correlation with the prognosis and the recurrence risk of a liver cancer patient; the more the "neutrophil extracellular trap" (the amount of CIT-H3 protein) is produced in the hepatoma tumor, the worse the prognosis level of the patient and the shorter the overall survival time, and vice versa; the more "neutrophil extracellular traps" (the amount of CIT-H3 protein) are produced in hepatoma tumors, the greater the risk of postoperative recurrence for the patient and vice versa. The result shows that the 'neutrophil extracellular trapping net' (the quantity of CIT-H3 protein) can be used as a marker for liver cancer prognosis and recurrence evaluation, and provides reference significance for clinical diagnosis and treatment.
Therefore, the invention claims the application of the detection reagent of CIT-H3 protein in the preparation of the liver cancer prognosis and/or recurrence prediction reagent.
And the application of the detection reagent of CIT-H3 protein in the preparation of a kit for predicting the prognosis and/or recurrence of liver cancer.
Preferably, the detection reagent of the CIT-H3 protein is a CIT-H3 antibody.
Preferably, the detection reagent of the CIT-H3 protein detects CIT-H3 protein in a liver cancer tumor region.
The invention also claims a liver cancer prognosis and/or recurrence prediction kit, which contains a detection reagent of CIT-H3 protein.
Preferably, the detection reagent of the CIT-H3 protein is a CIT-H3 antibody.
Preferably, a second antibody labeled with horseradish peroxidase is also included.
More preferably, the second antibody is anti-rabbit IgG.
Preferably, the liver cancer prognosis and/or recurrence prediction kit is an immunohistochemistry kit.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides an immunohistochemical detection kit for evaluating prognosis and recurrence risk of a liver cancer patient, which utilizes the immunohistochemical principle to detect a marker CIT-H3 (citrullinated histone H3) of a neutrophil extracellular trapping net, has the characteristics of objectivity, accuracy, simplicity, convenience, intuition, easiness in operation and the like, can be operated in a pathological room of a hospital by common technicians without the help of complex instruments; the method can effectively evaluate the prognosis and the recurrence risk of the liver cancer patient, thereby better helping a doctor to monitor the state of the patient, adjusting a proper treatment means in time, helping to improve the treatment effect and prolonging the survival time of the patient.
Drawings
FIG. 1 shows that neutrophil extracellular traps promote enhanced invasion of hepatoma cells.
FIG. 2 shows the expression of CIT-H3 in the tissues of liver cancer patients.
FIG. 3 is a survival curve analysis of CIT-H3 expression versus overall survival time and recurrence rate of patients.
Detailed Description
The present invention will be described in further detail with reference to the drawings and specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1 production of "neutrophil extracellular trap" by neutrophils promotes malignant progression of liver cancer
First, experiment method
In the embodiment, the neutrophil is separated from the peripheral blood of a healthy person, and the neutrophil extracellular trapping net is induced and purified by adding the tumor cell culture supernatant for in vitro culture. And then, a Transwell chamber experiment is utilized, the purified neutrophil extracellular trapping net is added, and the change of the invasion capacity of the human hepatoma cell line HepG2 cells in the Transwell chamber is detected, so that the influence of the neutrophil extracellular trapping net on the malignant progression of the tumor cells is evaluated.
Second, experimental results
The results are shown in fig. 1, and compared to the control group, the number of human liver cancer cells invading the lower surface of the Transwell chamber was increased after the addition of the "neutrophil extracellular trapping net" and was statistically significantly different, indicating the ability of the neutrophil extracellular trapping net to enhance the malignant progression of human liver cancer cells.
Example 2 kit for predicting poor and recurrence rate of liver cancer patients
In the embodiment, CIT-H3 antigen is used as a marker generated by ' neutrophil extracellular trap ' in tumor tissues, and a kit for detecting the generation level of the neutrophil extracellular trap ' is established by using traditional immunohistochemical staining.
A, make up
A primary antibody CIT-H3 (purchased from Abcam, Inc., cat # ab5103) and a secondary anti-rabbit IgG antibody with a horseradish peroxidase label (purchased from Dako, cat # P044801-2).
Second, use method
1. Specimen detection
(1) Selecting a liver cancer paraffin section containing a tumor area, and ensuring no large necrosis;
(2) obtaining 8 paraffin slices with the size of 4 microns, baking the slices at the temperature of 60 ℃ for 2 hours, taking out the slices, and slightly cooling the slices;
(3) dewaxing with xylene at room temperature for 2 times, each time for 10 minutes;
(4) washing xylene in 100% ethanol, and sequentially passing through 95% ethanol, 80% ethanol and 70% ethanol for 5 min each time;
(5) washing with double distilled water for 5 minutes;
(6) with 0.3% H2O2Blocking endogenous peroxidase activity for 10 minutes at room temperature;
(7) washing with double distilled water for 5 min for 4 times;
(8) antigen retrieval: 10mM sodium citrate buffer solution (pH6.0), and performing microwave thermal remediation for 20 min;
(9) naturally cooling for 30 minutes at room temperature;
(10) washing in PBS buffer solution for 4 times, each time for 3 minutes;
(11) first antibody CIT-H3 (purchased from Abcam, Inc., cat # ab5103) was added dropwise to the tissue slices and incubated at 4 ℃ for 12 hours;
(12) washing with PBS buffer for 4 times, 5 minutes each time;
(13) dripping a secondary antibody with horseradish peroxidase markers, and incubating for 30 minutes at 37 ℃;
(14) PBS wash 4 times, each for 5 minutes;
(15) washing with double distilled water for 5 min for 3 times;
(16) adding hematoxylin cell nucleus dye dropwise, and dyeing for 3 minutes;
(17) washing with double distilled water for 5 min for 3 times;
(18) after air drying, the neutral resin sealing agent is used for sealing.
2. Image analysis
(1) 5 pictures of the cancer nest area are obtained under a high-power visual field (200 times) of an optical microscope;
(2) respectively identifying CIT-H3 histochemical staining signals by adopting analysis software (as shown in figure 2);
(3) analyzing the quantity and the area of CIT-H3 staining signals;
(4) the final result is the average of 5 high power fields.
3. Interpretation of results
(1) The quantity of CIT-H3 staining signals is divided into a high proportion and a low proportion according to a median value. When the number of staining signals of CIT-H3 in the high power field (200 times, 615 μm × 460 μm) pictures is more than 10, dividing the pictures into high proportion groups (marked as "CIT-H3 is high"); when the number of staining signals of CIT-H3 was less than 10, the staining signals were divided into a low proportion group (marked as "CIT-H3 Low")
(2) Judging the treatment effect of the patient: when the patient is "CIT-H3 high", the patient is considered to have a better prognosis, a longer overall survival time, and a lower risk of relapse; when the patient is "CIT-H3 low", the patient is considered to have a poor prognosis, a short overall survival time, and a high risk of relapse.
Example 3 specific expression of CIT-H3 by "neutrophil extracellular trap" is associated with poor prognosis and high recurrence rate in patients
First, experiment method
The implementation case collects 80 liver cancer patients with surgical resection of liver cancer sample slices and clinical related pathological information, the kit of implementation 2 is used for detecting the expression of CIT-H3 in liver cancer tissues of the patients, COX risk regression analysis is carried out by combining with prognosis survival data of the patients after statistical analysis, and chi-square correlation test analysis is carried out by combining with pathological information such as recurrence conditions.
Second, experimental results
The results show that grouping with the high and low expression of CIT-H3 can effectively predict the overall survival and time to relapse of patients with significant differences. (overall survival P0.023; relapse rate P0.004, as in table 1) and the significance of the risk prediction was higher than that of the conventional detection marker AFP (as in table 1). Meanwhile, the expression level of the CIT-H3 protein is also in positive correlation with the recurrence condition of the patient (P is 0.001, as shown in Table 2).
TABLE 1 COX one-factor Risk regression analysis
TABLE 2 correlation analysis of CIT-H3 expression with recurrence of hepatocarcinoma patients:
example 4 testing of clinical patients
First, experiment method
The kit of example 2 was used to detect the expression of CIT-H3 protein in postoperative liver cancer tissue sections from clinical patients with liver cancer, and the images were analyzed by image analysis software for statistics and grouping, and the survival time was analyzed in combination with the overall survival time and recurrence time of the patients.
Second, experimental results
The results showed that there were significant differences in overall survival levels and recurrence rates (overall survival P0.012; recurrence rate P0.005, fig. 3) between the two groups of patients (high CIT-H3 and low CIT-H3), with the overall survival time being about long and the recurrence rate being lower in the high CIT-H3 group.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (9)
- Application of a detection reagent of CIT-H3 protein in preparation of a liver cancer prognosis and/or recurrence prediction reagent.
- Application of a detection reagent of CIT-H3 protein in preparation of a kit for predicting prognosis and/or recurrence of liver cancer.
- 3. The use of any one of claims 1 or 2, wherein the detection reagent for the CIT-H3 protein is CIT-H3 antibody.
- 4. The use of any one of claims 1 or 2, wherein the reagent for detecting CIT-H3 protein detects CIT-H3 protein in the tumor region of liver cancer.
- 5. A kit for predicting prognosis and/or recurrence of liver cancer, which is characterized by comprising a detection reagent of CIT-H3 protein.
- 6. The kit for predicting the prognosis and/or recurrence of liver cancer according to claim 5, wherein the reagent for detecting CIT-H3 protein is CIT-H3 antibody.
- 7. The kit for prognosis and/or prognosis of liver cancer according to claim 6, further comprising a second antibody labeled with horseradish peroxidase.
- 8. The kit for predicting the prognosis and/or recurrence of liver cancer according to claim 7, wherein the second antibody is anti-rabbit IgG.
- 9. The kit for predicting liver cancer prognosis and/or recurrence according to claim 5, wherein the kit for predicting liver cancer prognosis and/or recurrence is an immunohistochemistry kit.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115201473A (en) * | 2022-07-27 | 2022-10-18 | 苏州奎克泰生物技术有限公司 | Kit for detecting NETs, preparation method and detection method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102298053A (en) * | 2011-05-20 | 2011-12-28 | 中山大学肿瘤防治中心 | Composite antibody kit used in postoperative recurrence risk assessment of primary hepatocellular carcinoma |
| WO2017027379A1 (en) * | 2015-08-07 | 2017-02-16 | Thomas Helledays Stiftelse För Medicinsk Forskning | Method for diagnosisng cancer or cancer-associated thrombosis by measuring levels of h3cit in plasma |
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- 2020-12-30 CN CN202011631320.9A patent/CN112881704A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102298053A (en) * | 2011-05-20 | 2011-12-28 | 中山大学肿瘤防治中心 | Composite antibody kit used in postoperative recurrence risk assessment of primary hepatocellular carcinoma |
| WO2017027379A1 (en) * | 2015-08-07 | 2017-02-16 | Thomas Helledays Stiftelse För Medicinsk Forskning | Method for diagnosisng cancer or cancer-associated thrombosis by measuring levels of h3cit in plasma |
Non-Patent Citations (2)
| Title |
|---|
| LU-YU YANG ET AL.: "Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking timorous inflammatory response", 《JOURNAL OF HEMATOLOGY & ONCOLOGY》 * |
| MINGZHU LU ET AL.: "Elevated histone H3 citrullination is associated with increased Beclin1 expression in HBV-related hepatocellular carcinoma", 《J MED VIROL》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115201473A (en) * | 2022-07-27 | 2022-10-18 | 苏州奎克泰生物技术有限公司 | Kit for detecting NETs, preparation method and detection method thereof |
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