CN112763714B - Biomarker for liver cancer diagnosis and detection method thereof - Google Patents
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Abstract
The invention relates to a method forBiomarker for liver cancer diagnosis, wherein the biomarker is HSP90 alpha+EpCAM+EVs. The inventor finds that HSP90 alpha in liver cancer hydrothorax and ascites and peripheral blood of liver cancer patients+EpCAM+The proportion of EVs is obviously higher than that of noncancerous pleuroperitoneal water and healthy people, and the detection method of the biomarker comprises the following steps: collecting peripheral blood or hydrothorax and ascites anticoagulated by EDTA of liver cancer patients and healthy people, centrifuging to obtain extracellular vesicle concentrate, adding PBS solution containing 1% BSA for resuspension and precipitation, adding antibody against EpCAM and antibody against HSP90 alpha, mixing uniformly and incubating at room temperature, detecting HSP90 alpha by flow cytometry+EpCAM+The proportion of EVs. By HSP90 alpha+EpCAM+The EVs can be used for early diagnosis or prognosis evaluation of liver cancer, and has important significance for clinical liver cancer diagnosis, curative effect detection and prognosis evaluation.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to a biomarker for liver cancer diagnosis and a detection method thereof.
Background
Hepatocellular carcinoma (HCC) is the most common malignancy of the digestive system, with morbidity and mortality rates at the 4 th and 2 nd sites of malignancy respectively in our country. Because hepatocellular carcinoma clinically lacks a specific early screening marker and the disease progresses rapidly, patients are mostly diagnosed in middle and advanced stages and lose effective treatment, so that the overall 5-year survival rate is only 7-10%, and the difference between treatment results and prognosis is large. Therefore, finding markers of people who benefit from early diagnosis of liver cancer liquid biopsy or prediction of different treatment means, timely selecting reasonable subsequent treatment schemes for later period, and improving survival rate of patients are hot spots of liver cancer research at present.
Extracellular Vesicles (EVs) including: exosomes, microvesicles, apoptotic bodies, and the like, are important signal transmission media among cells. The EVs from the tumor cells are rich in related information of the tumor cells, and comprise various protein ligands, lipids, non-coding RNAs and other bioactive substances, so that the EVs not only participate in the growth, metastasis and immune escape of tumors, but also can be used as potential tumor diagnosis and treatment markers. In the past, it was found that Epithelial cell adhesion molecule (EpCAM) is expressed on the surface of partial normal Epithelial cells and most malignant tumor cells of Epithelial origin, the expression level of the Epithelial cell adhesion molecule is closely related to the prognosis of patients, and the Epithelial cell adhesion molecule can be used as a potential marker for tumor diagnosis, on the other hand, HSP90 α is an intracellular chaperone protein, besides assisting folding, maturation and transportation of intracellular proteins, HSP90 α can be released to the outside of cells through an unconventional secretion pathway and is involved in intracellular autophagy and IL-1 β autophagy secretion, and it is found that the plasma HSP90 α concentration has a good correlation with the occurrence and progression of liver cancer.
No extracellular vesicle (HSP90 alpha) which is double positive for HSP90 alpha and EpCAM in pleural ascites or plasma is adopted at present+EpCAM+EVs) as biomarkers for liver cancer diagnosis.
Disclosure of Invention
The invention aims to solve the defects of the liver cancer early diagnosis technology in the prior art and provides a biomarker for liver cancer diagnosis.
Technical scheme
A biomarker for liver cancer diagnosis, wherein the biomarker is HSP90 alpha+EpCAM+And (4) EVs. The inventor discovers that HSP90 alpha in liver cancer hydrothorax and ascites and peripheral blood of liver cancer patients+EpCAM+The proportion of EVs was significantly higher (16.45% + -8.34%) and (11.09% + -5.45%) than non-cancerous ascites (2.64% + -1.09%) and healthy humans (4.48% + -1.99%), respectively, in total extracellular vesicles of pleural effusion and plasma HSP90 alpha+EpCAM+The EVs proportion can be used as a potential liquid biopsy diagnosis marker for liver cancer patients.
The detection method of the biomarker comprises the following steps:
(1) collecting EDTA anticoagulated peripheral blood or hydrothorax and ascites of liver cancer patients and healthy people;
(2) centrifuging to obtain precipitate as extracellular vesicle concentrate;
(3) adding 1% BSA-containing PBS solution for resuspension and precipitation, then adding an anti-EpCAM antibody and an anti-HSP 90 alpha antibody, mixing uniformly, incubating at room temperature, adding the PBS solution, vortex, shaking and washing, centrifuging to obtain stained extracellular vesicles, finally adding the PBS solution for resuspension, and detecting and analyzing HSP90 alpha in the extracellular vesicles of peripheral blood or pleural effusion of liver cancer patients and healthy people by adopting a flow cytometer+EpCAM+The proportion of EVs.
Further, in the step (2), the centrifugation conditions are as follows: 14000g, 4 ℃ and 30 min.
Further, in step (3), the anti-EpCAM antibody is EpCAM-PE and the anti-HSP 90 α antibody is HSP90 α -AlexaFluor 647.
Further, in step (3), the volume ratio of the anti-EpCAM antibody to the anti-HSP 90 α antibody is 1: 1.
The invention has the beneficial effects that: the invention discloses a new biomarker HSP90 alpha for liver cancer diagnosis+EpCAM+EVs and provides a detailed detection method, namely, the proportion of extracellular vesicles which simultaneously express HSP90 alpha and EpCAM protein molecules in a sample obtained from a liver cancer patient is jointly detected by using a specific fluorescent antibody, and the extracellular vesicles are detected by HSP90 alpha+EpCAM+The EVs proportion is high and low, the kit can be used for early diagnosis, immune evaluation and curative effect detection of liver cancer, and the accuracy of the kit is obviously higher than that of a single protein marker. Therefore, the invention has important significance for comprehensively improving the prevention and treatment level of liver cancer and reducing the death rate of liver cancer in future.
Drawings
FIG. 1 is a graph of the particle size of extracellular vesicles obtained by separation;
FIG. 2 shows a liver cancer patient/healthy personHSP90 alpha in peripheral blood+EpCAM+The detection result of EVs;
FIG. 3 shows HSP90 alpha in peripheral blood of liver cancer patients+EpCAM+An ROC curve of EVs detection results;
FIG. 4 shows PD-1 in peripheral blood of liver cancer patients/healthy persons+CD4+T cells and PD-1+CD8+The detection result of T cells;
FIG. 5 shows HSP90 alpha in peripheral blood of liver cancer patients+EpCAM+Correlation analysis between EVs and the proportion of T cells depleted;
FIG. 6 shows HSP90 alpha in peripheral blood before and after operation of a liver cancer patient+EpCAM+The detection result of the proportion of EVs;
FIG. 7 shows HSP90 alpha in ascites-derived EVs of liver cancer patients+EpCAM+The detection result of EVs;
FIG. 8 shows HSP90 alpha in ascites-derived EVs of liver cancer patients+EpCAM+ROC curve of EVs detection results.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples.
Example 1
HSP90 alpha in peripheral blood of liver cancer patients+EpCAM+Detection of EVs
Sources of clinical specimens: 15 patients with liver cancer and 15 healthy people with EDTA anticoagulated peripheral blood samples were obtained from Xuzhou City center Hospital clinical laboratory.
Detecting HSP90 alpha in specimen+EpCAM+A method of EVs, comprising the steps of:
(1) collecting 2ml of EDTA anticoagulated peripheral blood of clinical liver Cancer Patients (CPs) and healthy people (HDs);
(2) centrifuging for 10min at 4 ℃ for 1000g to remove cells and cell debris, adding 1ml of plasma on the upper layer into a 1.5ml centrifuge tube, centrifuging for 30min at 4 ℃ for 14000g to obtain a precipitate, namely the total extracellular vesicles; the particle size diagram is shown in FIG. 1, and it can be seen that the EVs diameter obtained by separation is mainly distributed between 150-1000 nm;
(3) adding the precipitate with a pipetteAdding 50ul PBS solution containing 1% BSA, fully resuspending the precipitate, and incubating at room temperature for 30 min; 1ul of EpCAM-PE (manufacturer: Cell Signaling Technology; cat # 8995) and 1ul of HSP90 alpha-Alexa Fluor647 (manufacturer: Santa Cruz Biotechnology cat # sc-515081AF647) detection antibody were added to the above samples, vortexed and incubated at room temperature for 30 min; then adding 1ml PBS solution for vortex shaking washing, centrifuging at 14000g and 4 ℃ for 30min, discarding supernatant, and obtaining stained extracellular vesicles (HSP90 alpha)+EpCAM+EVs), adding 200ul of PBS solution, fully mixing, and detecting by using a flow cytometer, wherein the result is shown in figure 2.
FIG. 2 shows HSP90 alpha in peripheral blood of liver cancer patient/healthy person+EpCAM+The results of the EVs assay are shown in FIG. 3, which is HSP90 alpha in peripheral blood of liver cancer patients+EpCAM+ROC curve of EVs detection results. As can be seen from FIG. 2, HSP90 α in peripheral blood of liver Cancer Patients (CPs)+EVs、EpCAM+EVs and HSP90 alpha+EpCAM+The proportion of EVs was significantly higher than that of healthy persons (HDs), and the ROC curve analysis results of fig. 3 showed: HSP90 alpha+EpCAM+When the EVs cutoff value is 6.67%, the molecular marker has higher value in clinical diagnosis of liver cancer (AUC 0.911, sensitivity 86.67%, specificity 93.33%), while HSP90 alpha+EVs and EpCAM+EVs are respectively (cutoff value 10.97%, AUC 0.853, sensitivity 73.33%, specificity 86.67%) and (cutoff value 8.41%, AUC 0.88, sensitivity 80%, specificity 86.67%). This indicates that: HSP90 alpha in plasma total extracellular vesicles+EpCAM+The EVs proportion can be used as a potential liquid biopsy diagnosis marker for liver cancer patients.
Example 2
HSP90 alpha in peripheral blood of liver cancer patients+EpCAM+Correlation analysis between EVs and proportion of depleted T cells
Specimen source: 15 patients with liver cancer and 15 healthy people with EDTA anticoagulated peripheral blood samples were obtained from Xuzhou City center Hospital clinical laboratory.
The experimental method comprises the following steps: 100ul of EDTA anticoagulated peripheral blood is taken, added with 1ml of erythrocyte lysate, mixed evenly and incubated for 10min for lysis redAdding 1ml PBS solution into cells, uniformly mixing by vortex, centrifuging for 6min at 400g to obtain lymphocytes, respectively adding 1ul of CD3-FITC, 1ul of CD8-APC and 1ul of fluorescent antibody of PD-1-PE, incubating for 20min at room temperature, adding 1ml PBS solution, washing and centrifuging to obtain stained lymphocytes, finally adding 300ul of PBS solution, resuspending by vortex, and detecting and analyzing exhausted T cells (PD-1) in peripheral blood of liver cancer patients by using a flow cytometer+T cells). The results are shown in FIG. 4.
FIG. 4 shows PD-1 in peripheral blood of liver cancer patients/healthy persons+CD4+T cells and PD-1+CD8+FIG. 5 shows the result of T cell assay, showing HSP90 alpha in peripheral blood of liver cancer patients+EpCAM+Correlation analysis between EVs and the proportion of T cells depleted, it can be seen from FIGS. 4 and 5 that PD-1, a T cell depleted in peripheral blood of liver Cancer Patients (CPs)+CD4+T cells and PD-1+CD8+The proportion of T cells was significantly higher than that of healthy people (HDs), and the correlation analysis results showed that: HSP90 alpha in peripheral plasma of liver cancer patient+EVs and HSP90 alpha+EpCAM+Ratio of EVs to PD-1+CD4+T cells and PD-1+CD8+The proportion of T cells is positively correlated.
Example 3
HSP90 alpha in peripheral blood before and after operation of liver cancer patients+EpCAM+Detection of EVs
Specimen source: pre-operative (Pre-op) and Post-operative (Post-op) EDTA anticoagulated peripheral blood specimens from 9 liver cancer patients were obtained from the xu city central hospital laboratory.
Detection of HSP90 alpha in peripheral blood before (Pre-op) and after (Post-op) operation of liver cancer patients+EpCAM+The EVs ratio was determined in the same manner as in example 1. The results are shown in FIG. 6.
FIG. 6 shows HSP90 alpha in peripheral blood before and after operation of liver cancer patients+EpCAM+As a result of measuring the proportion of EVs, HSP90 alpha in total EVs in Post-operative (Post-op) peripheral blood of liver cancer patients was found to be higher than that in Pre-operative (Pre-op) patients+EVs、EpCAM+EVs and HSP90 alpha+EpCAM+The proportion of EVs is remarkably reducedLow.
Example 4
HSP90 alpha in ascites source EVs of liver cancer patients+EpCAM+Detection of EVs
Sample source: ascites (LCA) of liver cancer patients and ascites (NPF) of non-liver cancer patients in 14 cases are from Xuzhou city central hospital laboratory.
HSP90α+EpCAM+The EVs was detected in the same manner as in example 1 except that the EDTA-anticoagulated peripheral blood of the liver cancer patients and healthy persons was changed to ascites (LCA) of the liver cancer patients and ascites (NPF) of the non-liver cancer patients. The results are shown in FIG. 7.
FIG. 7 shows HSP90 alpha in ascites-derived EVs of liver cancer patients+EpCAM+The detection results of EVs, FIG. 8 shows HSP90 alpha in ascites-derived EVs of liver cancer patients+EpCAM+ROC curve of EVs detection result, as can be seen from FIGS. 7 and 8, HSP90 alpha in clinical Liver Cancer Ascites (LCA)+EVs、EpCAM+EVs and HSP90 alpha+EpCAM+The proportion of EVs is obviously higher than that of non-liver cancer ascites (NPF) group, wherein EpCAM is not only expressed in EVs from liver cancer ascites sources, but also hardly expressed in NPF group, HSP90 alpha is also expressed in NPF group in a certain proportion, and ROC curve analysis results show that: HSP90 alpha+EpCAM+EVs have higher value in clinical diagnosis of liver cancer in the pleural effusion (cutoff value 4.6%, AUC 0.985, sensitivity 92.86%, specificity 92.86%), while EpCAM+EVs and HSP90 alpha+EVs were (cutoff value 6.25%, AUC 0.964, sensitivity 92.86%, specificity 92.86%) and (cutoff value 20.68%, AUC 0.985, sensitivity 78.57%, specificity 92.86%), respectively, which indicated that: HSP90 alpha in extracellular vesicles derived from pleural effusion+EpCAM+The proportion of EVs can be used as a diagnostic marker of cancerous hydrothorax and ascites.
Claims (2)
1.HSP90α+EpCAM+Application of EVs as a detection target in preparation of liver cancer diagnosis products.
2. Detection of HSP90 alpha in peripheral blood or chest and abdomen of human+EpCAM+Ratio of EVsThe reagent is applied to the preparation of liver cancer diagnosis products.
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| WO2018200951A1 (en) * | 2017-04-28 | 2018-11-01 | Tran David T | Multi-targeted multi-valent ligand-drug particles for the treatment and prevention of diseases and conditions |
| WO2018216009A1 (en) * | 2017-05-22 | 2018-11-29 | The National Institute For Biotechnology In The Negev Ltd. Ben-Gurion University Of The Negev | Biomarkers for diagnosis of lung cancer |
| CN109837343A (en) * | 2019-02-22 | 2019-06-04 | 中国科学院北京基因组研究所 | Early stage adenocarcinoma of lung specificity excretion body miRNA and its application |
| CN111328287A (en) * | 2017-07-04 | 2020-06-23 | 库瑞瓦格股份公司 | Novel nucleic acid molecules |
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| WO2018200951A1 (en) * | 2017-04-28 | 2018-11-01 | Tran David T | Multi-targeted multi-valent ligand-drug particles for the treatment and prevention of diseases and conditions |
| WO2018216009A1 (en) * | 2017-05-22 | 2018-11-29 | The National Institute For Biotechnology In The Negev Ltd. Ben-Gurion University Of The Negev | Biomarkers for diagnosis of lung cancer |
| CN111328287A (en) * | 2017-07-04 | 2020-06-23 | 库瑞瓦格股份公司 | Novel nucleic acid molecules |
| CN109837343A (en) * | 2019-02-22 | 2019-06-04 | 中国科学院北京基因组研究所 | Early stage adenocarcinoma of lung specificity excretion body miRNA and its application |
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