CN114164268A - Application of hnRNPA1 in diagnosis, prognosis and treatment of pancreatic cancer - Google Patents
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Abstract
The invention discloses an application of hnRNPA1 in diagnosis, prognosis and treatment of pancreatic cancer, wherein hnRNPA1 is used as a molecular marker in pancreatic cancer, the hnRNPA1 is highly expressed in blood exosomes of pancreatic cancer patients, subjects with high expression of the hnRNPA1 have shorter overall survival time than subjects with low expression of the hnRNPA1, and subjects with high expression of the hnRNPA1 have shorter disease-free survival time than subjects with low expression of the hnRNPA 1; experiments show that the exosome hnRNPA1 can remarkably promote lymphatic vessel neogenesis and lymphatic metastasis of pancreatic cancer, and the exosome hnRNPA1 can be used as a molecular marker for pancreatic cancer diagnosis and prognosis and a new target for pancreatic cancer treatment.
Description
Technical Field
The invention relates to the technical field of biological medicines, and in particular relates to application of hnRNPA1 in diagnosis, prognosis and treatment of pancreatic cancer.
Background
Pancreatic cancer is one of the tumors with the highest malignancy degree in solid tumors, and has the characteristics of hidden morbidity, low surgical resection rate, strong local invasiveness, easy metastasis in early stage, easy relapse after surgery, very poor overall prognosis and the like. In recent years, with the change of dietary structure and life style of residents and the improvement of clinical detection rate, the incidence rate of pancreatic cancer is increased year by year, and the life health of residents is seriously threatened. It is estimated that in 2020, the number of pancreatic cancer patients increases to 42 ten thousand and the number of pancreatic cancer patients dies to 41 ten thousand. Pancreatic cancer has strong invasive, metastatic and recurrent characteristics, with lymphatic metastasis being one of the most important factors affecting the prognosis of pancreatic cancer patients. Research shows that the proportion of patients with lymph node metastasis in patients with pancreatic cancer radical surgery is as high as 70%, and the 5-year survival rate after surgery of patients with lymph node metastasis positive is only 12.5%. Therefore, exploring biomarkers and therapeutic targets for pancreatic cancer lymphatic metastasis is an urgent clinical problem to be solved. At present, more and more basic research results enable people to deeply understand the molecular mechanism of pancreatic cancer lymphatic metastasis, but efficient biomarkers and clinical treatment targets are still lacked in the aspects of diagnosis and treatment of pancreatic cancer lymphatic metastasis patients.
The exosome is a 30-150 nm microcapsule which is secreted by various cells and wrapped by a phospholipid double-layer membrane, and mainly comprises liposome, protein, DNA, miRNA and the like. Research shows that exosomes are involved in many important physiological and pathological processes of the body by carrying bioactive substances, especially in the aspects of invasion and metastasis of tumors. The exosome can lead tumor cells to obtain high invasiveness by inducing epithelial-mesenchymal transition in a pancreatic cancer tumor microenvironment and promote tumor lymphatic metastasis by regulating lymphatic vessel generation, and the exosome also participates in inducing a pre-metastasis microenvironment beneficial to metastatic tumor growth and inhibits the anti-tumor immune reaction of an organism by bioactive molecules so as to influence the lymphatic metastasis of pancreatic cancer. Therefore, blocking or inhibiting the generation of tumor-derived exosomes is expected to become a potential target for treating pancreatic cancer lymphatic metastasis. In addition, as exosomes are widely present in various body fluid samples and are easy to obtain, exosome detection can become a real noninvasive diagnosis method, and therefore, the exosome detection method has great application potential in the aspect of tumor diagnosis.
The Heterogeneous Nuclear Ribonucleoprotein (hnRNP) family is a group of intranuclear RNA-binding proteins that are involved in the development and progression of tumors in many ways, of which hnRNPA1 has been the most widely studied. It is now believed that hnRNPA1 plays a key role in tumor metastasis primarily through epigenetic regulation of gene transcription, involvement in precursor mRNA synthesis, and the like. Research shows that tumor cells can be targeted to transfer hnRNPA1 to mesenchymal cells in a tumor microenvironment through exosomes, so that the phenotypic change of the tumor cells is regulated and controlled, and invasion and metastasis of tumors are promoted. Therefore, the tumor cell-derived exosome hnRNPA1 is expected to become a novel marker and a potential target for early diagnosis and treatment of tumors, and has important clinical significance for exploring the diagnosis efficiency and the targeted treatment effect of the tumor cell-derived exosome in pancreatic cancer lymphatic metastasis patients, thereby being beneficial to improving the prognosis of pancreatic cancer patients.
Disclosure of Invention
The invention provides application of hnRNPA1 in diagnosis, prognosis and treatment of pancreatic cancer, which can be used as a molecular marker for diagnosis and prognosis of pancreatic cancer and a new target for treatment of pancreatic cancer.
The invention adopts the following technical scheme for solving the technical problems:
application of hnRNPA1 as a molecular marker in preparation of products for diagnosing pancreatic cancer and predicting pancreatic cancer patient prognosis.
The invention also provides a reagent for detecting the expression level of hnRNPA1, which is used for diagnosing pancreatic cancer or predicting the prognosis of a pancreatic cancer patient.
As one approach, the reagents include hnRNPA1 antibody.
As a scheme, the subject with high expression of hnRNPA1 has pancreatic cancer, and the subject with low expression of hnRNPA1 is a normal human.
As a scheme, the prognosis of the subject with high expression of hnRNPA1 is relatively poor, and the prognosis of the subject with low expression of hnRNPA1 is relatively good.
As a regimen, the subjects with high expression of hnRNPA1 had shorter overall survival than subjects with low expression of hnRNPA 1.
As a regimen, the subjects with high expression of hnRNPA1 had a shorter disease-free survival than subjects with low expression of hnRNPA 1.
The present invention also provides a kit comprising:
an hnRNPA1 expression level detection system, wherein the hnRNPA1 expression level detection system comprises a reagent for detecting the expression level of hnRNPA 1;
a label or instructions for use of the kit for the diagnosis and/or detection of a prognostic effect of pancreatic cancer.
The reagent for detecting the expression level of hnRNPA1 comprises hnRNPA1 antibody.
The kit also comprises a CA19-9 detection system, wherein the CA19-9 detection system comprises a reagent for detecting the content of CA19-9 in serum.
The invention also provides a medicament for treating pancreatic cancer, which comprises an inhibitor for inhibiting the expression of hnRNPA1 and a pharmaceutically acceptable carrier.
The invention has the beneficial effects that: (1) the invention discovers that hnRNPA1 is highly expressed in blood exosomes of pancreatic cancer patients, the hnRNPA1 highly expressed subjects have shorter overall survival time than hnRNPA1 low-expression subjects, and the hnRNPA1 highly expressed subjects have shorter disease-free survival rate than hnRNPA1 low-expression subjects; (2) experiments show that hnRNPA1 can remarkably promote lymphatic vessel neogenesis and lymphatic metastasis of pancreatic cancer, researches the mechanism of the hnRNPA1, and can be used as a molecular marker for pancreatic cancer diagnosis and prognosis and a new target for pancreatic cancer treatment.
Drawings
FIG. 1 is a scanning electron micrograph of exosomes;
FIG. 2 is a graph of the expression of exosome hnRNPA1 in pancreatic cancer cells detected by qRT-PCR;
FIG. 3 is a graph showing protein electrophoresis detection of the expression of exosome hnRNPA1 in pancreatic cancer cells;
FIG. 4 is a graph showing the relationship between the expression level of hnRNPA1 in serum exosomes and disease-free survival rate of patients;
FIG. 5 is a graph showing the relationship between the expression level of hnRNPA1 in serum exosomes and the overall survival rate of patients;
FIG. 6 is a graph of the diagnostic potency of serum exosomes hnRNPA1 on pancreatic cancer;
FIG. 7 is a graph of the diagnostic efficacy of CA19-9 in combination with exosome hnRNPA1 on pancreatic cancer;
FIG. 8 is a graph showing the lymph node metastasis efficacy of serum exosome hnRNPA1 on pancreatic cancer;
FIG. 9 is a representative image of lymphatic endothelial cell tubulation and transwell taken under a microscope,
FIG. 10 is a graph showing the difference in the number of cells penetrating through lymphatic endothelial cells in different groups of transwell experiments by statistical analysis;
FIG. 11 is an image of a live nude mouse in different treatment groups;
FIG. 12 is a graph showing the statistical analysis of in vivo fluorescence values of popliteal lymph nodes of nude mice in different groups;
FIG. 13 is a graph of statistical analysis of fluorescence values from in vivo imaging of the popliteal lymph nodes of a nude mouse;
FIG. 14 is a graph of a statistical table analyzing the number of nude mice with popliteal lymph node metastases between different groups;
FIG. 15 is a confocal microscope showing the uptake of fluorescent-labeled exosomes into lymphatic endothelial cells;
FIG. 16 is an electrophoretic protein detection map;
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
high expression of hnRNPA1 in serum exosomes of pancreatic cancer patients
The inventors first collected serum samples of 5 pancreatic cancer patients and 5 normal healthy volunteers, extracted and purified exosomes in serum by ultracentrifugation (supernatant was transferred to a new centrifuge tube after centrifugation for 2000g X20 min, then transferred to a new centrifuge tube after centrifugation for 10000g X40 min, then centrifuged for 120000g X70 min, finally discarded, and exosomes at the bottom of the resuspension tube were resuspended with PBS), and then screened protein hnRNPA1 highly expressed in serum exosomes of pancreatic cancer patients by proteomic analysis.
The inventor enlarges clinical samples, collects serum of 186 pancreatic cancer patients and serum samples of 186 healthy volunteers, extracts serum exosomes, and identifies the extracted vesicles as exosomes through scanning electron microscopy, NTA particle size analysis and protein electrophoresis analysis (figure 1: scanning electron microscopy); the expression of hnRNPA1 is detected by qRT-PCR, and the expression level of the serum exosome hnRNPA1 of the pancreatic cancer patient is found to be remarkably higher than that of a normal healthy volunteer.
Further, by collecting culture supernatants of pancreatic cancer cells, Capan-2, ASPC-1, PANC-1 and normal pancreatic cells (HPDE), extracting exosome total RNA and total protein therein, and detecting the expression of hnRNPA1 by qRT-PCR and protein electrophoresis, it was found that the expression of exosome hnRNPA1 in pancreatic cancer cells was significantly higher than that in normal pancreatic cells (FIG. 2, FIG. 3).
The results show that serum exosome hnRNPA1 can be used as a molecular marker for distinguishing pancreatic cancer patients from normal people.
Example 2
The relation between the expression level of exosome hnRNPA1 and disease-free survival and overall survival of pancreatic cancer patients:
clinical information of all pancreatic cancer patients is collected and statistically analyzed by combining the detection results of the qRT-PCR, and the expression of serum exosome hnRNPA1 of pancreatic patients with lymph node metastasis is found to be remarkably higher than that of pancreatic patients without lymph metastasis. And the disease-free survival period and the total survival period of the patient with high expression of the serum exosome hnRNPA1 are shorter (figure 4, analysis method: Kaplan-Meier survival curve analysis, wherein the high expression of the exosome hnRNPA1 is defined as the high expression of the exosome hnRNPA1 above the median, and the low expression of the exosome hnRNPA1 is defined as below).
The above results indicate that the subject with high expression of the exosome hnRNPA1 has shorter overall survival than the subject with low expression of the exosome hnRNPA 1; the subject with high expression of the exosome hnRNPA1 has shorter disease-free survival period than the subject with low expression of the exosome hnRNPA1, and the exosome hnRNPA1 can promote lymph node metastasis of a pancreatic patient.
The expression level of the exosome hnRNPA1 can be used as a molecular marker for diagnosing pancreatic cancer and judging pancreatic cancer progression and prognosis.
Example 3
Diagnostic potency of exosome hnRNPA1 for pancreatic cancer:
by detecting expression in serum exosome hnRNPA1, combined with Receiver Operating Characteristic (ROC) analysis, it was found that:
the serum exosome hnRNPA1 has good diagnostic efficacy on pancreatic cancer, and the area under the curve (AUC) is 0.85(95% confidence interval: 0.81-0.89), is significantly higher than CEA (AUC: 0.77; 95% CI: 0.72-0.82) or CA72-4 (AUC: 0.68; 95% CI: 0.63-0.73), and is substantially the same as CA19-9 (AUC: 0.90; 95% confidence interval: 0.87-0.94), as shown in FIG. 5.
The diagnostic efficacy of CA19-9 in combination with exosome hnRNPA1 on pancreatic cancer was better than that of CA19-9 alone, with a combination of AUC 0.9419 (95% CI: 0.92-0.96) and AUC 0.90 (95% CI: 0.87-0.94) for CA19-9 alone, as shown in FIG. 6.
Example 4
The exosome hnRNPA1 can remarkably promote lymphatic vessel neogenesis and lymphatic metastasis of pancreatic cancer:
up-regulating the expression of hnRNPA1 in pancreatic cancer cell lines by transfecting hnRNPA1 overexpression plasmid, and collecting cell culture supernatant thereof; exosomes in the supernatant thereof were extracted by ultracentrifugation, and the concentration of the extracted exosomes was measured by the BCA method. The lymphatic endothelial cells were seeded in six well plates, 1X 10 per well5(ii) individual cells; the extracted exosomes were then added to the extracted exosomes in an amount of 20ug per wellInducing to obtain PBS and EVvector、EVhnRNPA1Three groups. After the cells are placed in an incubator and cultured for 24 hours, the six-hole plate is taken out, the cells are digested by pancreatin and then centrifuged, and the culture medium is discarded.
For the tube experiments, cells were resuspended in normal complete medium containing 5% serum and counted. Take 2X 105And (4) adding each cell/hole into a 24-hole plate with matrix glue laid in advance, shaking up the cells gently, and laying the cells. Placing the cells in a cell incubator for culture, observing the tube forming condition of the cells every 2h, photographing the cells under an inverted microscope after the cells form tubes, measuring the tube forming length by using Image J software, comparing the difference of the tube forming conditions among different exosome induction groups through statistical analysis, and finding that the tube forming capacity of pancreatic cancer cell exosomes for inducing lymphatic vessel cells is obviously enhanced after the exosomes hnRNPA1 are over-expressed compared with a control group. The experimental process of spreading glue on the 24-hole plate is as follows: precooling a 24-pore plate, a centrifugal tube and the like in advance, and mixing the components according to the matrigel: serum-free medium = 1: 2, adding the diluted and uniformly mixed matrigel into a 24-pore plate according to the proportion of 700ul per hole, shaking and paving, then placing the 24-pore plate into an incubator, and using the matrigel after the matrigel is solidified.
For the transwell experiment, cells centrifuged after induction digestion were resuspended in fresh serum-free medium and counted, and 5X10 cells were removed4Diluting the cells with serum-free culture medium to a total volume of 300ul, adding cell suspension into the upper chamber of a transwell chamber, adding 700ul culture medium containing 5% serum into the lower chamber, placing the whole system in an incubator, culturing for 8h, taking out the chamber, fixing the cells with 4% paraformaldehyde for 15min, gently washing the cells with PBS for three times, then staining the cells with crystal violet staining solution for 15min, and washing away the redundant crystal violet staining solution with PBS. Cells on the inner surface of the chamber were gently wiped off with a cotton swab, photographed under a microscope for observation, counted in random fields using Image J, and statistically analyzed for differences in cell migration ability between different exosome-induced groups. As a result, compared with a control group, after the exosome hnRNPA1 is over-expressed, the migration capacity of the pancreatic cancer cell exosome for inducing the lymphatic vessel cells is obviously enhanced.
In vitro pipelining and transwell experiments (showing that exosomes hnRNPA1 promote the pipelining and migration capabilities of lymphatic endothelial cells, where FIG. 7 is a representative image of lymphatic endothelial cell pipelining and transwell taken under a microscope, FIG. 8 is a statistical analysis of the difference in the width of the canalization of lymphatic endothelial cells in different groups, three dots represent three repetitions of the experiment, the statistical method is one-way ANOVA followded by Dunnett's tests, FIG. 9 is a statistical analysis of the difference in the number of transwell penetrating cells of lymphatic endothelial cells in different groups, three dots represent three repetitions of the experiment, the statistical method is one-way ANOVA followded by Dunnett's tests, where two represent comparative statistical analyses between groups and the P value is less than 0.01.
In vivo experiments prove that the exosome hnRNPA1 can remarkably promote the lymphatic metastasis of pancreatic cancer (a PANC-1 pancreatic cancer cell line with GFP fluorescence markers is constructed; a PANC-1 pancreatic cancer cell line stably overexpressed by hnRNPA1 is constructed, culture supernatant is collected, exosomes in the supernatant are extracted by an ultracentrifugation method, the concentration of the exosomes is detected by a BCA method, the exosomes are stored in a refrigerator at the temperature of-80 ℃ for later use, 24 healthy female nude mice with the age of 4-5 weeks are purchased, randomly divided into two groups, each group comprises 12 mice, the extracted exosomes are injected at the right foot pad of each group, and one group is injected with EVVectorGroup of EV for injectionhnRNPA120ug each time, once every 3 days; simultaneous injection of GFP-labeled PANC-1 cells 5X105One/only, to construct a tumor footpad popliteal lymph node metastasis model. Then, living body imaging is carried out once every week to observe the transfer condition of popliteal lymph node of footpad of the nude mouse until the tumor volume of the footpad of the nude mouse is more than 200mm3Or the nude mouse died. The popliteal lymph node of the nude mouse is separated, the volume of the popliteal lymph node of the nude mouse is measured, and the difference of the popliteal lymph node metastasis rate of the nude mouse between different exosome induction groups is recorded and analyzed (the metastasis result is based on the pathological result). It was found that pancreatic cancer cell exosomes overexpressing hnRNPA1 significantly promoted lymphatic metastasis of pancreatic cancer, where fig. 10: is a statistical analysis chart of fluorescence values of popliteal lymph node living imaging of nude mice among different groups, and the statistical method is two-tailed Student's t test; FIG. 11: statistical Table analysis of the number of nude mice with popliteal lymph node metastasis between different groupsQuantity, and analysis of differential significance was performed using the chi-square test, where one represents a statistical P value of less than 0.05.
The mechanism part is as follows: exosomes hnRNPA1 are taken up by lymphatic endothelial cells (HLECs) and up-regulate expression of PROX 1:
extracting exosomes of pancreatic cancer cells PANC-1 and ASPC-1 cell culture supernatants, labeling the exosomes with PKH67 fluorescent dye, co-culturing the exosomes with HLECs, and observing the uptake condition of the fluorescently-labeled exosomes by the HLECs through a confocal microscope (figure 12); after overexpression of hnRNPA1 in pancreatic cancer cells ASPC-1 and extraction of exosomes in the cell supernatant, after 2 days of co-culture with HLECs, total RNA and total protein in HLECs were extracted, and the ASPC-1 cell exosomes overexpressing hnRNPA1 were found to significantly promote expression of PROX1 in HLECs by qRT-PCR and protein electrophoresis detection, respectively (FIG. 13).
In light of the foregoing description of preferred embodiments according to the invention, it is clear that many changes and modifications can be made by the person skilled in the art without departing from the scope of the invention. The technical scope of the present invention is not limited to the contents of the specification, and must be determined according to the scope of the claims.
Claims (10)
- Application of hnRNPA1 as a molecular marker in preparation of products for diagnosing pancreatic cancer and predicting pancreatic cancer prognosis.
- 2. A reagent for detecting the expression level of hnRNPA1, which is useful for diagnosing pancreatic cancer or predicting the prognosis of pancreatic cancer.
- 3. The reagent for detecting the expression level of hnRNPA1 as claimed in claim 2, wherein the reagent comprises hnRNPA1 antibody.
- 4. The reagent for detecting the expression level of hnRNPA1 as claimed in claim 2, wherein the subject with high expression of hnRNPA1 has pancreatic cancer and the subject with low expression of hnRNPA1 is a normal human.
- 5. The reagent for detecting the expression level of hnRNPA1 as claimed in claim 2, wherein the prognosis of the subject with high expression level of hnRNPA1 is relatively poor, and the prognosis of the subject with low expression level of hnRNPA1 is relatively good.
- 6. The reagent for detecting the expression level of hnRNPA1 as claimed in claim 2, wherein the hnRNPA 1-highly expressed subject has a shorter overall survival time than the hnRNPA 1-underexpressed subject; the subjects with high expression of hnRNPA1 had shorter disease-free survival than subjects with low expression of hnRNPA 1.
- 7. A kit, comprising:an hnRNPA1 expression level detection system, wherein the hnRNPA1 expression level detection system comprises a reagent for detecting the expression level of hnRNPA 1;a label or instructions for use of the kit for the diagnosis and/or detection of a prognostic effect of pancreatic cancer.
- 8. The kit according to claim 7, wherein said reagent for detecting the expression level of hnRNPA1 comprises hnRNPA1 antibody.
- 9. The kit for detecting the expression level of hnRNPA1 as claimed in claim 7, wherein the kit further comprises a CA19-9 detection system, and the CA19-9 detection system comprises reagents for detecting the content of CA19-9 in serum.
- 10. A medicament for the treatment of pancreatic cancer, comprising an inhibitor that inhibits the expression of hnRNPA1 and a pharmaceutically acceptable carrier.
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