CN117425827A - Kit for diagnosing cancer and use thereof - Google Patents
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Abstract
A kit for diagnosing cancer, a kit for determining prognosis of a cancer patient, a method for determining a biological sample, a method for collecting data for determining whether a subject has cancer, and a method for predicting prognosis of a cancer patient are provided. A kit for diagnosing cancer comprising: specific binding substances for SOCS box protein 2 (SPSB 2) protein containing SPRY domain, primer set for amplifying cDNA of SPSB2 gene or probe specifically hybridized with mRNA of SPSB2 gene.
Description
Technical Field
The invention relates to a kit for diagnosing cancer and application thereof. More particularly, the present invention relates to a kit for diagnosing cancer, a kit for determining prognosis of a cancer patient, a method for determining biological samples, a method for collecting data for determining whether a subject has cancer, a method for predicting prognosis of a cancer patient, and a method for screening for an anticancer agent. Priority is claimed for japanese patent application No. 2021-097456 filed in japan at month 6 and 10 of 2021 and japanese patent application No. 2021-201094 filed in japan at month 12 of 2021, the contents of which are incorporated herein by reference.
Background
Of cancers, the incidence and mortality of bladder cancer have been rising (for example, see non-patent document 1). Examples of methods of treatment for bladder cancer include surgery, chemotherapy, and radiation therapy. However, the efficacy of treating bladder cancer is not considerable. Examples of the causes thereof include no useful cancer markers and subsequent markers.
[ quotation list ]
[ non-patent literature ]
Non-patent document 1
Fitzmaurec et al, 1990to 2017, global, regional and national cancer incidence, mortality, years of life loss, years of disability and years of disability-adjusted life of 29cancer groups: systemic analysis of Global disease burden studies ("Global, regional, and National Cancer Incidence, molar, years of Life Lost, years Lived With Disability, and Disability-Adjusted Life-Years for 29Cancer Groups,1990to 2017:A Systematic Analysis for the Global Burden of Disease Study"), "journal of medical society oncology (JAMA Oncol.), volume 5, 12, pages 1749-1768, 2019.
Disclosure of Invention
[ technical problem ]
The present invention aims to provide a technique for diagnosing cancer.
[ solution to problem ]
The present invention includes the following aspects.
[1] A kit for diagnosing cancer, comprising: specific binding substances for SOCS box protein 2 (SPSB 2) proteins containing SPRY domains; primer set for amplifying cDNA of SPSB2 gene; or a probe that specifically hybridizes to mRNA of the SPSB2 gene.
[2] The kit for diagnosing cancer according to [1], wherein the cancer is bladder cancer, pancreatic cancer or hepatocellular carcinoma.
[3] A kit for determining prognosis of a cancer patient, comprising: specific binding substances for SPSB2 protein, primer sets for amplifying cDNA of SPSB2 gene, or probes specifically hybridizing with mRNA of SPSB2 gene.
[4] The kit for determining prognosis according to [3], wherein the cancer is bladder cancer, pancreatic cancer or hepatocellular carcinoma.
[5] A method for determining a biological sample, comprising: a step of determining the expression level of the SPSB2 protein or the SPSB2 gene in a biological sample, wherein the fact that the determined expression level of the protein or gene is higher than the expression level of a control indicates that the biological sample is from a cancer patient.
[6] The method of determining according to [5], wherein the cancer is bladder cancer, pancreatic cancer or hepatocellular cancer.
[7] A method for collecting data for determining whether a subject has cancer, the method comprising: a step of determining the expression level of an SPSB2 protein or an SPSB2 gene in a biological sample from the subject, wherein the determined expression level of the protein or gene is data for determining whether the subject has cancer, provided that medical practice by a doctor is excluded.
[8] The method of [7], wherein the cancer is bladder cancer, pancreatic cancer or hepatocellular cancer.
[9] A method for predicting prognosis of a cancer patient, the method comprising: a step of determining the expression level of an SPSB2 protein or an SPSB2 gene in a biological sample from the cancer patient, wherein the fact that the determined expression level of the protein or gene is higher than the expression level of a control indicates that the cancer patient has poor prognosis.
[10] The method of [9], wherein the cancer is bladder cancer, pancreatic cancer or hepatocellular cancer.
[11] A method for screening for an anticancer agent, the method comprising: a step of determining the expression level of an SPSB2 protein or an SPSB2 gene in a cancer cell cultured in the presence of a test substance, wherein the fact that the expression level is significantly reduced compared to the expression level of the SPSB2 protein or the SPSB2 gene in the absence of the test substance indicates that the test substance is an anticancer agent.
[12] The method of [11], wherein the cancer cell is a cancer cell derived from bladder cancer, pancreatic cancer or hepatocellular cancer.
[ advantageous effects of the invention ]
According to the present invention, a novel technique for diagnosing cancer can be provided.
Drawings
Fig. 1 is a graph showing the results of experimental example 2.
Fig. 2 (a) to 2 (c) are photographs showing representative results of immunostaining in experimental example 3.
Fig. 3 is a graph showing the results of experimental example 5.
Fig. 4 is a graph showing the results of experimental example 5.
Fig. 5 (a) to 5 (d) are photographs showing representative results of immunostaining in experimental example 6.
Fig. 6 is a graph showing the results of experimental example 7.
Fig. 7 is a graph showing the results of experimental example 7.
FIG. 8 is a photograph showing the result of Western blotting in Experimental example 8.
FIG. 9 is a photograph showing the result of Western blotting in Experimental example 8.
FIG. 10 is a graph showing quantitative values of SPSB2 protein in a urine sample measured in Experimental example 9.
FIG. 11 is a graph showing quantitative values of SPSB2 protein in a urine sample measured in Experimental example 9.
FIG. 12 is a graph showing quantitative values of SPSB2 protein in a urine sample measured in Experimental example 9.
FIG. 13 is a graph showing quantitative values of SPSB2 protein in a urine sample measured in Experimental example 9.
FIG. 14 is a ROC curve prepared in Experimental example 10.
Fig. 15 is a ROC curve prepared in experimental example 10.
FIG. 16 is a graph showing the results of analysis of cancer-specific survival in Experimental example 10.
FIG. 17 is a graph showing the results of analysis of the deterioration-free survival rate in Experimental example 10.
FIG. 18 (a) is a photograph showing the result of Western blotting in Experimental example 11. Fig. 18 (b) is a diagram showing the result of fig. 18 (a).
Detailed Description
[ kit for diagnosing cancer and kit for determining prognosis of cancer patient ]
In one embodiment, the invention provides a kit for diagnosing cancer comprising: substances that specifically bind to the SPSB2 protein, primer sets capable of amplifying the cDNA of the SPSB2 gene, or probes that specifically hybridize to the mRNA of the SPSB2 gene.
As described in the examples that follow, the inventors have clarified that the SPSB2 protein or the SPSB2 gene can be used as a cancer marker. In addition, the inventors have clarified that the SPSB2 protein or SPSB2 gene can be used not only as a marker for bladder cancer but also as a marker for pancreatic cancer and hepatocellular carcinoma. Thus, in the kit for diagnosing cancer of the present embodiment, examples of cancer include bladder cancer, pancreatic cancer, and hepatocellular carcinoma.
Using the kit of this example, the expression level of the SPSB2 protein or the SPSB2 gene in a biological sample from a subject can be determined to determine whether the subject has cancer. Examples of biological samples include serum, plasma, urine, and tissue. In addition, particularly in the case where the cancer is bladder cancer, examples of the biological sample include urine, tissue, and the like. Here, with respect to urine, exosomes in urine may be extracted and used as biological samples.
In addition, as described in the subsequent examples, the inventors analyzed bladder cancer patients and hepatocellular carcinoma patients, and clarified that in the case where the SPSB2 protein or the SPSB2 gene is highly expressed, prognosis tends to be poor. Therefore, it can also be said that the kit for diagnosing cancer of the present embodiment is a kit for determining prognosis. In the present specification, bad prognosis may mean low survival rate, short survival period without deterioration, and the like.
That is, it can be said that the present invention provides a kit for determining prognosis of a cancer patient, comprising: substances that specifically bind to the SPSB2 protein, primer sets capable of amplifying the cDNA of the SPSB2 gene, or probes that specifically hybridize to the mRNA of the SPSB2 gene. In a kit for determining prognosis of a cancer patient (a kit for predicting prognosis of a cancer patient), examples of cancer include bladder cancer, pancreatic cancer, and hepatocellular cancer.
NCBI accession numbers of human SPSB2 protein are NP-001139788.1, NP-001306599.1, and NP-116030.1, etc. In addition, NCBI accession numbers of mDNA of human SPSB2 gene are NM_001146316.2, NM_001146317.1, NM_001319670.2, NM_032641.4, and the like.
[ specifically bound substance ]
The kit of this embodiment may include a substance that specifically binds to the SPSB2 protein. Solids of specifically bound substancesExamples include antibodies, antibody fragments, and aptamers, among others. Examples of antibody fragments include F (ab') 2 Fab', fab, fv, scFv, and the like. Antibodies or antibody fragments may be polyclonal or monoclonal. The aptamer is not particularly limited as long as it has a specific binding ability to the SPSB2 protein, and examples thereof may include a nucleic acid aptamer, a peptide aptamer, and the like.
For example, the expression level of SPSB2 protein can be determined by immunostaining an immobilized tissue section with a specifically bound species. The determination of the expression level of the SPSB2 protein is not limited to immunostaining, but may be performed by extracting the protein from the test sample and using western blotting or ELISA.
The fact that the expression level of SPSB2 protein in the test sample is higher than the expression level of the control indicates that the test sample is from a cancer patient. In this specification, "above control" preferably means statistically significantly above the control. Here, examples of the control include the expression level of SPSB2 protein measured using a sample from a normal tissue.
(primer set)
The kit for diagnosing cancer of the present embodiment may include a primer set for amplifying cDNA of SPSB2 gene. The sequence of the primer set is not particularly limited as long as the sequence of the primer set can amplify at least a part of the cDNA of the SPSB2 gene.
The fact that the expression level of the SPSB2 gene in the test sample is higher than that of the control indicates that the test sample is from a cancer patient. In addition, examples of controls include expression levels of the SPSB2 gene determined using samples from normal tissues.
(Probe)
The kit of this embodiment may include a probe that specifically hybridizes to mRNA of the SPSB2 gene.
The probe may be, for example, a nucleic acid fragment having a base sequence complementary to a base sequence of at least a part of mRNA of the SPSB2 gene. In addition, the probe may have various chemical modifications for the purpose of improving stability, specificity at the time of hybridization, and the like. For example, to prevent degradation by hydrolytic enzymes such as nucleases, phosphate residues such as phosphorothioates (phosphorothioate PS), methylphosphonates and phosphorodithioates may be replaced with chemically modified phosphate residues. In addition, at least a portion thereof may be composed of nucleic acid analogs such as peptide nucleic acids (peptide nucleic acid, PNA).
The probe may be immobilized on a solid phase. Examples of the solid phase include beads, plate-like substrates, membranes, and the like. For example, probes may be immobilized on the surface of a plate-like substrate to form a microarray. In this case, for example, the expression of the SPSB2 gene in the test sample can be detected by extracting RNA from the test sample, labeling the RNA with a fluorescent substance, and hybridizing the RNA to the microarray to detect RNA bound to probes on the microarray.
The fact that the expression level of the SPSB2 gene in the test sample is higher than that of the control indicates that the test sample is from a cancer patient. Here, examples of the control include the expression level of the SPSB2 gene measured using a sample from a normal tissue.
[ method for determining biological sample, method for collecting data for determining whether a subject has cancer, and method for predicting prognosis of cancer patient ]
In one embodiment, the invention provides a method for determining a biological sample comprising the step of determining the expression level of an SPSB2 protein or gene in the biological sample, wherein the fact that the determined expression level of the protein or gene is higher than the expression level of a control indicates that the biological sample is from a cancer patient.
As described in the examples that follow, the inventors have clarified that the SPSB2 protein or the SPSB2 gene can be used as a cancer marker. In addition, the inventors have clarified that the SPSB2 protein or SPSB2 gene can be used not only as a marker for bladder cancer but also as a marker for pancreatic cancer and hepatocellular carcinoma. Thus, it may be determined whether the biological sample is from a cancer patient by the method of the present embodiment. In the determination method of the present embodiment, examples of the cancer include bladder cancer, pancreatic cancer, and hepatocellular carcinoma.
As described above, serum, plasma, urine, tissue, and the like from a subject can be used as biological samples. In addition, particularly in the case where the cancer is bladder cancer, examples of the biological sample include urine, tissue, and the like. Here, with respect to urine, exosomes in urine may be extracted and used as biological samples. In addition, similar to the above, "above control" preferably means statistically significantly above the control. In addition, examples of controls include expression levels of the SPSB2 protein or the SPSB2 gene determined using samples from normal tissues.
It can also be said that the determination method of the present embodiment is a method for collecting data for determining whether or not a biological sample is from a cancer patient. The method for collecting data does not include medical practice of the physician.
That is, it can be said that the present invention provides a method for collecting data for determining whether a biological sample is derived from a cancer patient, the method comprising the step of determining the expression level of an SPSB2 protein or gene in the biological sample, wherein the determined expression level of the protein or gene is data for determining whether the biological sample is derived from a cancer patient. The fact that the expression level of the SPSB2 protein or gene in the biological sample is higher than the expression level of the control indicates that the biological sample is from a cancer patient.
Alternatively, it can be said that the present invention provides a method for collecting data for determining whether a subject has cancer, the method comprising the step of determining the expression level of an SPSB2 protein or gene in a biological sample from the subject, wherein the determined expression level of the protein or gene is the data for determining whether the subject has cancer. The fact that the expression level of the SPSB2 protein or gene in the biological sample from the subject is higher than the expression level of the control indicates that the subject has cancer. In the method for collecting data, examples of cancer include bladder cancer, pancreatic cancer, and hepatocellular carcinoma.
In addition, as described in the subsequent examples, the inventors analyzed bladder cancer patients and hepatocellular carcinoma patients, and clarified that in the case where the SPSB2 protein or the SPSB2 gene is highly expressed, prognosis tends to be poor. Therefore, it can be said that the determination method of the present embodiment is a method for predicting prognosis.
That is, it can be said that the present invention provides a method for predicting prognosis of a cancer patient, the method comprising the step of determining the expression level of the SPSB2 protein or the SPSB2 gene in a biological sample from the cancer patient, wherein the fact that the determined expression level of the protein or gene is higher than the expression level of the control indicates that the prognosis of the cancer patient is poor. In a method of predicting prognosis of a cancer patient, examples of cancer include bladder cancer, pancreatic cancer, and hepatocellular carcinoma.
[ method for screening anticancer Agents ]
In one embodiment, the present invention provides a method for screening an anticancer agent, the method comprising the step of determining the expression level of an SPSB2 protein or an SPSB2 gene in cancer cells cultured in the presence of a test substance, wherein the fact that the expression level is significantly reduced compared to the expression level of the SPSB2 protein or the SPSB2 gene in the absence of the test substance indicates that the test substance is an anticancer agent.
As described in the subsequent examples, the higher the malignancy of the cancer cells, the higher the expression level of the SPSB2 protein or SPSB2 gene tends to be. Therefore, it can be said that a test substance that reduces the expression level of the SPSB2 protein or the SPSB2 gene is a candidate substance for an anticancer agent.
In the screening method of the present embodiment, the test substance is not particularly limited, and examples thereof include a natural compound library, a synthetic compound library, an existing drug library, a metabolite library, and the like.
In the screening method of the present embodiment, the cancer cells may be cancer cells derived from bladder cancer, pancreatic cancer, hepatocellular carcinoma, and the like.
Alternatively, the cancer cells may be cisplatin-resistant lines obtained by culturing in the presence of cisplatin while gradually increasing the cisplatin concentration. Cisplatin-resistant strains tend to be resistant to anticancer agents other than cisplatin, and often have a high degree of malignancy.
Other embodiments
In one embodiment, the invention provides a method of treating cancer comprising the step of determining the expression level of an SPSB2 protein or an SPSB2 gene in a biological sample from a subject, wherein the fact that the expression level is higher than the expression level of a control indicates that the subject has cancer; and a step of, in the case where the subject has cancer, surgically resecting cancer tissue from the subject or treating the subject with an anticancer agent.
In the treatment method of the present embodiment, examples of cancer include bladder cancer, pancreatic cancer, hepatocellular carcinoma, and the like. In addition, examples of biological samples include serum, plasma, urine, tissue, and the like. In particular, in the case where the cancer is bladder cancer, examples of the biological sample include urine, tissue, and the like. Here, with respect to urine, exosomes in urine may be extracted and used as biological samples.
As described in the subsequent examples, in the case of using urine as a biological sample, there is a case where the expression level of the SPSB2 protein or the SPSB2 gene may be high not only in cancer patients but also in urinary tract infection patients. In this case, whether the subject suffers from urinary tract infection may be diagnosed by a urine culture test or the like. That is, a subject having a high expression level of the SPSB2 protein or the SPSB2 gene and no urinary tract infection can be diagnosed as having cancer.
In the treatment method of the present embodiment, examples of anticancer agents include cisplatin, M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin in combination, combination of methotrexate, vinblastine, adriamycin, and cislatin), GC (cisplatin and gemcitabine in combination, combination of cisplatin and Gemzar), vecantu You Shan antibody (enfortumab vedotin) targeting nectin-4 as an antibody-drug complex (ADC), enrolment mab (Padcev), keytruda (palbocuzumab), pembrolizumab) and the like.
These anticancer agents are typically administered by intravenous drip. In addition, the dosages of these anticancer agents vary depending on the symptoms, weight, age, sex, etc. of the patient, but appropriate dosages may be appropriately selected by those skilled in the art.
Examples (examples)
Next, the present invention will be described in more detail by showing experimental examples, but the present invention is not limited to the following experimental examples.
Experimental example 1
To date, the inventors have prepared a large number of bladder cancer specific antibodies in research. In addition, a technique for recognizing a target protein by dot blotting using an autoantibody in serum has been established, and recognition of a large number of autoantibodies against bladder cancer has been achieved. These prepared bladder cancer specific antibodies and autoantibodies against bladder cancer were examined for their reactivity with the collected large amounts of serum and tumor tissue of bladder cancer patients. Thus, the SPSB2 protein or SPSB2 gene is designated as a candidate for a novel cancer marker.
Experimental example 2
Expression levels of the SPSB2 gene in bladder cancer tissues were examined using public database cancer genomic maps (The Cancer Genome Atlas, TCGA). Fig. 1 is a diagram showing the inspection result. In FIG. 1, the vertical axis represents the expression level of the SPSB2 gene. In addition, "normal" means the expression level of the SPSB2 gene in normal tissue, and "primary tumor" means the expression level of the SPSB2 gene in bladder cancer tissue. The results showed that the expression level of the SPSB2 gene was significantly increased in bladder cancer tissues.
Experimental example 3
Tissue sections prepared from whole bladder resected specimens were immunostained with anti-SPSB 2 antibodies. As a total bladder resection specimen, 126 specimens of total bladder resections performed in university of north medical college in 1990to 2015 were taken as subjects. Immunostaining was performed using Bond-MAX automatic immunostaining apparatus (Leica Biosystems).
The intensity of nuclear staining of tumor cells with anti-SPSB 2 antibody in the tissue sections was compared with that of surrounding cells with anti-SPSB 2 antibody, and the intensities were evaluated in three sections according to the following evaluation criteria. Evaluation criteria 0to 1 were classified into an SPSB2 protein low expression group, and evaluation criteria 2 was classified into an SPSB2 protein high expression group, to conduct the following analysis.
(evaluation criteria)
0: low expression
1: equal to each other
2: high expression
Fig. 2 (a) to 2 (c) are photographs showing representative immunostaining results. FIG. 2 (a) is a photograph showing the result of immunostaining of normal urothelial tissue. In addition, fig. 2 (b) is a photograph showing the result of immunostaining of bladder cancer tissue classified into the SPSB2 protein-low expression group. Further, fig. 2 (c) is a photograph showing the result of immunostaining of bladder cancer tissue classified into a group in which SPSB2 protein is highly expressed.
Experimental example 4
Based on the results of experimental example 3, the relationship between the expression of the SPSB2 protein and the clinical pathological factors was analyzed. The analysis results are shown in table 1 below. In Table 1, "p-value" means a p-value calculated by Fisher's exact test. p <0.05 was determined to be a significant difference. Bold letters indicate that there is a significant difference. The results indicate that SPSB2 protein expression is related to sex, vertical infiltration (pT staging), allotype and vascular infiltration.
TABLE 1
Table 2 below shows the results of studying the correlation between the expression of S100A8 protein, S100A9 protein, uroflavin (Uroplakin) III protein and HNRNPA3 protein reported as markers of bladder cancer and the expression of SPSB2 protein. In Table 2, "p-value" means a p-value calculated by Fisher's exact test. p <0.05 was determined to be a significant difference. Bold letters indicate that there is a significant difference.
The results indicate that the expression of SPSB2 protein is associated with the expression of each of the S100A8 protein, the S100A9 protein, the uroflavin (Uroplakin) III protein, and the HNRNPA3 protein.
TABLE 2
Experimental example 5
Based on the results of experimental example 3, the relationship between the expression of the SPSB2 protein and prognosis was analyzed. FIG. 3 is a graph showing the results of analysis of cancer specific survival by the Kaplan-Meier method. In FIG. 3, "SPSB2 low" indicates the result of the SPSB2 protein low expression group, and "SPSB2 high" indicates the result of the SPSB2 protein high expression group. In addition, "risk number" means the number of survivors at each time point. The results indicate that there is a significantly higher risk of death due to bladder cancer, a high expression group of the SPSB2 protein.
FIG. 4 is a graph showing the results of analysis of non-worsening survival by the Kaplan-Meier method based on the results of experimental example 3. In FIG. 4, "SPSB2 low" indicates the result of the SPSB2 protein low expression group, and "SPSB2 high" indicates the result of the SPSB2 protein high expression group. Furthermore, "risk number" means the number of non-worsening survivors at each time point. The results show that the period of time until bladder cancer recurs is significantly shortened in the SPSB2 protein highly expressed group.
Table 3 below shows the results of univariate analysis and multivariate analysis based on Cox proportional hazards models for cancer specific survival. In addition, table 4 below shows the results of univariate analysis and multivariate analysis based on Cox proportional hazards models for non-worsening survival. In tables 3 and 4, "HR" represents the risk ratio, and "95% ci" represents the 95% confidence interval. p <0.05 was determined to be a significant difference. Bold letters indicate that there is a significant difference.
The results indicate that expression of SPSB2 protein together with lymph node metastasis acts as an independent factor for cancer-specific and non-exacerbating survival.
TABLE 3
TABLE 4
Experimental example 6
Expression of the SPSB2 protein in types of cancers other than bladder cancer was investigated. Fig. 5 (a) to 5 (c) are photographs showing representative results of immunostaining each tissue section of pancreatic cancer, hepatocellular carcinoma, and ovarian cancer with an anti-SPSB 2 antibody. Fig. 5 (a) shows the result of tissue section of pancreatic cancer, fig. 5 (b) shows the result of tissue section of hepatocellular carcinoma, fig. 5 (c) shows the result of tissue section of ovarian cancer, and fig. 5 (d) shows the result of tissue section of normal tissue of pancreas.
The results showed that the SPSB2 protein was confirmed to be strongly expressed in pancreatic cancer and moderately expressed in hepatocellular carcinoma and ovarian cancer. On the other hand, the SPSB2 protein is weakly expressed or not expressed in kidney cancer, prostate cancer, esophageal cancer, stomach cancer, colon cancer, breast cancer and lung cancer.
Experimental example 7
The expression level of the SPSB2 gene in hepatocellular carcinoma tissues was examined using a public database cancer genomic map (The Cancer Genome Atlas, TCGA). Fig. 6 is a diagram showing the inspection result. In FIG. 6, the vertical axis represents the expression level of the SPSB2 gene. In addition, "normal" means the expression level of the SPSB2 gene in normal tissue, and "primary tumor" means the expression level of the SPSB2 gene in hepatocellular carcinoma tissue.
The results showed that the expression level of SPSB2 gene was significantly increased in the hepatocellular carcinoma tissue.
Fig. 7 is a graph showing a relationship between the expression level of the SPSB2 gene in hepatocellular carcinoma and prognosis in TCGA samples. In FIG. 7, "high expression" indicates the result of the SPSB2 protein high expression group, and "low/moderate expression" indicates the result of the SPSB2 protein low to moderate expression group. The results show that the SPSB2 gene high expression group of the hepatocellular carcinoma has a remarkably poor prognosis.
Experimental example 8
The abundance of SPSB2 protein in serum and urine exosomes from healthy subjects and bladder cancer patients was studied by western blotting.
First, exosomes were extracted from serum samples and urine samples using a total exosome separation reagent (sameir feishier technologies, thermo Fisher Scientific).
Subsequently, SPSB2 protein was detected using the extracted exosomes. In addition, it was demonstrated that exosomes can be extracted by western blotting of CD9, one of the exosome markers. The molecular weight of the SPSB2 protein is about 26kDa and the molecular weight of the CD9 protein is about 24kDa.
Fig. 8 is a photograph showing the result of western blotting of exosomes in serum. In fig. 8, "C" represents exosomes from healthy subjects, and "T" represents exosomes from bladder cancer patients.
The results confirm that exosomes can be extracted as CD 9can be detected. In addition, it was also clarified that the presence of SPSB2 protein was not confirmed in exosomes in serum in both healthy subjects and bladder cancer patients.
Fig. 9 is a photograph showing the result of western blotting of exosomes in urine. In fig. 9, "C" represents exosomes from healthy subjects, "T" represents exosomes from bladder cancer patients.
The results confirm that exosomes can be extracted as CD 9can be detected. In addition, the presence of SPSB2 protein was not confirmed in the exosomes in serum from healthy subjects, whereas the presence of SPSB2 protein was detected in the urine exosomes from bladder cancer patients.
Experimental example 9
The abundance of SPSB2 protein in urine from healthy subjects, urinary tract stone patients, urinary tract infection patients and bladder cancer patients was quantified and studied by enzyme-linked immunosorbent assay (ELISA).
As bladder cancer patients, 91 cases of urine were collected immediately before transurethral cystectomy by university of north hospital in 2009 to 2015. The background of bladder cancer patients is shown in table 5 below. In table 5, "NMIBC" indicates non-muscle invasive bladder cancer and "MIBC" indicates muscle invasive bladder cancer. Urine specific gravity of all urine samples was corrected to 1.002 and abundance of SPSB2 protein was determined by ELISA.
TABLE 5
FIG. 10 is a graph showing quantitative values of SPSB2 protein in urine samples of each group. In addition, FIG. 10 also shows the results of analysis by the Mann-Whitney U-test. In fig. 10, "BC" indicates the result of a bladder cancer patient, "healthy" indicates the result of a healthy subject, "stone" indicates the result of a urinary system stone patient, and "UTI" indicates the result of a urinary tract infection patient.
Thus, the abundance of SBSP2 protein in urine from patients with bladder cancer is higher than the abundance of SBSP2 protein in urine from healthy subjects and patients with urinary tract stones, but lower than the abundance of SBSP2 protein in urine from patients with urinary tract infections. Urinary tract infection can be diagnosed by urine culture examination or the like.
Fig. 11 is a graph showing quantitative values of SPSB2 protein in urine samples of non-muscle-invasive bladder cancer patients and muscle-invasive bladder cancer patients. In addition, fig. 11 also shows the analysis results by the mann-whitney U test. In fig. 11, "NMIBC" indicates non-muscle invasive bladder cancer and "MIBC" indicates muscle invasive bladder cancer.
The results indicate that the abundance of SBSP2 protein in urine from patients with bladder cancer shows a higher value than the abundance of SBSP2 protein in urine from patients with muscle invasive bladder cancer.
Fig. 12 is a graph showing quantitative values of SPSB2 protein in urine samples of patients with pathological grade 1 and grade 2 bladder cancer and patients with pathological grade 3 bladder cancer. In addition, fig. 12 also shows the analysis results by the mann-whitney U test.
The results indicate that the abundance of SBSP2 protein in urine of patients with pathological grade 3 bladder cancer tends to show higher values than the abundance of SBSP2 protein in urine of patients with pathological grade 1 and grade 2 bladder cancer.
Fig. 13 is a graph showing quantitative values of SPSB2 protein in urine samples of patients with muscle invasive bladder cancer and patients with urinary tract infection. In addition, fig. 13 also shows the analysis results by the mann-whitney U test. In fig. 13, "MIBC" represents muscle invasive bladder cancer, and "UTI" represents the result of a patient with urinary tract infection.
Thus, no significant difference was confirmed in the abundance of SBSP2 protein in the urine of myometrial invasive bladder cancer and urinary tract infection patients. Urinary tract infection can be diagnosed by urine culture examination or the like.
Experimental example 10
Based on the results of experimental example 9, the relationship between the expression of the SPSB2 protein and prognosis was analyzed. Fig. 14 is a ROC curve prepared based on quantitative values of SPSB2 protein in urine samples of bladder cancer patients and healthy subjects measured in experimental example 9. The results showed 0.7791 as the area under the ROC curve (AUC: area under the curve, area under the curve).
Fig. 15 is a ROC curve prepared based on quantitative values of SPSB2 protein in urine samples of patients with muscular layer invasive bladder cancer and healthy subjects measured in experimental example 9. The results indicated that the area under the ROC curve (AUC) was 0.8699.
Subsequently, based on the ROC curve, the critical value was set to 162.8ng/mL (sensitivity: 58.2%, specificity: 80.0%), and survival analysis was performed in which patients with an abundance of SPSB2 protein in urine lower than 162.8ng/mL were the SPSB2 protein low expression group, and patients with an abundance of SPSB2 protein in urine of 162.8ng/mL or greater than 162.8ng/mL were the SPSB2 protein high expression group.
FIG. 16 is a graph showing the results of analysis of cancer specific survival by the Kaplan-Meier method. In FIG. 16, "SPSB2 low" indicates the result of the SPSB2 protein low expression group, and "SPSB2 high" indicates the result of the SPSB2 protein high expression group. In addition, "risk number" means the number of survivors at each time point. The results indicate that there is a significantly higher risk of death due to bladder cancer, a high expression group of the SPSB2 protein.
FIG. 17 is a graph showing the results of analysis of non-worsening survival by the Kaplan-Meier method. In FIG. 17, "SPSB2 low" indicates the result of the SPSB2 protein low expression group, and "SPSB2 high" indicates the result of the SPSB2 protein high expression group. In addition, "risk number" means the number of non-worsening survivors at each time point. Thus, no significant difference was confirmed between the SPSB2 protein low expression group and the SPSB2 protein high expression group until the period of time in which bladder cancer recurred.
Table 6 below shows the results of univariate analysis and multivariate analysis based on Cox proportional hazards models for cancer specific survival. In table 6, "NMIBC" represents non-muscle invasive bladder cancer, "MIBC" represents muscle invasive bladder cancer, "G3" represents grade 3, "G1,2" represents grade 1 or grade 2, "HR" represents risk ratio, "95% ci" represents 95% confidence interval. p <0.05 was determined to be a significant difference. Bold letters indicate that there is a significant difference.
The results indicate that expression of SPSB2 protein, together with the vertical extent of infiltration of cancer, is a prognostic factor for cancer-specific survival.
TABLE 6
Experimental example 11
T24 and 5637 as human bladder cancer cell lines were cultured in the presence of cisplatin while gradually increasing concentrations to obtain T24CDDPR and 5637CDDPR, both of which are cisplatin resistant lines. T24CDDPR and 5637CDDPR are considered to have a higher degree of malignancy than T24 and 5637.
Subsequently, the expression level of SPSB2 protein was determined by western blotting of each cell line of T24, T24CDDPR, 5637 and 5637 CDDPR. In addition, the expression level of β -actin was measured as a control.
Fig. 18 (a) is a photograph showing the western blot result. Fig. 18 (b) shows the result of fig. 18 (a) in the form of a graph. The vertical axis in fig. 18 (b) represents the expression level of SPSB2 relative to the expression level of β -actin, "×" represents a significant difference when p <0.05, and "×" represents a significant difference when p < 0.01.
The results indicate that the expression level of SPSB2 in T24CDDPR and 5637CDDPR is significantly higher than the expression level of SPSB2 in each of T24 and 5637.
The results indicate that the higher the malignancy of the cancer, the higher the expression level of SPSB2 in the cancer cells.
[ Industrial Applicability ]
According to the present invention, a novel technique for diagnosing cancer can be provided.
Claims (12)
1. A kit for diagnosing cancer, comprising:
specific binding substances for SOCS box protein 2 (SPSB 2) proteins containing SPRY domains;
primer set for amplifying cDNA of SPSB2 gene; or (b)
Probes specifically hybridizing with mRNA of SPSB2 gene.
2. The kit for diagnosing cancer according to claim 1, wherein the cancer is bladder cancer, pancreatic cancer or hepatocellular carcinoma.
3. A kit for determining prognosis of a cancer patient, comprising:
specific binding substances for the SPSB2 protein;
primer set for amplifying cDNA of SPSB2 gene; or (b)
Probes specifically hybridizing with mRNA of SPSB2 gene.
4. The kit for determining prognosis as claimed in claim 3, wherein the cancer is bladder cancer, pancreatic cancer or hepatocellular carcinoma.
5. A method for determining a biological sample, comprising:
a step of measuring the expression level of SPSB2 protein or SPSB2 gene in the biological sample,
wherein the fact that the expression level of the protein or gene is determined to be higher than the expression level of the control indicates that the biological sample is from a cancer patient.
6. The method for determining according to claim 5, wherein the cancer is bladder cancer, pancreatic cancer or hepatocellular carcinoma.
7. A method for collecting data for determining whether a subject has cancer, the method comprising: a step of determining the expression level of an SPSB2 protein or an SPSB2 gene in a biological sample from the subject, wherein the determined expression level of the protein or gene is data for determining whether the subject has cancer, provided that medical practice by a doctor is excluded.
8. The method of claim 7, wherein the cancer is bladder cancer, pancreatic cancer, or hepatocellular cancer.
9. A method for predicting prognosis of a cancer patient, the method comprising: a step of determining the expression level of SPSB2 protein or SPSB2 gene in a biological sample from the cancer patient,
wherein the fact that the expression level of the protein or gene determined is higher than the expression level of the control indicates that the cancer patient has poor prognosis.
10. The method of claim 9, wherein the cancer is bladder cancer, pancreatic cancer, or hepatocellular cancer.
11. A method for screening for an anticancer agent, the method comprising: a step of measuring the expression level of SPSB2 protein or SPSB2 gene in cancer cells cultured in the presence of a test substance,
wherein the fact that the expression level is significantly reduced compared to the expression level of the SPSB2 protein or the SPSB2 gene in the absence of the test agent indicates that the test agent is an anti-cancer agent.
12. The method of claim 11, wherein the cancer cell is a cancer cell from bladder cancer, pancreatic cancer, or hepatocellular carcinoma.
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