CN113785200A - Marker composition for diagnosing cancer or predicting prognosis based on exosomes overexpressing TUBA1C protein - Google Patents
Marker composition for diagnosing cancer or predicting prognosis based on exosomes overexpressing TUBA1C protein Download PDFInfo
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Abstract
According to one embodiment of the present invention, there is provided a marker composition for diagnosing cancer or predicting prognosis, comprising an exosome overexpressing tubulin α -1C chain (TUBA1C) protein, a kit, and a method for providing information required for diagnosing cancer or predicting prognosis, comprising the step of measuring the expression level of TUBA1C gene or protein in an exosome isolated from a biological sample.
Description
Technical Field
The present invention relates to marker compositions for diagnosing cancer or predicting prognosis comprising exosomes overexpressing alpha-Tubulin specific 1C chain (Tubulin alpha-1C chain, TUBA1C) protein.
Background
Tumors (tumors) are the product of uncontrolled and disordered cellular proliferation caused by an abnormal cellular excess, which when destructively proliferated, spread and metastasized, would be classified as malignant tumors (cancers).
Cancer is currently diagnosed by methods such as X-ray, endoscopy, and pathological examination. Although the above-mentioned examination methods have a relatively simple examination procedure, the success rate of diagnosis is not high, there are also health problems, and patients feel pain during the examination, and therefore, it is required to develop a cancer diagnosis method instead of the above-mentioned method.
For the treatment of cancer, highly sensitive and specific cancer diagnosis is required before treatment. Only by such diagnosis, the early detection of cancer can improve the cure rate.
Therefore, there is a need to develop a method for non-invasively and specifically diagnosing cancer at an early stage, but there is still a lack of molecular diagnostic techniques for detecting a lesion at an early stage and determining whether the lesion is present, and particularly, a method specifically applicable to a specific cancer has not been developed.
Prior patent document
Patent document
Korean granted patent No. 10-2080887
Disclosure of the invention
Technical problem to be solved
Under these circumstances, the present inventors have continued research for developing a novel exosome-derived marker for diagnosing cancer or predicting prognosis, and as a result, they have confirmed that when TUBA1C (Tubulin alpha-1C chain) protein specifically expressed in cancer cell-derived exosomes is used, it is possible to accurately and rapidly diagnose cancer or predict prognosis, and thus they have completed the present invention.
The present invention aims to provide a marker composition capable of improving the accuracy of cancer diagnosis by a non-invasive method, the composition comprising exosomes based on the over-expression TUBA1C protein, and a method for providing information required for diagnosing cancer or predicting prognosis using the composition.
However, the problems to be solved by the present invention are not limited to the above technical problems, and other technical problems not mentioned can be clearly understood by those of ordinary skill in the art through the following description.
Means for solving the problems
According to one embodiment of the present invention, there is provided a marker composition for diagnosing cancer or predicting prognosis, comprising exosomes overexpressing TUBA1C (Tubulin alpha-1C chain) protein.
According to one aspect, the exosome further comprises a GCC2(GRIP and woven-core domain-binding protein) protein.
According to one aspect, the cancer is lung cancer, thymus cancer, or esophageal cancer.
According to another embodiment of the present invention, there is provided a composition for diagnosing cancer or predicting prognosis, comprising a primer or probe that specifically binds to TUBA1C protein in exosomes; and an antibody that specifically binds to the TUBA1C protein in the exosomes.
According to one aspect, the composition further comprises a primer or probe that specifically binds to the in-exosome GCC2 gene; and an antibody that specifically binds to the GCC2 protein in exosomes.
According to one aspect, the cancer is lung cancer, thymus cancer, or esophageal cancer.
According to still another embodiment of the present invention, there is provided a kit for diagnosing cancer or predicting prognosis comprising the composition.
According to one aspect, the kit is one or more selected from the group consisting of an RT-PCR kit, a microarray chip kit, a DNA kit, and a protein chip kit.
According to still another embodiment of the present invention, there is provided a providing method of information required for diagnosing cancer or predicting prognosis, comprising the step of measuring the expression level of TUBA1C gene or protein in exosomes isolated from a biological sample.
According to one aspect, further comprising the step of measuring the expression level of GCC2 gene or protein in said exosomes.
According to one aspect, the biological sample is one or more selected from the group consisting of whole blood, serum, plasma, saliva, urine, sputum, lymph fluid and cells.
ADVANTAGEOUS EFFECTS OF INVENTION
The marker composition of the present invention comprises TUBA1C protein overexpressed in exosomes of cancer patients, and by measuring its expression level, it is possible to accurately diagnose cancer or predict prognosis non-invasively.
In addition, the marker composition of the invention takes TUBA1C and GCC2 which are overexpressed in exosomes as dual biomarkers, and can further improve the sensitivity and accuracy of cancer diagnosis.
However, the effects intended by the present invention are not limited to the above-described effects, and all effects that can be derived based on the description of the embodiments of the present invention or the claims should be included.
Drawings
FIG. 1 is an ELISA result comparing the expression levels of GCC2 and TUBA1C proteins in blood-derived exosomes of lung cancer patients with those of the normal group.
FIG. 2 is an ELISA result comparing the expression level of TUBA1C protein in plasma-derived exosomes of esophageal cancer patients with that of a normal control group.
FIG. 3 is an ELISA result comparing the expression level of TUBA1C protein in plasma-derived exosomes of thymus cancer patients with that of a normal control group.
FIG. 4 shows ELISA results of measurements of the expression levels of TUBA1C and GCC2 in plasma-derived exosomes of lung cancer patients in terms of number of stages.
Fig. 5 is a ROC curve confirming the change in sensitivity of lung cancer diagnosis when TUBA1C and GCC2 were used alone and when both markers were used.
Detailed Description
The embodiments are described in detail below with reference to the accompanying drawings. Like reference symbols in the various drawings indicate like elements.
Various modifications can be made to the embodiments described below. Embodiments of the present invention are not limited to the following examples, but include all modifications, equivalents, and alternatives thereof to the following examples.
The terminology used in the description is for the purpose of describing particular embodiments only and is not intended to limit the scope of the protection. Where not otherwise stated in the context, singular expressions include plural meanings. In the present specification, the terms "comprising" or "having" are used to express that there are the features, numerals, steps, operations, constituent elements, components or combinations thereof described in the specification, and do not exclude that there are one or more other features, numerals, steps, operations, constituent elements, components or combinations thereof or additional functions.
All terms used herein, including technical or scientific terms, have the ordinary meaning as understood by one of ordinary skill in the art without further definition. Terms commonly used as dictionary definitions should be understood as meanings in the related art, and cannot be interpreted as idealised or over formalised meanings without being explicitly defined in the specification.
In the description with reference to the drawings, the same components are denoted by the same reference numerals regardless of the reference numerals, and redundant description is omitted. In describing the embodiments, when it is judged that a detailed description of the related well-known art may unnecessarily obscure the embodiments, a detailed description thereof is omitted.
According to an embodiment of the present invention, there is provided a marker composition for diagnosing cancer or predicting prognosis comprising exosomes overexpressing TUBA1C (Tubulin alpha-1C chain) protein. Furthermore, the above exosomes may also include GRIP and coiled-coil domain-2 (GRIP and coiied-coil domain-containing protein, GCC2) proteins.
The terms "exosome overexpressing TUBA1C protein" and "exosome overexpressing GCC2 protein" as used in the present specification refer to exosomes capable of achieving higher levels of GCC2 or TUBA1C protein expression than exosomes present in normal cells.
Exosomes (exosomes) are small membrane vesicles of nanometer size (30-150 nm) secreted by most cells. It is known that various proteins, genetic materials (DNA, mRNA, miRNA), lipids, and the like derived from cells are included in exosomes and phospholipid bilayer membranes. Furthermore, since tissue-derived exosomes reflect the state of the tissue from which they are secreted, they can be used for diagnosing diseases.
Thus, the present inventors have found that the use of TUBA1C or GCC2 protein specifically expressed in exosomes of cancer patients enables accurate and rapid diagnosis of cancer or prediction of prognosis, and have completed the present invention.
Here, the cancer includes all cancers, and non-limiting examples include lung cancer, esophageal cancer, thymus gland cancer, breast cancer, liver cancer, stomach cancer, rectal cancer, pancreatic cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, bladder cancer, head and neck cancer, bone marrow cancer, biliary tract cancer, and preferably lung cancer, esophageal cancer or thymus gland cancer.
The term "diagnosing" as used in the present specification refers to confirming the presence or absence of a pathological state or a characteristic of a pathological state, i.e., confirming whether cancer is present. And, the "prognosis" refers to the judgment of whether the corresponding individual has recurrence, metastasis, drug reaction, drug resistance, etc. after cancer treatment. That is, by measuring the expression level of TUBA1C or GCC2 in exosomes isolated from a sample of an individual, it is determined whether the corresponding individual has cancer, and it is predicted whether the prognosis is good after survival of the corresponding individual.
Thus, a primer or probe specifically binding to the gene, or an antibody specifically binding to the protein can be used to diagnose cancer or predict a prognosis composition, which is capable of diagnosing cancer or predicting prognosis by measuring the expression level of TUBA1C or GCC2 protein derived from exosomes.
Furthermore, the present invention can provide a kit for diagnosing cancer or predicting prognosis by applying any one or more of a primer, a probe, or an antibody specifically binding to TUBA1C or GCC2 protein, which specifically binds to TUBA1C or GCC2 gene, to the kit.
Non-limiting examples of the kit may include an RT-PCR kit, a microarray chip kit, a DNA kit, a protein chip kit, and the like. The kit can confirm and detect the expression level of TUBA1C and GCC2 proteins corresponding to markers in exosomes, thereby diagnosing cancer or predicting prognosis.
For diagnosing cancer or predicting prognosis, the kit comprises primers, probes or antibodies that selectively recognize markers, and, in addition, compositions, solutions or devices of one or more other components suitable for use in analytical methods.
For example, for immunological detection of an antibody, the kit may include a substrate, an appropriate buffer solution, a secondary antibody labeled with a chromogenic enzyme or a fluorescent substance, a chromogenic substrate, and the like. Also, as the substrate, a nitrocellulose membrane, a 96-well plate synthesized from polyethylene resin, a 96-well plate synthesized from polystyrene resin, and a glass slide made of glass; examples of the chromogenic enzyme include peroxidase (peroxidase), alkaline phosphatase (alkaline phosphatase), and the like; as the fluorescent substance, Fluorescein Isothiocyanate (FITC), Rhodamine Isothiocyanate (RITC), etc. can be used; as the chromogenic substrate, ABTS (2, 2-diaza-bis (3-ethyl-benzothiazole-6-sulfonic acid) diammonium salt) or OPD (o-phenylenediamine), TMB (tetramethylbenzidine) may be used, but not limited thereto.
According to another embodiment of the present invention, there is provided a providing method of information required for diagnosing cancer or predicting prognosis, including the steps of: a step of measuring the expression level of TUBA1C gene or protein in exosomes (exosomes) isolated from a biological sample.
In order to improve the sensitivity and accuracy of diagnosing cancer, the method of the present invention may further comprise the step of measuring the expression level of GCC2 gene or protein in exosomes.
The biological sample may be one or more selected from the group consisting of whole blood, serum, plasma, saliva, urine, sputum, lymph fluid and cells, and preferably may be whole blood or cells, but is not limited thereto.
The measurement of the gene expression level is a process of confirming the presence or absence of mRNA of TUBA1C and GCC2 genes and the expression level thereof from a biological sample for the purpose of diagnosis of cancer or prediction of prognosis, i.e., measuring the expression amount of mRNA.
Non-limiting examples of analytical methods used for this purpose include reverse transcription-polymerase chain reaction (RT-PCR), Competitive RT-PCR, Real-time RT-PCR and RNase Protection Assay (RPA), Northern blotting, DNA chips and the like.
Also, measuring the expression level of the protein is a process of confirming the presence or absence of TUBA1C, GCC2 protein and the expression degree thereof in a biological sample for the purpose of diagnosing cancer or predicting prognosis.
Non-limiting examples of the method of measuring the expression level of the protein or the comparative analysis method include: protein chip analysis, immunoassay, ligand binding analysis, Matrix Assisted Laser Desorption-Ionization Time of Flight Mass Spectrometry (MALDI-TOF) analysis, surface Enhanced Laser Desorption-Ionization Time of Flight Mass Spectrometry (SELDI-TOF) analysis, radioimmunoassay, radioimmunodiffusion, Austenity immunodiffusion, immunoelectrophoresis, immunohistological staining, complement fixation, two-dimensional electrophoresis, liquid chromatography-Mass Spectrometry (liquid chromatography-Mass Spectrometry)
Spectrometry, LC-MS), liquid chromatography-Mass Spectrometry/Mass Spectrometry (liquid chromatography-Mass Spectrometry)
Spectrometry/Mass Spectrometry, LC-MS/MS), Western blot method, and enzyme-linked immunosorbent assay (ELISA).
When the expression level of the gene or protein of TUBA1C or GCC2 is measured and compared with that of a normal control group, it can be judged that the cancer is more likely to develop or the onset of cancer is more likely to develop when the expression level is higher than that of the normal control group.
Also, according to an embodiment of the present invention, there is provided a cancer therapeutic agent screening method including the steps of: (a) a step of applying a cancer therapeutic agent candidate substance to a collected cancer patient biological sample; (b) a step of isolating exosomes (exosomes) from the biological sample; and (c) measuring the expression level of TUBA1C gene or protein in the exosome.
Extension of the provision of information required for diagnosing cancer or predicting prognosis can be used as a candidate for screening the therapeutic agent. That is, when it is confirmed that the expression level of TUBA1C gene or protein is decreased in exosomes present therein after a cancer therapeutic candidate substance is applied to a biological sample isolated from a cancer patient, it can be confirmed that the corresponding candidate substance has an effective function as a cancer therapeutic.
The present invention will be described in more detail below with reference to examples. The following examples are intended to illustrate the invention, the scope of which is not limited thereto.
Example 1: preparation of isolated exosomes and analysis of proteomes
5 cancer cell lines (H522, A549, H1650, PC9 and H1299), a thymic cancer cell line and an esophagus cancer cell line are respectively cultured in a culture dish with the diameter of 150 mm. At this time, the cells were centrifuged at 120000g for 4 hours using an ultra-high speed centrifuge, and a supernatant of Fetal Bovine Serum (FBS) from which exosomes was removed was used as a culture solution. The culture is continuously carried out for 2-3 days by using the culture solution until the cell fusion degree reaches 70-80%.
The resulting culture broth was centrifuged at 10000g for 30 minutes to remove cell debris (cell debris), and then a large-volume material was preferentially removed by passing through a 0.45 μm, 0.22 μm filter in order. Thereafter, as for the filtered cell culture solution, only particles of a desired size were retained by an Amicon tube 100K (Amicon tube 100K) (Millipore Co., U.S.A.) and then concentrated.
Thereafter, only the particles having an exosome size (50 to 100nm) were separated from the concentrated cell culture solution by column liquid chromatography (column liquid chromatography), and the cell culture solution was concentrated again by an Amicon tube 100K.
Proteins were obtained from concentrated exosomes using RIPA lysate (RIPA lysis buffer, Thermo Fisher Scientific, usa) and proteome analysis results were obtained by committing to korean basic science research institute (KBSI).
Based on this, TUBA1C (Tubulin alpha-1C chain) and GCC2(GRIP and ground-core domain-linking protein 2) which were overexpressed in exosomes of cancer cell lines were finally screened.
Example 2: measuring the expression levels of GCC2 and TUBA1C proteins in exosomes of lung cancer patients
To confirm whether exosomes including GCC2 and TUBA1C proteins screened in example 1 were feasible as markers for diagnosing lung cancer or predicting prognosis, the expression levels of GCC2 and TUBA1C in exosomes extracted from blood of the normal group (n-3) and lung cancer patient group (n-5) were analyzed using elisa (enzyme linked immunosorbent).
As a result, as shown in fig. 1, the expression of GCC2 and TUBA1C was increased in the lung cancer patient group as compared with the normal group (control).
Thereafter, in order to confirm the characteristics of exosomes isolated from the plasma of lung cancer patients, 20 lung cancer patients from stage 1 to stage 3 in the hospital were collected and exosomes were isolated from the plasma using Exoquick (Systembio, usa). Expression levels of GCC2 and TUBA1C derived from exosomes of isolated blood were confirmed by ELISA (GCC 2: GRIP and linked-mail domain linking protein 2 of Mybiosource Co., Ltd.; ELISA KIT (Cat No. MBS9330667),2) TUBA 1C: TUBA1C ELISA KIT from Mybiosource (Cat No. MBS9336377)). As a result, as shown in fig. 4, the expression levels of GCC2 and TUBA1C were significantly increased in all lung cancer stages compared to the normal group, and the expression levels of GCC2 and TUBA1C were also increased with the increase in the lung cancer stage.
Example 3: measurement of TUBA1C expression levels in exosomes of esophageal and thymus cancer patients
First, exosomes were extracted from plasma (plasma) samples of 5 normal human and 5 esophageal cancer patients, and then the concentration of TUBA1C protein in the samples was confirmed using TUBA1C ELISA KIT (TUBA1C ELISA KIT by Mybiosource corporation (Cat No. mbs9336377)).
The results are shown in fig. 2, the average concentration of the exosome-derived TUBA1C protein in normal humans is 939.306ng/ml, whereas the average concentration of exosome-derived TUBA1C protein in esophageal cancer patients is 1236.764ng/ml higher. The concentration of exosome-derived TUBA1C protein in esophageal cancer patients is increased by 1.36 times compared with that of normal people, and the p value (value p value) is 0.021 and is statistically significant.
Exosomes were then extracted from plasma (plasma) samples of normal 5 human subjects, 5 human subjects with thymus cancer, and the concentration of TUBA1C protein in the samples was confirmed using TUBA1C ELISA KIT (TUBA1C ELISA KIT by Mybiosource corporation (Cat No. mbs9336377)).
The results are shown in fig. 3, in contrast to the average concentration of 939.306ng/ml of the normal human exosome-derived TUBA1C protein, the average concentration of the normal human exosome-derived TUBA1C protein was 3503.15ng/ml, which is very high in esophageal cancer patients. The concentration of exosome-derived TUBA1C protein in esophageal cancer patients is increased by 3.85 times compared with that in normal people, and the p value is 0.005, which is statistically significant.
Example 4: assessment of diagnostic efficacy when TUBA1C and GCC2 were used as dual biomarkers
In order to evaluate the effectiveness of TUBA1C and GCC2 as dual biomarkers in diagnosing cancer, changes in diagnostic sensitivity were confirmed by ROC curves in the case of using TUBA1C and GCC2 alone and in the case of using both markers simultaneously. Specifically, after exosomes were extracted from plasma (plasma) of 7 normal persons and 21 lung cancer patients, the concentrations of GCC2 and TUBA1C proteins in exosomes were obtained using GCC2ELISA KIT and TUBA1C ELISA KIT, and then the AUC values were confirmed using a statistical ROC curve and are shown in fig. 5.
Referring to fig. 5, AUC was 0.905(p ═ 0.002) when GCC2 antibody alone was used and 0.8787(p ═ 0.003) when TUBA1C antibody alone was used. In contrast, when GCC2 and TUBA1C antibodies were used together, the AUC was 1(P0.0000963), and diagnosis was more accurate when TUBA1C and GCC2 were used as dual biomarkers than when TUBA1C or GCC2 were used alone.
In summary, the embodiments have been described with limited drawings, and those skilled in the art will be able to make various technical modifications and variations based on the description. For example, the techniques described may be performed in a different order than the methods described, and/or the components described may be combined or combined in a different manner than the methods described, or substituted or replaced with other components or equivalents, to achieve suitable results.
Accordingly, other embodiments, and equivalents to the claims are intended to fall within the scope of the claims.
Claims (11)
1. A marker composition for diagnosing cancer or predicting prognosis, characterized in that,
exosomes overexpressing TUBA1C protein are included.
2. The marker composition for diagnosing cancer or predicting prognosis according to claim 1,
the exosomes also include the GCC2 protein.
3. The marker composition for diagnosing cancer or predicting prognosis as set forth in claim 1 or 2,
the cancer is lung cancer, thymus cancer or esophageal cancer.
4. A composition for diagnosing cancer or predicting prognosis,
including primers or probes that specifically bind to the TUBA1C protein in exosomes; and an antibody that specifically binds to the TUBA1C protein in the exosomes.
5. The composition for diagnosing cancer or prognosing according to claim 4,
the composition further comprises a primer or probe that specifically binds to the GCC2 gene in exosomes; and
any one or more of antibodies that specifically bind to the GCC2 protein in exosomes.
6. The composition for diagnosing cancer or predicting prognosis according to claim 4 or 5,
the cancer is lung cancer, thymus cancer or esophageal cancer.
7. A kit for diagnosing cancer or predicting prognosis,
comprising the composition of claim 4 or 5.
8. The kit for diagnosing cancer or prognosing cancer according to claim 7,
the kit is one or more selected from the group consisting of an RT-PCR kit, a microarray chip kit, a DNA kit and a protein chip kit.
9. A method for providing information required for diagnosing cancer or predicting prognosis,
comprising the step of measuring the level of expression of TUBA1C gene or protein in exosomes isolated from a biological sample.
10. The method for providing information required for diagnosing cancer or predicting prognosis as set forth in claim 9,
further comprising the step of measuring the expression level of a GCC2 gene or protein in said exosomes.
11. The method for providing information required for diagnosing cancer or predicting prognosis as set forth in claim 9 or 10,
the biological sample is one or more selected from the group consisting of whole blood, serum, plasma, saliva, urine, sputum, lymph fluid and cells.
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