KR101873486B1 - Marker composition for diagnosising uterine leiomyoma - Google Patents
Marker composition for diagnosising uterine leiomyoma Download PDFInfo
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- KR101873486B1 KR101873486B1 KR1020150175029A KR20150175029A KR101873486B1 KR 101873486 B1 KR101873486 B1 KR 101873486B1 KR 1020150175029 A KR1020150175029 A KR 1020150175029A KR 20150175029 A KR20150175029 A KR 20150175029A KR 101873486 B1 KR101873486 B1 KR 101873486B1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57442—Specifically defined cancers of the uterus and endometrial
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/136—Screening for pharmacological compounds
Abstract
The present invention relates to a marker composition for diagnosing myoma of the uterine myometrium, which comprises an agent for detecting a GPER (G protein-coupled estrogen receptor 1, GPR 30) protein or a nucleic acid which regulates its expression, Provided marker compositions and the like.
Description
The present invention relates to a marker composition for diagnosing uterine myoma.
Leiomyoma is a very common disease in the gynecologic area. In many cases, there are no specific symptoms. Depending on its size and position, leiomyoma can cause various clinical symptoms such as infertility, vaginal bleeding, menorrhagia, abdominal mass, pelvic pain, It can exist as a single mass, but there are many cases.
If uterine leiomyoma is accompanied by pregnancy, it may be affected by hormones and may cause serious complications such as miscarriage, prematurity, placental abruption and postpartum hemorrhage. In addition, hemorrhagic infarction and pregnancy is often caused by pain.
The diagnosis of uterine leiomyoma is made by radiologic methods such as ultrasound, computed tomography, and physical examination. It is usually limited to uterine muscle such as subserous, intramural, and submucosal. And may protrude into the abdominal cavity or vagina due to its hardness.
The treatment of uterine leiomyoma is medication such as GnRH agonist, progesterone, danazol, etc. However, there is no effect on this, and when the size of the uterus due to severe dysmenorrhea, pelvic pain, dyspareunia, , When postmenopausal increases in size, and causes infertility and obstetric problems, surgical treatment is considered. Hysterectomy is the ultimate treatment for uterine myoma. However, if myomectomy is performed to preserve the uterus for pregnancy or psychological reasons, it is likely that myoma will recur. In addition, uterine artery embolization is a less invasive procedure than myomectomy or hysterectomy, but its clinical effect has not been well established. It is not recommended if you want to get pregnant.
Although uterine myoma is clinically very important, many studies have been conducted in relation to hormones, heredity, and growth factors. However, the precise mechanism and cause of the disease are still unknown.
There is a study that the uterine leiomyoma is caused by a single neoplasm like a cell located in the smooth muscle of the uterine muscle layer. It is also related to hormones, which increase in size when pregnant and decrease in secretion of hormones.
Adenomyosis is a disease in which endometriosis is located within the peritoneal cavity of the uterus but invasion of the endometrial line and epilepsy into the uterine muscle layer is considered to be associated with endometriosis. Therefore, it is affected by estrogen like endometriosis. Sometimes it is accompanied with uterine leiomyoma, endometriosis, etc, and it sometimes causes infertility, increase of lighter weight and pelvic pain.
If uterine squamous cell carcinoma is associated with pregnancy, uterine rupture, ectopic pregnancy, placenta previa and uterine relaxation may be induced. The uterine leiomyoma is encapsulated and relatively easy to distinguish from the normal uterine muscle layer, whereas the lesion of the uterine leiomyosus appears to be mixed in the uterine muscle layer and the uterus is generally bulging.
The diagnosis of uterine squamous cell carcinoma is presumed to be based on ultrasound images and clinical signs, but the diagnosis is based on histologic findings. Treatment is similar to the treatment of endometriosis, and depending on the symptoms, analgesics may be used. Like uterine myoma, medication and uterine artery embolization are the methods of treatment, but the ultimate treatment of uterine lesion is hysterectomy.
G-protein coupled receptor (GPCR) is a cell-surface protein that interacts with various hormones or neurotransmitters to regulate the biological response. Approximately 800 GPCRs are expressed in mammals It is known to exist.
GPCRs are activated by a variety of extracellular stimuli to mediate various cellular responses. GPCR activates intracellular signal transduction through the activation of intracellular G-protein (Heterotrimeric G-protein). The G-protein is activated by binding to GTP by its receptor and then converted to GDP Activated. Activated G-proteins then mediate down-signaling by inducing the activity of various signaling molecules in the cell.
G protein-coupled estrogen receptor 1 (GPER, GPR30) is a recently recognized functional membrane receptor that is involved in the non-genomic mechanism of estrogen. Was discovered by Owman.
It is an object of the present invention to provide a marker composition which distinguishes from normal uterine tissue and provides information for diagnosing uterine myoma. Another object of the present invention is to provide a method for screening a substance having an activity for preventing or treating uterine myoma by lowering the expression of a target protein of the marker composition.
In order to achieve the above object, a marker composition for diagnosing uterine leiomyoma according to an embodiment of the present invention includes an agent for detecting GPER (G protein-coupled estrogen receptor 1, GPR 30) protein or a nucleic acid that regulates its expression, Provides information for prediction or diagnosis of myoma.
The composition may detect the degree of expression of the GPER protein or a nucleic acid that controls its expression and provide information for predicting or diagnosing uterine myoma having the property of increasing GPER protein expression.
The kit for diagnosing uterine leiomyoma, which is another embodiment of the present invention, includes the marker composition for diagnosing uterine leiomyoma described above.
The kit may provide information for predicting or diagnosing uterine myoma by detecting the expression level of GPER (G protein-coupled estrogen receptor 1, GPR 30) protein or nucleic acid that regulates its expression from a biological sample.
In another embodiment of the present invention, there is provided a method for screening an active substance for preventing or treating uterine leiomyoma, comprising the steps of: screening uterine cells overexpressing GPER (G protein-coupled estrogen receptor 1, GPR 30) And determining whether the protein or nucleic acid is overexpressed in the test sample.
Hereinafter, the present invention will be described in more detail.
As used herein, the term " diagnosis " means identifying the presence or characteristic of a pathological condition. For the purpose of the present invention, the diagnosis is to confirm the onset of uterine myoma.
In the present invention, the term "diagnostic (bio) marker, (bio) marker or diagnostic marker" for diagnosing uterine leiomyoma is distinguished from non-uterine leiomyoma tissue, The levels of organic biomolecules such as polypeptides or nucleic acids (such as mRNA), lipids, glycolipids, glycoproteins, sugars (monosaccharides, disaccharides, oligosaccharides, etc.) Or an agent capable of measuring its level.
The term 'biological sample' in the present invention includes, but is not limited to, uterine muscle tissue, uterus derived cells, saliva, and samples such as menstrual blood, which show differences in gene or protein expression levels due to myomas.
G-protein coupled receptors (GPCRs) are activated by the binding of extracellular ligands outside the cell to produce various intracellular G-proteins (Gq / 11, Gs, Gi / / 13). Activated G-proteins transmit signals by inducing the activity of lower signaling molecules (Effector Molecules) such as phospholipase C-β, adenylate cyclase, phosphoinositide-3-kinase, Ras and Rho family G-protein.
It is known that estrogen binds to ERα and β nuclear estrogen receptors to transmit signals and react. On the other hand, estrogen signal transduction by the non-mammalian G protein-coupled estrogen receptor 1 (GPER, GPR30) is thought to be membrane-dependent and involves a relatively rapid signaling pathway involving a substance called G protein . G S protein-mediated signal transduction, increased cAMP production, increased EGF receptor due to increased epithelial growth factor (EGF), intracellular calcium mobilization, ERK1 / 2 activation, and Src activation.
The inventors of the present invention confirmed the expression level of GPER in the normal uterine myometrium, uterine uterine myometrium and adenomyosis of premenopausal women to predict the occurrence of uterine myoma or to utilize information for diagnosing uterine myoma And the present invention has been completed.
The marker composition for diagnosing uterine leiomyoma according to one embodiment of the present invention includes a composition for detecting GPCR (G protein-coupled estrogen receptor 1, GPR 30) protein or a nucleic acid that regulates its expression, Information.
The composition may detect the degree of expression of the GPER protein or a nucleic acid that controls its expression and provide information for predicting or diagnosing uterine myoma having the property of increasing GPER protein expression.
The biological sample to which the composition is applied may be a uterine cell, an uterine cell-containing secretion, a uterine tissue, and preferably a uterine smooth muscle tissue.
The agent for detecting the protein is one of methods for confirming the amount of the protein in the biological sample and preferably includes an antibody that specifically binds to the protein to confirm the expression amount of the protein. That is, the agent for detecting the protein may be, for example, an antibody that specifically binds to GPER protein.
The antibody refers to a specific protein molecule directed to an antigenic site. For purposes of the present invention, an antibody refers to an antibody that specifically binds to a marker protein, and includes a polyclonal antibody, a monoclonal antibody, and a recombinant antibody . As described above, since expression of GPER protein itself and its myoma is known, the production of an antibody using the GPER protein can be easily performed using a technique well known in the art. Polyclonal antibodies can be produced by methods well known in the art for obtaining sera containing antibodies by injection of the protein antigens into the animal and collection from the animal. Such polyclonal antibodies can be prepared from any animal species host, such as goats, rabbits, sheep, monkeys, horses, pigs, small dogs, and the like.
As an assay method for detecting the protein, an enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA), radioimmunodiffusion, Ouchterlony immunodiffusion, Immunohistochemistry Assay, Immunoprecipitation Assay, Complement Fixation Assay, Fluorescence Activated Cell Assay, Immunoassay Assay, Immunoassay Assay, Immunoprecipitation Assay, Complement Fixation Assay, Fluorescence Activated Cell Assay, Sorter, FACS, and protein chips.
The agent for detecting the nucleic acid may be a reagent capable of quantitatively detecting DNA or mRNA involved in overexpression of GPER protein, and may be measured using, for example, a primer or a probe for mRNA. RT-PCR, competitive RT-PCR, real-time RT-PCR, RNase protection assay (RPA) , Northern blotting, and DNA chips may be used.
The kit for diagnosing uterine myoma according to another embodiment of the present invention contains the marker composition for diagnosing uterine myoma. The description of the characteristics of the marker composition for diagnosing uterine leiomyoma, the detection agent contained therein, and the like are the same as those described above.
The kit may be, but is not limited to, an immunoassay kit.
The method for screening an active substance for preventing or treating uterine leiomyoma according to another embodiment of the present invention is a method for screening an active substance for uterine leiomyoma for screening for overexpressing GPER (G protein-coupled estrogen receptor 1, GPR 30) protein or a nucleic acid And screening for an active substance for preventing or treating uterine leiomyoma targeting GPER, comprising the step of confirming whether or not the cell inhibits overexpression of the protein or nucleic acid.
Specifically, the screening method comprises: a first step of preparing a screening cell overexpressing the GPER protein or a nucleic acid overexpressing the GPER protein; A second step of treating the screening cell or the nucleic acid with a substance that inhibits overexpression of GPER protein to produce a treatment group; And a third step of comparing the degree of protein expression of the treatment group with the degree of protein expression by a cell or gene including an untreated control group not treated with the second step, You can explore the material.
In this case, the screening cell may be a cell into which a gene encoding the overexpression of the GPER protein is introduced. Specifically, the cell may be an uterine muscle cell, an uterine stem cell, or the like.
The marker composition for diagnosing uterine leiomyoma of the present invention can easily distinguish normal uterine tissue from leiomyoma tissue to provide information for predicting or diagnosing uterine leiomyoma development. In addition, a method for screening a substance that regulates the expression of a protein targeted by the marker composition can be screened for a preventive or therapeutic agent for uterine myoma.
1 to 3 are photographs showing the expression of GPR 30 (G-protein coupled receptor 30) protein in a sample of uterine myoma using immunohistochemical staining in Example 1 of the present invention.
FIGS. 4 to 6 are photographs showing the expression of GPR 30 protein in a sample of uterine hepatic fibrosis tissue using immunohistochemical staining in Example 1 of the present invention, respectively. FIG.
FIGS. 7 and 8 are photographs showing the expression levels of GPR 30 protein in normal uterine tissue samples using immunohistochemical staining in Example 1 of the present invention, respectively.
FIG. 9 is a graph showing the results of representing the H score by quantifying the brown expressed area as a percentage by observing the staining results of the samples using immunohistochemical staining in the example of the present invention.
Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily carry out the present invention. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Like parts are designated with like reference numerals throughout the specification.
<Preparation of samples and clinical characteristics>
(N = 40), uterine leiomyoma (n = 20), uterine leiomyosarcoma (n = 20) and uterine leiomyosarcoma (N = 20), and the following experiment was carried out. The normal uterine tissue was separated from the uterine myomas by extraction of normal uterine myoma. However, if the patient is undergoing surgery for malignant disease, has received hormone therapy within the past year, currently undergoing hormone therapy, severe inflammation in the vagina during surgery, mothers undergoing hysterectomy, (N = 5), uterine leiomyoma (n = 7), uterine leiomyoma (n = 7), and uterine leiomyoma Three different tissues, adenomyosis (n = 3), were used for further experiments. The clinical characteristics of the tissue applied to the experiment are shown in Table 1 below.
(height, cm)
(weight, kg)
(BMI, kg / m 2 )
(n = 5)
(n = 7)
(n = 3)
\ Body mass index = weight (kg) / height (m) 2
Each tissue sample was excised with 1 cm 3 to produce a paraffin block, which was then used in the experiment.
< Example : Identification of G-protein coupled receptor 30 expression in each tissue>
Immunohistochemistry (IHC) experiments were performed after histological examination of the tissues by conventional hematoxylin & eosin method.
The patient's paraffin embedded tissues were cut to a thickness of 4 to 5 μm and immersed in xylene for 20 minutes, immersed in new xylene, deparaffinized, and dissolved in anhydrous alcohol, 100%, 100%, 100 %, 90%, 80% and 70% ethanol for five minutes each.
After treatment with 0.3% hydrogen peroxide-methanol for 10 minutes, the cells were washed with distilled water and then washed with 50 mM Tris buffer (TBS, pH 7.5) to remove the non-specific reaction , Treated with goat serum for 30 minutes and the excess solution was removed.
The primary antibody was incubated with anti-G-protein coupled receptor 30 antibody (ab39742; Cambridge, UK), and the primary antibody was allowed to react at room temperature for 10 minutes at 4 ° C overnight (about 16-18 hours).
After the primary antibody reaction, the cells were washed with TBS three times for 10 minutes, and then reacted with a biotin-conjugated secondary antibody (1: 300, Zymed Co.) for 1 hour and then stained with a conventional avidin-biotin complex method. At this time, ABC complex was used as a coloring agent and contrast dyeing proceeded with Mayer's hematoxylin.
The expression level of G-protein coupled receptor 30 antibody by immunohistochemistry was determined by visual inspection with an optical microscope (Olympus BX50) at 100, 200, and 400 times by a pathologist, The results of observation of the uterine leiomyosin samples are shown in Figs. 1 to 3, the results of observation of the uterine leiomyosin samples are shown in Figs. 4 to 6, and the results of observation of the normal uterine tissue samples are shown in Figs. 7 and 8 Respectively. The number of cells stained dark brown in the nucleus was counted and expressed as a percentage. Negative cases were judged to be negative if less than 10%, and positive cases when more than 10% were stained.
As shown in Table 2 below, the area without the expression area is 0 point (none), and 1 to 20% is 1 point (none), as shown in Table 2 below through H score, weak, 21-40% moderate, and 41% strong. The results are shown in FIG. 9.
Referring to the photographs of FIGS. 1 to 8 and the results of FIG. 9, it was confirmed that the amount of expression of GPER1 was increased in the case of the uterine myoma sample compared to the normal uterine tissue sample, because the portion of the uterine myoma sample was expressed in brown color. In addition, compared with normal uterine tissue samples, uterine squamous cell carcinoma samples were found to have many brown areas, and both uterine leiomyoma and uterine squamous cell carcinoma were controlled for estrogen, and the expression level of GPER1 was higher than that of normal tissues And to compare this with the amount of GPER1 expression in the normal uterine muscle layer, it can be used as a marker for new biomarkers or uterine leiomyoma prevention or treatment drug screening in uterine myoma.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, Of the right.
* The above experiment is Hanmi Pharm - Hanmi Pharm Co. LTD was supported in part.
Claims (3)
Wherein the composition detects the degree of expression of the GPER protein or a nucleic acid that regulates expression of the GPER protein to provide information for predicting or diagnosing uterine eosinophilia having the property of increasing GPER protein expression.
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| KR101873486B1 true KR101873486B1 (en) | 2018-07-03 |
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| KR102169346B1 (en) * | 2019-03-27 | 2020-10-23 | 덕성여자대학교 산학협력단 | Method for manufacturing xenograft animal model and method for predicting success of xenograft |
| RU2704817C1 (en) * | 2019-07-09 | 2019-10-31 | Федеральное государственное бюджетное учреждение "Ивановский научно-исследовательский институт материнства и детства имени В.Н. Городкова" Министерства здравоохранения Российской Федерации | Method for predicting uterine leiomyoma size increase |
| RU2704819C1 (en) * | 2019-07-09 | 2019-10-31 | Федеральное государственное бюджетное учреждение "Ивановский научно-исследовательский институт материнства и детства имени В.Н. Городкова" Министерства здравоохранения Российской Федерации | Method for predicting uterine leiomyoma size increase |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100190199A1 (en) | 2008-09-26 | 2010-07-29 | Rhode Island Hospital | Gpr30 estrogen receptor in breast and ovarian cancers |
| JP2012034633A (en) | 2010-08-06 | 2012-02-23 | Yamaguchi Univ | Method for determining estrogen-related disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100190199A1 (en) | 2008-09-26 | 2010-07-29 | Rhode Island Hospital | Gpr30 estrogen receptor in breast and ovarian cancers |
| JP2012034633A (en) | 2010-08-06 | 2012-02-23 | Yamaguchi Univ | Method for determining estrogen-related disease |
Non-Patent Citations (3)
| Title |
|---|
| Endocrine Research, (2013), 38(4), pp 223-231. |
| Fertility and Sterility, (2013), Vol. 99, No. 1, pp 256-263. |
| Reproductive Sciences, (2012), 19(7), pp 684-693. |
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