WO2017034173A1 - Composition de biomarqueur permettant de diagnostiquer des métastases cancéreuses contenant awp1 - Google Patents

Composition de biomarqueur permettant de diagnostiquer des métastases cancéreuses contenant awp1 Download PDF

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Publication number
WO2017034173A1
WO2017034173A1 PCT/KR2016/008612 KR2016008612W WO2017034173A1 WO 2017034173 A1 WO2017034173 A1 WO 2017034173A1 KR 2016008612 W KR2016008612 W KR 2016008612W WO 2017034173 A1 WO2017034173 A1 WO 2017034173A1
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awp1
cancer
protein
gene
metastasis
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PCT/KR2016/008612
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English (en)
Korean (ko)
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장은주
이은진
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울산대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to a biomarker composition for diagnosing cancer metastasis comprising AWP1.
  • cancer The smallest unit of the human body, the cell, normally divides, grows and dies by intracellular control and maintains cell balance. If a cell is damaged for some reason, it is treated and recovered to act as a normal cell, but if it is not recovered, it dies on its own.
  • cancer is defined as a condition in which abnormal cells, which are not controlled for such proliferation and suppression, proliferate excessively, invade surrounding tissues and organs, and cause mass formation and destruction of normal tissues for various reasons. Cancer is the proliferation of non-suppressive cells, which destroys the structure and function of normal cells and organs, so the diagnosis and treatment are of great importance.
  • AWP1 is known to be a regulator involved in NF-kB signaling in combination with Tumor necrosis factor receptor-associated factor 2 (TRAF2).
  • NF-kB signaling is an important signaling system of cancer metastasis, and it has been reported that various NF-kB signaling regulators influence cancer cell metastasis.
  • the present invention is a biomarker composition for diagnosing cancer metastasis comprising the AWP1 gene or a protein encoded by the gene, a method for diagnosing cancer metastasis using the same, a pharmaceutical composition for preventing or treating cancer metastasis comprising an AWP1 protein expression promoter or activator as an active ingredient. And to provide a method for screening cancer metastasis therapeutic agent by measuring the AWP1 protein expression level.
  • the present invention provides a biomarker composition for diagnosing cancer metastasis comprising the AWP1 gene or a protein encoded by the gene.
  • the present invention also provides a kit for diagnosing cancer metastasis comprising a primer or probe specifically binding to the AWP1 gene, an antibody, peptide, aptamer or compound specifically binding to a protein encoded by the gene.
  • the present invention also provides a method of providing information necessary for diagnosing cancer metastasis by measuring the expression level of AWP1 protein.
  • the present invention also provides a pharmaceutical composition for preventing or treating cancer metastasis, comprising an AWP1 protein, an AWP1 protein expression promoter or an activator as an active ingredient.
  • the present invention also provides a method for screening a cancer metastasis agent by measuring the expression level of AWP1 protein.
  • the present invention relates to a biomarker composition for diagnosing cancer metastasis including AWP1, and it can be used as a clinical indicator for cancer metastasis by confirming that the expression of AWP1 is reduced in well-metastatic cancers compared to non-metastatic cancers.
  • the inhibition of AWP1 expression using siRNA increased cancer growth and metastasis.
  • overexpression of AWP1 suppressed cancer growth and migration, it was found that AWP1 could be used as a cancer metastasis inhibitor. have.
  • Figure 1 shows the change in cancer cells after knocking down the expression level of AWP1 and AWP1 in the mouse breast cancer cell line E0771.
  • FIG. 2 shows the expression levels of AWP1, proliferation assay and wound healing assay in human breast cancer cell lines.
  • Figure 3 shows the change in cancer cells after knocking down AWP1 in MCF7 cell line with a high expression of AWP1.
  • Figure 4 shows the results of over-expressing AWP1 in MDA-MB-231 cell line with relatively low expression of AWP1 and reaffirming its effect.
  • 5 shows miRNA selection results that regulate expression at AWP1 protein levels in breast cancer cell lines.
  • FIG. 6 shows the results for expression, cell proliferation and cell migration of AWP1 in prostate cancer cell lines.
  • FIG. 7 shows the overexpression effect of AWP1 on Epithelial Mesemchymal Transition (EMT) in PC3 cells.
  • the present invention provides a biomarker composition for diagnosing cancer metastasis comprising the AWP1 gene or a protein encoded by the gene.
  • the cancer may be breast cancer or prostate cancer, but is not limited thereto.
  • ABP1 gene or protein encoded by the gene of the present invention is NCBI accession no. NM019006 may be, but is not limited thereto.
  • ADP1 of the present invention may be named "ZFAND6 (Zinc Finger, AN1-type Domain 6)".
  • diagnosis refers to determining the susceptibility of an object to a particular disease or condition, determining whether an object currently has a particular disease or condition, or as long as a person has a particular disease or condition. Determining the prognosis of the object, or therametrics (eg, monitoring the condition of the object to provide information about treatment efficacy).
  • the present invention also provides a kit for diagnosing cancer metastasis comprising a primer or probe specifically binding to the AWP1 gene, an antibody, peptide, aptamer or compound specifically binding to a protein encoded by the gene.
  • the cancer may be breast cancer or prostate cancer, but is not limited thereto.
  • primer refers to a nucleic acid sequence having a short free 3-terminal hydroxyl group, which is capable of forming base pairs with complementary templates and acting as a starting point for template strand copying. Refers to the sequence. Primers can initiate DNA synthesis in the presence of four different nucleoside triphosphates and reagents for polymerization (ie, DNA polymerase or reverse transcriptase) at appropriate buffers and temperatures. PCR conditions, sense and antisense primer lengths may be appropriately selected according to techniques known in the art.
  • probe refers to a nucleic acid fragment such as RNA or DNA, which is short to several bases to hundreds of bases capable of specifically binding other than mRNA, and is labeled so that the presence or absence of a specific mRNA is expressed. You can check the amount.
  • the probe may be manufactured in the form of an oligonucleotide probe, a single strand DNA probe, a double strand DNA probe, an RNA probe, or the like. Selection of appropriate probes and hybridization conditions may be appropriately selected according to techniques known in the art.
  • the term “antibody” refers to a specific immunoglobulin directed to an antigenic site as is known in the art.
  • the antibody in the present invention means an antibody that specifically binds to AWP1 of the present invention, and the antibody can be prepared according to conventional methods in the art. Forms of such antibodies include polyclonal antibodies or monoclonal antibodies, including all immunoglobulin antibodies.
  • the antibody means a complete form having two full length light chains and two full length heavy chains.
  • the said antibody also contains special antibodies, such as a humanized antibody.
  • the kit of the present invention is an antibody that specifically binds to a marker component, a secondary antibody conjugate conjugated with a label that is developed by reaction with a substrate, a color substrate solution to be reacted with the label, a washing solution, and an enzyme. It may include a reaction stop solution and the like, and may be prepared in a number of separate packaging or compartments containing the reagent components used.
  • the term "peptide” has the advantage of high binding power to the target material, and no degeneration occurs even during thermal / chemical treatment.
  • the small size of the molecule can be used as a fusion protein by attaching to other proteins. Specifically, since it can be used by attaching to a polymer protein chain, it can be used as a diagnostic kit and drug delivery material.
  • aptamer refers to a particular kind of single-stranded nucleic acid (DNA, RNA or modified nucleic acid) that has a stable tertiary structure and which is capable of binding with high affinity and specificity to a target molecule. It means a kind of polynucleotide consisting of). As described above, aptamers are composed of polynucleotides that can bind specifically to antigenic substances like antibodies, but are more stable than proteins, simple in structure, and easy to synthesize. Can be.
  • the cancer may be breast cancer or prostate cancer, but is not limited thereto.
  • the method of measuring the mRNA expression level is RT-PCR, competitive RT-PCR (Real-time RT-PCR), RNase protection assay (RPA; RNase protection assay ), Northern blotting and DNA chips are used, but are not limited to these.
  • the method of measuring the protein expression level is Western blot, ELISA (enzyme linked immunosorbent asay), radioimmunoassay (RIA), radioimmunodiffusion, Ouchterlony immunodiffusion method, Rocket immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation assay, FACS and protein chips are used, but are not limited thereto.
  • patient sample refers to tissues, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid, or urine that differ from the control group in the expression level of the AWP1 gene or protein, which is a biomarker for diagnosing cancer metastasis. Samples include, but are not limited to.
  • the present invention also provides a pharmaceutical composition for preventing or treating cancer metastasis, comprising an AWP1 protein, an AWP1 protein expression promoter or an activator as an active ingredient.
  • the cancer may be breast cancer or prostate cancer, but is not limited thereto.
  • the AWP1 protein expression promoter or activator may be a compound, a peptide, an aptamer or an antibody that specifically binds to the AWP1 protein, but is not limited thereto.
  • the AWP1 protein may be regulated by miRNA181b, but is not limited thereto.
  • the pharmaceutical composition of the present invention may include chemicals, nucleotides, antisenses, siRNA oligonucleotides, and natural extracts as active ingredients.
  • the pharmaceutical compositions or complex preparations of the present invention may be prepared using pharmaceutically acceptable and physiologically acceptable auxiliaries in addition to the active ingredients, which may include excipients, disintegrants, sweeteners, binders, coatings, swelling agents, lubricants. Solubilizers such as lubricants and flavoring agents can be used.
  • the pharmaceutical composition of the present invention may be preferably formulated into a pharmaceutical composition including one or more pharmaceutically acceptable carriers in addition to the active ingredient for administration.
  • Acceptable pharmaceutical carriers in compositions formulated in liquid solutions are sterile and physiologically compatible, including saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • compositions of the present invention may be granules, powders, coated tablets, tablets, capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and sustained release formulations of the active compounds, and the like.
  • the pharmaceutical compositions of the present invention may be administered in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, sternum, transdermal, nasal, inhalation, topical, rectal, oral, intraocular or intradermal routes.
  • An effective amount of the active ingredient of the pharmaceutical composition of the present invention means an amount required to prevent or treat a disease.
  • the type of disease the severity of the disease, the type and amount of the active and other ingredients contained in the composition, the type of formulation and the age, weight, general health, sex and diet, sex and diet, time of administration, route of administration and composition of the patient. It can be adjusted according to various factors including the rate of secretion, the duration of treatment, and the drug used concurrently.
  • the composition of the present invention is administered once or several times a day, when the compound is 0.1ng / kg to 10g / kg, a polypeptide,
  • 0.1ng / kg ⁇ 10g / kg antisense nucleotides, siRNA, shRNAi, miRNA can be administered at a dose of 0.01ng / kg ⁇ 10g / kg.
  • the present invention (1) contacting the test substance to cancer cells; (2) measuring the expression or activity of AWP1 protein in cancer cells in contact with the test substance; And (3) selecting a test substance having an increased expression or activity level of the AWP1 protein compared to the control sample.
  • test material refers to an unknown candidate used in screening to examine whether it affects the expression level of a gene or affects the expression or activity of a protein. do.
  • the sample includes, but is not limited to, chemicals, nucleotides, antisense-RNAs, small interference RNAs (siRNAs), and natural extracts.
  • sequences of the primers are as follows: AWP1 5'- CCA AGT GCC TAT GCT TTG TTC CA-3 '(sense) (SEQ ID NO: 1) and 5'- ACA GAG GTT GCA GGT GGG CTT AT-3' (antisense) ( SEQ ID NO: 2); Vimentin 5'- CCG CAC ATT CGA GCA AAG AC-3 '(sense) (SEQ ID NO: 3) and 5'- CCT GCT GTC CCG CCG-3' (antisense) (SEQ ID NO: 4); SMA 5'- CTT GTC CAG GAG TTC CGC TC-3 '(sense) (SEQ ID NO: 5) and 5'- ACG CTG GAG GAC TTG CTT TT-3' (antisense) (SEQ ID NO: 6); MMP9 5'- TCT ATG GTC CTC GCC CTG AA-3 '(sense) (SEQ ID NO: 7) and 5'-CAT CGT CCA
  • Quantitative real-time RT-PCR is a manufacturer's instruction using the Power SYBR Green 1-Step Kit and an ABI 7000 Real Time PCR System (Applied Biosystems, Carlsbad, CA, USA). It was performed according to.
  • the amplification protocol consisted of an initial reverse transcription step of 48 ° C., 30 minutes, denaturation step 95 ° C., 15 seconds, 40 times and a linkage and extension step 60 ° C., 1 minute.
  • the results are expressed as the ratio of target PCR product to GAPDH product. Values were normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) levels. Quantification was performed using the ⁇ CT method (Applied Biosystems) with RQ manager 1.2 software. Data are expressed as mean ⁇ standard deviation. All samples were repeated three times for each experiment.
  • siRNA small interfering RNA
  • SMARTpool ON-TARGET plus Human AWP1
  • negative control siRNA of siRNA against AWP1 a combination of four siRNA oligonucleotide sequences selected, were purchased from Thermo Scientific Dharmacon (Lafayette, Co., USA).
  • Cancer cells eg. MDA-MB-231, MCF7, PC3, DU-145
  • RNAiMAX Invitrogen, Carlsbad, Calif.
  • Silence efficiency was measured by RT-PCR.
  • Cells were transfected with miRNAs using RNAiMAX and transfected myc-tagged AWP1 overexpression vector with lipofectamine 2000 (Invitrogen, Carlsbad, Calif.).
  • Cells were seeded on 96 plates for CCK-8 analysis (Dojindo Molecular Technologies Inc, Japan) and then transfected with SiRNAs or myc-tagged AWP1 overexpressing constructs. Cultures were maintained at 37 ° C. for 24 or 48 hours. At the indicated times, cell growth was measured according to the manufacturer's instructions via a CCK-8 colorimetric assay. All analyzes were repeated three or more times. 10 ⁇ l cell counting kit-8 was added to each well, and the plates were incubated for additional 1-4 hours at 37 ° C. The absorbance of each aliquot at 450 nm was measured using a microplate reader.
  • AWP1 silencing experiments cells were transfected with negative controls or AWP1 siRNA and scraped off the cell layer. Cells were stained with CellTracker Green (CMFDA) (Invitrogen) according to the manufacturer's instructions, and wound healing was measured using fluorescence microscopy (LSM700, Carl Zeiss). The percentage of filled wound area was measured using Adobe Photoshop 9.0.2 software and compared with baseline measurements. Wound healing was measured as a percentage of the wound confluence compared to the negative control. Each experiment was repeated three times.
  • CMFDA CellTracker Green
  • LSM700 Carl Zeiss
  • Protein supernatants collected from cells were boiled in 5 ⁇ SDS sample buffer, cell lysates were separated on 10-12% SDS-PAGE gels and transferred to polyvinylidene difluoride membrane (Bio-Rad, Hercules, CA). .
  • Membrane was washed for 1 hour using 5% I-block solution dissolved in Tris-buffered saline (20 mM Tris / HCl, pH 7.6, 150 mM NaCl, and 0.1% Triton X-100) to rule out unspecific protein binding. After blocking, the reaction was stirred gently at 4 ° C. overnight with an appropriate primary antibody. After reacting with the HRP-conjugated secondary antibody for 1 hour at room temperature, immunoreactivity was detected using an enhanced chemiluminescence solution (Milli-pore, Billerica, MA).
  • an enhanced chemiluminescence solution Milli-pore, Billerica, MA.
  • AWP1 AWP1 knockdown mice
  • FIG. 1A E0771, a mouse breast cancer cell line
  • FIG. 1B E0771 knocked down AWP1 was injected with mouse mammary-fat-pad to observe cancer cell progression and metastasis. Mice were observed for about 25 days after injection, and their weight and tumor size were measured. The AWP1 knockdown mouse group did not show any significant difference in weight and tumor size when compared to the control group (FIGS. 1C and 1D).
  • FIG. 3A MCW7 cell lines with relatively high expression of AWP1 knocked down AWP1 and observed the effect.
  • Wound healing analysis showed that wound healing was faster in the AWP1 knockdown group compared to the control group (FIG. 3B) and the statistical values were displayed (FIG. 3C). It was observed that no effect on the viability of the MCF7 cell line by AWP1 knockdown (FIG. 3D). Therefore, it was confirmed that cancer cell migration may be increased by knockdown of AWP1.
  • AWP1 overexpressing AWP1 in MDA-MB-231 cell line with relatively low expression of AWP1.
  • RT-PCR observed an increase in AWP1 mRNA (FIG. 4A), and Western blot also confirmed that protein levels were increased (FIG. 4B). It was observed that AWP1 overexpression did not affect viability in the MDA-MB-231 cell line (FIG. 4C).
  • overexpression of AWP1 reduced wound closure (FIGS. 4D and 4E) and reduced cancer metastasis or EMT-related markers (FIG. 4F). Therefore, it was confirmed that overexpression of AWP1 may inhibit cancer cell migration and cancer metastasis or EMT-related markers.
  • the present invention revealed that the protein level of AWP1 is critically involved in cancer metastasis, and that the protein level of AWP1 is regulated by miRNA181b.
  • AWP1 has a function related to cancer metastasis in prostate cancer cells.
  • AWP1 in human prostate cancer cell lines was confirmed by GEO profile. It was confirmed that the expression of AWP1 was significantly inhibited in PC3 cell line compared to DU-145 (FIG. 6A). As a result of RT-PCR and Western blot, the expression of AWP1 in PC3 cell line was lower than that of DU-145 as in GEO profile (FIGS. 6B and 6C). Proliferation assay showed that PC3 cells grow relatively faster than DU-145 (FIG. 6D), and wound healing assay also showed the ability of PC3 cells to move compared to DU-145. (migration ability) was also confirmed to be high (Figs. 6E and 6F). Therefore, PC3 cells with relatively low expression of AWP1 were found to have rapid proliferation or migration.
  • FIG. 9A the effect of knocking down AWP1 in the DU-145 cell line where AWP1 expression was relatively high was observed.
  • AWP1 knockdown was observed to have no effect on the viability of the DU-145 cell line (FIG. 9B).
  • Wound healing assay (Wound closure) of the AWP1 knockdown group compared to the control group (wound closure) can be observed faster (Fig. 9C), the statistical value was displayed (Fig. 9D).
  • EMT Epithelial Mesemchymal Transition
  • FIG. 9E Epithelial Mesemchymal Transition

Abstract

L'invention concerne un composition de biomarqueur permettant de diagnostiquer des métastases cancéreuses contenant AWP1, la composition étant utilisable comme indicateur clinique de métastases cancéreuses par identification d'une diminution de l'expression de AWP1 dans des cancers facilement métastasés par comparaison à des cancers non métastasés. En outre, il est établi que la croissance tumorale et les métastases augmentent lorsque l'expression de AWP1, avec utilisation d'un ARNsi, est inhibée et que, lorsque AWP1 est surexprimé, la métastase cancéreuse est inhibée par réduction de la croissance cancéreuse et de la migration.
PCT/KR2016/008612 2015-08-27 2016-08-04 Composition de biomarqueur permettant de diagnostiquer des métastases cancéreuses contenant awp1 WO2017034173A1 (fr)

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KR1020150120878A KR101821455B1 (ko) 2015-08-27 2015-08-27 Awp1을 포함하는 암 전이 진단용 바이오마커 조성물

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CN112384806A (zh) 2018-08-03 2021-02-19 西托根有限公司 癌症的骨转移诊断用组成物及包括其的试剂盒

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