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WO2005001126A1 - Necessaire de detection du cancer gastrique et cancer gastrique metastatique - Google Patents

Necessaire de detection du cancer gastrique et cancer gastrique metastatique Download PDF

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Publication number
WO2005001126A1
WO2005001126A1 PCT/KR2004/000677 KR2004000677W WO2005001126A1 WO 2005001126 A1 WO2005001126 A1 WO 2005001126A1 KR 2004000677 W KR2004000677 W KR 2004000677W WO 2005001126 A1 WO2005001126 A1 WO 2005001126A1
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WIPO (PCT)
Prior art keywords
gastric cancer
genes
gastric
regulated
metastatic
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PCT/KR2004/000677
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English (en)
Inventor
Nam-Soon Kim
Yong Sung Kim
Ju-Yeon Lee
Jung-Hwa Oh
Hong-Seog Park
Hee-Young Ahn
Sun-Young Yoon
Yoonsoo Han
Sangsoo Kim
Jeong-Min Kim
Sang-Soon Byun
Seung-Moo Noh
Kyu-Sang Song
Hyang Sook Yoo
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Korea Research Institute Of Bioscience And Biotechnology
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Priority claimed from KR1020030038034A external-priority patent/KR100643046B1/ko
Priority claimed from KR1020030084001A external-priority patent/KR100588471B1/ko
Application filed by Korea Research Institute Of Bioscience And Biotechnology filed Critical Korea Research Institute Of Bioscience And Biotechnology
Priority to JP2006516902A priority Critical patent/JP2006526998A/ja
Publication of WO2005001126A1 publication Critical patent/WO2005001126A1/fr

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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407Specifically defined cancers
    • G01N33/57446Specifically defined cancers of stomach or intestine
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING 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
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886Nucleic 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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    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING 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
    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/112Disease subtyping, staging or classification
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING 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
    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/136Screening for pharmacological compounds
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING 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
    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/158Expression markers
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING 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
    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/16Primer sets for multiplex assays
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00Screening for compounds of potential therapeutic value

Definitions

  • the present invention relates to a detection kit for diagnosing gastric cancer and metastatic gastric cancer, more particularly to the diagnostic kit for detecting gastric cancer, which has been designed and developed for detecting the expression levels of the up-regulated and the down-regulated genes in gastric cancer to determine whether or not a given gastric sample is cancer; and to the diagnostic kit for detecting the metastatic gastric cancer, designed and developed for detecting the expression levels of the up-regulated and the down-regulated genes in the metastatic gastric cancer to diagnose whether the gastric cancer sample is metastatic cancer or not.
  • Gastric cancer is one of the leading causes of cancer death in East Asia, especially in Korea and Japan and the mortality due to the cancer has been ranked in the top among various diseases [Parkin et al, Int. J.
  • EGF epidermal growth factor
  • EGFR EGF- receptor
  • c-erbB-2 a well-known cell growth factor
  • the gastric cancer cell lines utilized in the present invention comprise 11 kinds of gastric cancer cell lines (SNU-1, SNU-5, SNU- 6, SNU-216, SNU-484, SNU- 520, SNU-601, SNU-620, SNU-638, SNU-668, SNU-719) kindly established by Park et al., and one cell line.(KMS5) established by Korean Research Institute of Bioscience and Biotechnology, in which the primary gastric cancer cell lines derived from primary tumor were SNU-1, SNU-484, SNU-520 and SNU-719, and the metastatic gastric cancer cell lines derived from malignant ascites after gastric cancer became malignant were SNU-5, SNU-16, SNU-601, SNU-620, SNU-638, SNU-668 [Park et al., Cancer Res.
  • gastric cancer used in the present invention are 30 gastric tissues (4 normal gastric tissues, 1 gastric cancer tissue, 4 pairs of normal/ gastric cancer tissues, 10 primary gastric cancer tissues and 7 metastatic gastric cancer tissues), which were provided by the College of Medicine, Chungnam National University (Korea). To date, studies to identify a few of genes showing specific expressions among SNU gastric cancer cell lines have been reported.
  • the inventors of the present invention selected out those genes which show similar changes of gene expression in the primary gastric cancer cell Tines, the metastatic cancer cell lines and the normal gastric tissues, respectively, and tested the for their potentials as markers for diagnosis of gastric cancer or metastatic gastric cancer.
  • EST expressed Sequence Tag
  • FKBPl A FK506 binding protein 1A
  • RPL4 ribosomal protein L4
  • ARF1 ADP-ribosylation factor 1
  • GTP-hinding protein effects as a heterotropic allosteric kinase of chlorella toxin catalytic subunits.
  • FTH1 (ferritin, heavy polypeptide 1) is an intracellular molecule which stores iron.
  • SH3GLB2 SH3- domain GRB2-like endophilin B2
  • HSPCA heat shock 90kDa protein 1, alpha
  • TMSB4X thymosin, beta 4, X chromosome
  • PYCR1 pyrroline-5-carboxylate reductase 1
  • ATF4 activating transcription factor 4
  • SURF4 surfeit 4
  • ACTB actin, beta
  • K-ALPHA-1 and keratin 8 participate in the formation of cell structure
  • LDHA lactate dehydrogenase A
  • GAPD glycoPD
  • PKM2 pyruvate kinase, muscle
  • PGK1 phosphoglycerate kinase 1
  • HMGIY high mobility group protein isoforms I and Y
  • JUN v-jun sarcoma virus 17 oncogene homolog (avian)
  • CD44 CD44 antigen
  • HSPA8 heat shock 70kDa protein 8
  • HSPCB heat shock 90kDa protein 1, beta
  • HSPB1 heat shock mechanism
  • EEF1A1 eukaryotic translation elongation factor 1 alpha 1 is a cof actor for protein synthesis in eukin
  • Syndecan 1 (SDC1) is known to be a heparan sulfate-bearing protoglycan and is related to human malignant tumors [Mastumoto et al., Int. J. Cancer 74: 482-91, 1997] including liver cancer [Mastumoto et al., Int. ⁇ . Cancer 74: 482-91, 1997], head and neck cancer [Inki et al., Br. J. Cancer 70: 319-323, 1994], colon cancer [Day et al., Virchows Arch. 434: 121-125, 1999], etc.
  • genes such as CD74 (invariant polypeptide of major histocompatibility complex), LOC131177 (FAM3D), AGR2 (anterior gradient 2 homolog, Xenopus laevis), IMAGE:4296901 (pepsinA), SNC73 and IGKC (immunoglobulin kappa constant) which are highly expressed in normal gastric tissues than gastric cancer cell lines.
  • CD74 invariant polypeptide of major histocompatibility complex
  • LOC131177 FAM3D
  • AGR2 anterior gradient 2 homolog, Xenopus laevis
  • IMAGE:4296901 pepsinA
  • SNC73 immunoglobulin kappa constant
  • JUN v-jun sarcoma virus 17 oncogene homolog (avian)
  • AP-1 a transcription factor
  • HMGIY high mobility group protein isoforms I and Y
  • HMGIY is a transcription factor involved in DNA binding, and abnormalities have been reported in the region of chromosome 6p21.3, at which this gene is located, in the case of benign mesenchymal tumors [Kazmierczak et al., Genes Chromosomes Cancer 23: 279-285, 1998].
  • HMGIY high mobility group protein isoforms I and Y
  • GSTP1 Glutathione S-transferase PI
  • GST Glutathione S-transferase enzymes involved in detoxification of various carcinogens
  • its level of expression is known to increase in various cancers such as lung cancer, gastric cancer, breast cancer, etc.
  • recent reports showed that the methylation of this gene would be deeply involved in carcinogenesis of gastric cancer [Howie et al., Carcinogenesis 11: 451-458, 1990; Kang et al., Lab. Investigation 83: 635-641, 2003].
  • LMNA Lact A/C gene
  • ESRRA Estrogen-related receptor alpha gene encodes a protein for the membrane receptor of estrogen, an important hormone for human reproduction and osteogenesis, and the protein is known essential in estrogen signal transduction [Giguere, Trends Endocrinol. Metab. 13: 220-225, 2002].
  • ESRRA Estrogen-related receptor alpha
  • PLK Poly-like kinase
  • IGFBP3 insulin-like growth factor binding protein 3
  • IGF Insulin-like growth factor
  • the aforementioned genes are those whose level of expression increases in cell lines derived from the malignant ascites where the metastasis of gastric cancer was progressed than in the primary gastric cancer cell lines. Numerous studies have been conducted to prove the relevance of these genes to cancers, however, these studies have been rarely focused on identifying their functional relationship to gastric cancer and its metastasis. Besides, the inventors of the present invention also selected those genes whose level of expression is reduced in the metastatic gastric cancer progresses in order to use them as markers for diagnosis of metastasis of gastric cancer.
  • the genes are down-regulated in metastatic gastric cancer compared to the primary gastric cancer cell lines/ tissues.
  • FKBPIA FK506 binding protein 1A
  • TMSB4X thymosin, beta 4, X chromosome
  • PKM2 pyruvate kinase, muscle
  • GAPD glycolaldehyde-3-phosphate dehydrogenase
  • KRT8 (Keratin 8) is known as a binding protein which is related to cell migration and invasion [Martens et al., Cancer 87: 87-92, 1999; Sakakura et al., Bri. J. Cancer 87: 1153-1161, 2002]. However, its gene was identified as a low level expression gene in metastatic gastric cancer until now.
  • PTMA prothymosin-alpha
  • PTMA is a nuclear protein involved in mitosis whose expression is regulated by c-myc transcriptional factor but there is no relation between its gene and gastric cancer or metastatic gastric cancer [Szabo et al, Hum. Genet. 90: 629-634, 1993; Haggerty et al., Proc. Natl.
  • ATP5A1 ATP synthase alpha subunit
  • CALM2 calmodulin 2
  • NET1 neuroepithelial cell transforming gene 1
  • the invention provides a method and a kit for diagnosis of gastric cancer based on the predetermined expression level of at least one gastric cancer-related gene selected from a group consisting of EEFA1A, TUBA6, FKBPIA, PKM2, LDHA, RPL4, ARF1, SURF4, KRT8, GAPD, HSPCB, PGK1, HMGIY, K-ALPHA-1, FTH1, HSPA8, SH3GLB2, ACTB, HSPCA, TMSB4X, SDCl, PYCRl, ATF4, JUN, CD44, HSPBl, IGKC, SNC73, CD74, LOC131177 (FAM3D), AGR2 and IMAGE:4296901 (pepsinA).
  • EEFA1A TUBA6, FKBPIA, PKM2, LDHA, RPL4, ARF1, SURF4, KRT8, GAPD, HSPCB, PGK1, HMGIY, K-ALPHA-1, FTH1, HSPA
  • the invention also provides a method and a kit ior diagnosis of the metastatic gastric cancer based on the predetermined expression level of at least one metastatic gastric cancer- related gene selected from a group consisting of GADD45B, JUN, HMGIY, GSTP1, LMNA, ESRRA, PLK, CD44, IGFBP3, PKM2, FKBPIA, KRT8, TMSB4X, GAPD, ATP5A1, PTMA, CALM2 and NET1.
  • a metastatic gastric cancer- related gene selected from a group consisting of GADD45B, JUN, HMGIY, GSTP1, LMNA, ESRRA, PLK, CD44, IGFBP3, PKM2, FKBPIA, KRT8, TMSB4X, GAPD, ATP5A1, PTMA, CALM2 and NET1.
  • the kit for diagnosis of gastric cancer comprises: a sense primer and an anti-sense primer of at least one gene selected from a group consisting of EEFA1A, TUBA6, FKBPIA, PKM2, LDHA, RPL4, ARF1, SURF4, KRT8, GAPD, HSPCB, PGK1, HMGIY, K-ALPHA-1, FTH1, HSPA8, SH3GLB2, ACTB, HSPCA, TMSB4X, SDCl, PYCRl, ATF4, JUN, CD44, HSPBl and a mixture thereof, wherein the above genes are up-regulated in gastric cancers compared to the normal gastric tissues; and a sense primer and an anti-sense primer of at least one gene selected irom a group consisting of IGKC, SNC73, CD74, LOC131177 (FAM3D), AGR2, IMAGE:4296901 (pepsinA) and a mixture thereof, wherein the above genes are up-regulated in gastric cancer
  • the kit for diagnosis oi gastric cancer comprises: a probe corresponding to at least one gene selected from a group consisting of EEFA1A, TUBA6, FKBPIA, PKM2, LDHA, RPL4, ARF1, SURF4, KRT8, GAPD, HSPCB, PGK1, HMGIY, K- ALPHA-1, FTH1, HSPA8, SH3GLB2, ACTB, HSPCA, TMSB4X, SDCl, PYCRl, ATF4, JUN, CD44, HSPBl and a mixture thereof, wherein the above genes are up-regulated in gastric cancers compared to the normal gastric tissues; and a probe corresponding to at least one gene selected from a group consisting of IGKC, SNC73, CD74, LOC131177 (FAM3D), AGR2, IMAGE:4296901 (pepsinA) and a mixture thereof, wherein the above genes are down-regulated in
  • the kit for diagnosis of gastric cancer comprises: an antibody that recognizes the protein encoded by at least one gene selected from a group consisting of EEFA1A, TUBA6, FKBPIA, PKM2, LDHA, RPL4, ARF1, SURF4, KRT8, GAPD, HSPCB, PGK1, HMGIY, K-ALPHA-1, FTH1, HSPA8, SH3GLB2, ACTB,
  • HSPCA HSPCA, TMSB4X, SDCl, PYCRl, ATF4, JUN, CD44, HSPBl and a mixture thereof, wherein the above genes are up-regulated in gastric cancers compared to the normal gastric tissues; and an antibody that recognizes the protein encoded by at least one gene selected from a group consisting of IGKC, SNC73, CD74, LOC131177 (FAM3D), AGR2, IMAGE:4296901 (pepsinA) and a mixture thereof, wherein the above genes are down-regulated in gastric cancers compared to the normal gastric tissues.
  • the kit for diagnosis of metastatic gastric cancer comprises: a sense primer and an anti-sense primer of at least one gene selected from a group consisting of GADD45B, JUN, HMGIY, GSTP1, LMNA, ESRRA, PLK, CD44 and IGFBP3 and a mixture thereof, wherein the above genes are up-regulated in metastatic gastric cancers compared to the primary gastric cancers; and a sense primer and an anti-sense primer of at least one gene selected from a group consisting of PKM2, FKBPIA, KRT8, TMSB4X, GAPD, ATP5A1, PTMA, CALM2 and NET1 and a mixture thereof, wherein the above genes are down-regulated in metastatic gastric cancers compared to the primary gastric cancers.
  • the kit for diagnosis of gastric cancer comprises: a probe corresponding to at least one gene selected irom. a group consisting of GADD45B, JUN, HMGIY, GSTP1, LMNA, ESRRA, PLK, CD44 and IGFBP3 and a mixture thereof, wherein the above genes are up-regulated in metastatic gastric cancers compared to the primary gastric cancers; and a probe corresponding to at least one gene selected from a group consisting of PKM2, FKBPIA, KRT8, TMSB4X, GAPD, ATP5A1, PTMA, CALM2 and NET1 and a mixture thereof, wherein the above are down-regulated in metastatic gastric cancers compared to the primary gastric cancers.
  • the kit for diagnosis of metastatic gastric cancer comprises: an antibody that recognizes the protein encoded by at least one gene selected from a group consisting of GADD45B, JUN, HMGIY, GSTP1, LMNA, ESRRA, PLK, CD44 and IGFBP3, wherein the above genes are up-regulated in metastatic gastric cancers compared to the primary gastric cancers; and an antibody that recognizes the protein encoded by at least one gene selected from a group consisting of PKM2, FKBPIA, KRT8, TMSB4X, GAPD, ATP5A1, PTMA, CALM2 and NET1, wherein the above genes are down-regulated in metastatic gastric cancers compared to the primary gastric cancers.
  • the present invention provides 32 marker genes for diagnosing gastric cancer, consisting of 26 up-regulated genes in gastric cancers, and 6 down-regulated genes in gastric cancers.
  • the present invention also provides 18 marker genes for diagnosing metastatic gastric cancer, consisting of 9 up-regulated genes in metastatic gastric cancers, and 9 down-regulated genes in metastatic gastric cancers.
  • the marker genes for gastric cancer according to the present invention comprise full-length and/ or fragments of up-regulated or down-regulated genes in gastric cancers.
  • the marker genes for metastatic gastric cancer according to the present invention comprise full-length and/ or fragments of up-regulated or down-regulated genes in metastatic gastric cancers.
  • the information for nucleotide sequence of gastric cancer marker genes is provided in the io ⁇ lowing Table 1, and the nucleotide sequence information of marker genes for metastatic gastric cancer is provided in the following Table 2.
  • 19 cDNA libraries were constructed from 14 gastric cancer cell lines (SNU5, SNU668, SNU16, SNU484, SNU1[3 strains], SNU620, SNU719, SNU638, SNU601, SNU216, SNU520, KMS5), 1 gastric cancer tissue (T665307) and 4 normal gastric tissues (K402, N258215, JM669761, N665307); nucleotide sequences of about 65,209 EST from these cDNA libraries were determined, and EST frequencies for the specific genes from a gastric cancer pool (gastric cancer cell lines + gastric cancer tissues) and a normal gastric pool (normal gastric tissues) were analyzed; and 26 genes (EEFA1A, TUBA6, FKBPIA, PKM2, LDHA, RPL4, ARF1, SURF4, KRT8, GAPD, HSPCB, PGK1, HMGIY, K-ALPHA-1, FTH1, HSPA8, SH3GLB2, ACTB, H
  • the candidate genes that may be involved with cancer progression and 6 strains of genes (IGKC, SNC73, CD74, LOC131177 (FAM3D), AGR2, IMAGE:4296901 (pepsinA)) which are down-regulated in the cancer pool, i.e. the candidate genes that may be associated with suppression of gastric cancer, were finally selected as marker genes for gastric cancer.
  • 12 cDNA libraries constructed from 6 primary gastric cancer cell lines (SNU1[3 strains], SNU484, SNU719, SNU520) and 6 metastatic gastric cancer cell lines derived from malignant ascites (SNU5, SNU668, SNU16, SNU620, SNU638, SNU601) were selected; about 39,315 ESTs were sequenced from the selected libraries; the EST frequency for the specific genes from primary gastric cancer cell lines (primary pool) and the metastatic cancer cell lines derived from malignant ascites (ascites pool) were analyzed; and 9 genes (GADD45B, JUN, HMGIY, GSTPl, LMNA, ESRRA, PLK, CD44, IGFBP3) which are up-regulated in the ascites pool, and 9 genes (PKM2, FKBPIA, KRT8, TMSB4X, GAPD, ATP5A1, PTMA, CALM2, NET1) which are down- regulated in
  • gastric cancer can be diagnosed based on the expression level of gastric cancer-related genes such as EEFA1A, TUBA6, FKBPIA, PKM2, LDHA, RPL4, ARFl, SURF4, KRT8, GAPD, HSPCB, PGKl, HMGIY, K-ALPHA-1, FTH1, HSPA8, SH3GLB2, ACTB, HSPCA, TMSB4X, SDCl, PYCRl, ATF4, JUN, CD44, HSPBl, IGKC, SNC73, CD74, LOC131177 (FAM3D), AGR2, IMAGE:4296901 (pepsinA), and also metastatic gastric cancer can be diagnosed by measuring the expression level of metastatic gastric cancer-related genes such as GADD45B, JUN, HMGIY, GSTPl, LMNA, ESRRA, PLK, CD44, IGFBP3, PKM2, FKBPIA, KRT8, TMSB4X, GAPD
  • the present invention also provides a method for diagnosing gastric cancer by measuring the expression levels of the gastric cancer-related genes, which comprises the steps of: (a) measuring the expression levels of RNA or protein of at least one gene selected from up-regulated genes in gastric cancers consisting of EEFA1A, TUBA6, FKBPIA, PKM2, LDHA, RPL4, ARFl, SURF4, KRT8, GAPD, HSPCB, PGKl, HMGIY, K-ALPHA-1, FTH1, HSPA8, SH3GLB2, ACTB, HSPCA, TMSB4X, SDCl, PYCRl, ATF4, JUN, CD44, HSPBl and/ or their mixture in tested gastric cancer tissues.
  • RNA or protein of at least one gene selected from up-regulated genes in gastric cancers consisting of EEFA1A, TUBA6, FKBPIA, PKM2, LDHA, RPU, ARFl, SURF4, KRT8, GAPD, HSPCB, PGKl, HMGIY, K-ALPHA-1, FTH1, HSPA8, SH3GLB2, ACTB, HSPCA, TMSB4X, SDCl, PYCRl, ATF4, JUN, CD44, HSPBl and/ or their mixture in tested normal tissues; (c) measuring the expression levels of RNA or protein of at least one gene selected from down-regulated genes in gastric cancers consisting of IGKC, SNC73, CD74, LOC131177 (FAM3D), AGR2, IMAGE:4296901 (pepsin A) and/ or their mixture in tested gastric cancer tissues; (d) measuring the expression levels of RNA or protein of at least one gene selected from down-regulated genes in gastric cancers consisting of
  • the present invention also provides a method for diagnosing metastatic gastric cancer by measuring the expression levels of the metastatic gastric cancer- related genes, which comprises the steps of : (a) measuring the expression levels of RNA or protein of at least one gene selected from up-regulated genes in metastatic gastric cancers consisting of
  • the expression levels of the marker genes of gastric cancer and metastatic gastric cancer can be measured by the known method using a sense primer and an anti-sense primer having nucleotide sequences complementary to the marker genes or the fragments thereof.
  • the expressed amounts of the genes are measured by real-time RT-PCR and competitive RT-PCR.
  • Such primers should include a partial sequence of DNA region encoding the protein from the marker genes, and the primer is a DNA fragment with a size greater than 15 bp in length.
  • the primers listed in Table 5 to Table 7 can be used in the present invention.
  • gastric cancer and metastatic gastric cancer marker genes can be measured by the known hybridization methods using the fragments of marker genes as probes. For example, Northern hybridization ["Molecular Cloning - A Laboratory Manual “Cold Spring Habor Laboratory, NY, Maniatis, T.
  • the probes has 200 ⁇ 1000bp containing nucleotide sequences of selected 32 marker genes in general, preferably 400 ⁇ 800bp.
  • the nucleotide sequences may only have the homology of at least 70% to the nucleotide sequences of gastric cancer and metastatic gastric cancer marker genes.
  • the probes of gastric cancer and metastatic gastric cancer marker genes according to the present invention can be produced by the common process, such as PCR method using the sense primer and anti-sense primer of gastric cancer marker genes and metastatic gastric cancer marker genes. Further, the expression level of gastric cancer and metastatic gastric cancer marker genes according to the present invention can be determined by measuring the amount of protein encoded by each gene. In the above process, the protein can be quantified by the common processes, such as ELISA and immunoprecipitation method, using an antibody which specifically binds to the protein oi gastric cancer and metastatic gastric cancer marker genes.
  • the antibodies corresponding to the up-regulated genes and the down- regulated genes in gastric cancers or metastatic gastric cancers can be produced by cloning the genes into the expression vector using the common processes, harvesting the proteins encoded by the marker gene, and obtaining the antibodies from those proteins using the common method.
  • the present invention includes the peptide fragments derived from the above proteins, and the peptide fragments of the invention comprise at least 7 amino acids, preferably at least 9 amino acids, more preferably at least 12 amino acids.
  • the antibody of the invention is not limited to specific antibody type and may include the polyclonal antibodies [Current protocols in Molecular Biology edit. Ausubel et al. (1987) Publish.
  • the antibody according to the present invention also includes special antibody such as a humanized antibody [Methods in Enzymology 203, 99-121 (1991)], etc. Thirty-two gastric cancer marker genes or their proteins may be used alone or in combination for diagnosing gastric cancer, and 18 of metastatic gastric cancer marker genes or the proteins may also be used alone or in combination for diagnosing metastatic gastric cancer.
  • the kit for . diagnosing gastric cancer or metastatic gastric cancer includes the reagents for isolating RNA or poly(A)+RNA, in addition to the sense and anti-sense primers or probes of marker genes specific to the gastric cancer and metastatic gastric cancer, and may also include a solid supporter for the above marker genes when the expression level is measured by microarray.
  • 32 gastric cancer marker genes may possibly be the activating genes or suppressing genes of gastric cancer
  • the compounds having low molecular weight which binds to the proteins encoded by the above marker genes may be the candidate compounds inhibiting or promoting the function of target proteins encoded by these marker genes, and may also be used as a drug, such as anticancer drugs, therapeutic agents, etc.
  • the compounds having low molecular weight which binds to the proteins encoded by the above marker genes may be the candidate compounds inhibiting or promoting the function of target proteins encoded by these marker genes, and may also be used as a drug, such as antimetastatic cancer drugs, therapeutic agents, etc.
  • the methods to screen these compounds include various known methods, such as a method of fixing each protein encoded by 32 gastric cancer marker genes or 18 metastatic gastric cancer marker genes onto the affinity column and purifying the proteins by contacting with the samples for screening [Pandya et al., Virus Res 87: 135-143, 2002], a method using two-hybrid system [Fields, S and Song, O., Nature 340: 245-246, 1989], Western blotting analysis ["Molecular Cloning - A Laboratory Manual” Cold Spring Harbor Laboratory, NY, Maniatis, T. et al. (1982) section 18.30- 18.74], high throughput screening [Aviezer et al., / Biomol Screen 6: 171-7, 2001], etc.
  • the tested samples may include, but not limited to cell extracts, expression products from gene libraries, synthesized compounds with low molecular weight, synthesized peptides, natural compounds, etc.
  • Fig.l depicts a result oi analyzing the EST frequency for selecting gastric cancer-related genes, according to the present invention.
  • Fig. 2 depicts a result of analyzing the EST frequency for selecting metastatic gastric cancer-related genes, according to the present invention.
  • Fig. 3 shows the expression levels of the up-regulated genes and down- regulated genes in gastric cancers by using real time RT-PCR in various gastric samples, [from (a) to (n) represent the up-regulated genes; and from (o) to (q) represent down-regulated genes.
  • X-axis represents various samples, in which S14, S17, S18, S19 indicate the normal gastric tissues; SI, S2, S3, S5, S6, S7, S8, S9, S10, S12, S13, S21 indicate gastric cancer cell lines; and S20 indicates a gastric cancer tissue.
  • Y-axis represents the expression level of a target gene in various samples, in which the expression levels of the up-regulated genes were indicated as a rate against the average expression levels in normal gastric tissues; and the expression levels of the down-regulated genes were indicated as a rate against the average of expression levels in gastric cancer cell lines and gastric cancer tissues. Expression level of each gene was calculated relative to the amount of B2M expressed in each sample].
  • FIG. 4 depicts the expression levels of the up-regulated genes and down- regulated genes in gastric cancers by using competitive RT-PCR in various gastric samples, [from (a) to (1) represent the up-regulated genes; and from (m) to (o) represent the down-regulated genes.
  • X-axis represents the various samples, in which S14, S18, S19 indicate the normal gastric tissues; SI, S2, S3, S5, S6, S7, S8, S9, S10, S12, S13, S21 indicate gastric cancer cell lines; and S20 indicates a gastric cancer tissue.
  • Y-axis represents the expression level of a target gene in various samples, in which the expression levels of the up-regulated genes were indicated as a rate against the average of expression levels in the normal gastric tissues; and the expression levels of the down-regulated genes were indicated as a rate against the average oi expression levels in gastric cancer cell lines and gastric cancer tissues. Expression level of each gene was calculated relative to the amount of B2M expressed in each sample].
  • Fig. 5 depicts the expression levels of the up-regulated genes and down-regulated genes in the metastatic gastric cancers by using competitive RT-PCR in various gastric samples, [from (a) to (i) represent the up-regulated genes; and from (j) to (r) represent the down-regulated genes.
  • X-axis represents the various samples, in which S10, S5, S7, S21 indicate the primary gastric cancer cell lines; SI, S2, S3, S6, S8, S9 indicate the metastatic gastric cancer cell lines.
  • Y-axis represents the expression level of a target gene in various samples, in which the expression levels of up- regulated genes were indicated as a rate against the average of expression levels in the primary gastric cancer cell lines; and the expression levels of down-regulated genes were indicated as a rate against the average of expression levels in the metastatic gastric cancer cell lines. Expression level of each gene was calculated relative to the amount of B2M expressed in each sample].
  • Fig. 6 depicts the expression levels of the up-regulated genes and down-regulated genes in gastric cancers by using competitive RT-PCR in patient samples with gastric cancer, [from (a) to (d) represent the up-regulated genes; and from (e) to (h) represent the down-regulated genes.
  • X-axis represents the tested samples taken from 4 patients suffering gastric cancer, in which Nl, N2, N3, N4 indicate the normal gastric tissues; Tl, T2, T3, T4 indicate gastric cancer tissues.
  • Y-axis represents the expression level of a target gene in patient tissues, which expression level of each gene was calculated relative to the amount of B2M expressed in each sample].
  • FIG. 7 depicts the expression levels of the up-regulated genes and down-regulated genes in metastatic gastric cancers by using competitive RT-PCR in patient samples with metastatic gastric cancer, [from (a) to (d) represent the up-regulated genes; and from (e) to (h) represent the down-regulated genes.
  • X-axis represents the patient samples taken from 10 patients suffering the primary gastric cancer and 7 patients suffering the metastatic gastric cancer, in which El, E2, E3, E4, E5, E6, E7, E8, E9, E10 indicate the primary gastric cancer tissues; and Al, A2, A3, A4, A5, A6, A7 indicate the metastatic gastric cancer tissues.
  • Y-axis represents the expression level of a target gene in the patient samples, which expression level of each gene was calculated relative to the amount of B2M expressed in each sample].
  • Example 1 Isolation of total RNA from gastric cancer cell lines, gastric cancer tissues and normal gastric tissues
  • Gastric cancer cell lines, SNU5, SNU668, SNU16, SNU1, SNU484, SNU620, SNU719, SNU638, SNU601, SNU216, SNU520 (Korean Cell Line Bank, http://cellbank.snu.ac.kr) and KMS5 (the Korea Research Institute of Bioscience and Biotechnology (KRIBB)) were cultured in RPMI culture media containing 10% FBS; and 1 sample of gastric cancer tissue (T665307) and 4 samples of normal gastric tissues, K402, N258215, N669761, N665307 (The College of Medicine, Chungnam National University, Korea) were obtained from the tissues removed by surgery and stored in liquid nitrogen until it is used for analysis.
  • KRIBB Korean Cell Line Bank
  • RNAs were isolated from cells and tissues by using QIAGEN kit (RNeasy Maxi kit: cat#75162). First, the adherent cells were recovered using trypsin-EDTA solution and then dissolved in 15ml of RLT buffer in the kit where 150 ⁇ i of ⁇ -Mercaptoethanol was added. Meanwhile, about lg of tissue was taken, dissolved in 15ml of RLT buffer solution in the kit where 150 ⁇ l of ⁇ - Mercaptoethanol was added, and crushed using a homogenizer. The sample solution was centrifuged at 3000g for 10 min to separate the supernatant, to which 15 ml of 70% EtOH was added and homogeneously mixed, and was centrifuged at 3000g for 5 min to attach total RNAs to the membrane. After washing twice, 1.2ml oi RNase-f ree water was added, and total RNAs were eluted.
  • Example 2 Screening of the up-regulated genes and the down-regulated genes in gastric cancer and metastatic gastric cancer by analysis of EST frequency.
  • the present inventors constructed various cDNA libraries from gastric cancer cell lines including the primary gastric cancer cell lines and the metastatic gastric cancer cell lines, a gastric cancer tissue and normal gastric tissues, randomly selected the cDNA clones from these cDNA libraries, sequenced these cDNAs and selected the up-regulated genes and the down-regulated genes in gastric cancer or metastatic gastric cancer by analysis of EST frequency.
  • RNAs from each sample obtained in Example 1 was treated with 3U of BAP (Bacterial alkaline Phosphatase, TakaRa) enzyme in the BAP enzyme reaction solution (lOOmM Tris-HCl (pH 7.0), 2mM DTT, 80U Rnasin (promega)), and then was reacted with 1000U of TAP (tobacco acid pyrophosphatase) enzyme in the TAP (Waco) enzyme reaction solution (50mM sodium acetate (pH 5.5), ImM EDTA, 2mM DTT, 80U Rnasin (promega)). Then, a reaction between 40 pmole of oligonucleotides (SEQ No. 1) and 250U RNA ligase
  • Tumor Tissue T665307 S20T665307 3371 1274 Total 65209 19762 a Number of clones and clusters in NCBI UniGene build #151 contributed by our EST sequence.
  • 6 cDNA libraries of primary gastric cancer cell lines and 6 cDNA libraries of metastatic gastric cancer cell lines are as seen from the following Table 4.
  • cDNA clones were picked from constructed cDNA libraries and cultured on LB agar medium which contains ampicillin (100 # g/ml).
  • the plasmids DNA of cultured clones were isolated by using a MWG 96 well plasmid prep-system (MWG Biotech), and sequencing reactions of the cDNAs were performed using automatic sequencer ABI 3700 (PE Applied Biosy stems).
  • the individual ESTs were searched against the human mRNA subset extracted from the GenBank database and then against the UniGene database (Hs.seq.all, build#151) for similarity comparisons using BLASTN.
  • Fig. 1 26 up-regulated genes and 6 down-regulated genes in gastric cancer were selected as gastric cancer marker genes (Fig. 1). Further, 9 up-regulated genes, and 9 down-regulated genes in metastatic gastric cancer were selected as metastatic gastric cancer marker genes (Fig. 2).
  • Example 3 Analysis of expression level of selected marker genes by RT-PCR Each expression level of gastric cancer-related genes and metastatic gastric cancer-related genes were quantitatively analyzed by RT-PCR.
  • the cDNA synthesis was completed by reacting on the 70 ° C heating block for 15 min.
  • ⁇ -2-microglobulin was used as a standard gene for the quantitative analysis of marker genes. That is, 1.2 ⁇ g of B2M DNA, was diluted to 1/10, 1/100, 1/1000 and 1/10000, respectively, and then 2 ⁇ i of each diluted solutions was used as templates of the real-time PCR as aforementioned. The standard graph for the amount of B2M was calculated from the amplified B2M products. Based on the standard data, the amount of marker genes in gastric samples was quantitatively analyzed by the PCR products of marker genes. In PCR reaction of B2M, 5'- ⁇ rimer (SEQ No. 39) and 3'- ⁇ rimer (SEQ No. 40) were used as primers, respectively. These primers were designed based on the nucleotide sequence in the protein coding region of the gene.
  • the genes EEFA1A, FKBPIA, PKM2, LDHA, KRT8, GAPD, HSPCB, PGKl, K-ALPHA-1, FTH1, HSPA8, ACTB, HSPCA, HSPBl were shown to be potential and efficient carcinogenic markers of gastric cancer.
  • the genes of IGKC, SNC73, IMAGE:4296901 (pepsinA) were also shown to be potential and efficient suppressing markers of gastric cancer.
  • B2M gene was used as a standard gene for the quantitative analysis of the marker genes.
  • a competitor DNA for B2M which have same priming parts with the B2M of standard genes but have different size of PCR products, are used in competitive RT- PCR.
  • B2M competitor DNA was prepared by performing PCR in 50 i of reaction buffer containing 3 / d oi pCNS vector, DNA (2ng), 10 / of 5x PCR premix (Bioneer), I ⁇ i of 5'-primer (20pmole: SEQ No.
  • B2M competitor DNA was diluted to 7/108, 1/107, 3/107, 7/107, 1/106 and 3/106 via 6 steps, each 2 ⁇ i oi dilutions were mixed with 1 st cDNA (an amount corresponding to lOng of RNA used for reverse transcription) of Example 3-(l), and a competitive RT-PCR for 6 samples was performed in 20 ⁇ i oi reaction solutions containing ⁇ i of 5X Taq DNA polymerase, 2 ⁇ i of B2M primers (5 ⁇ mole/ / ⁇ ) (SEQ No. 39 and 40), S ⁇ i of distilled water.
  • PCR The condition for PCR was 94 ° C (40sec), 55 ° C (lmin), 72 °C (lmin) and conducted for 25 cycles. 3 ⁇ l of PCR products were loaded on 3% agarose gel, were separated at 100 V for 30min., and then were taken image files by using FrogTM apparatus (Gel Image
  • the concentration having the similar sensitivity between two bands (322bp in B2M competitor DNA, 390b ⁇ in the original B2M genes) was selected, and quantitatively analyzed to correct the concentrations oi each sample.
  • the marker genes were amplified by PCR reaction containing 1st cDNA of the sample corrected according to (a) as template.
  • the sense- and antisense-primers for gastric cancer-related marker genes were showed in Table 6, and the sense- and antisense-primers for metastatic gastric cancer related marker genes were showed in Table 7.
  • the PCR condition was 94 ° C (lmin), 55 °C (30sec), 72 "C (lmin) and conducted for 25 cycles.
  • the primers for the genes in Table 6 and Table 7 were designed in the protein encoding region, and the size of each primer was 17 ⁇ 20bp and GC contents were about 50 ⁇ 70% (CoreBiosystem, Korea).
  • the composition oi PCR reaction mixture is as follows. cDNA 5 ⁇ i
  • IGFBP3 SEQ No.: 83 SEQ No.: 84
  • up-regulated genes such as TMSB4X, RPL4, TUBA6, HMGIY, ATF4, JUN, SDCl, ARFl, PYCRl, SURF4, SH3GLB2, CD44 are shown to be potential and efficient carcinogenic markers of gastric cancer, and the 3 genes such as CD74, AGR2, LOC131177 (FAM3D) are shown to be potential and efficient suppressing markers of gastric cancer. Further, as shown in Fig.
  • 9 up-regulated genes in the metastatic gastric cancer such as GADD45B, JUN, HMGIY, GSTPl, LMNA, ESRRA, PLK, CD44, IGFBP3 and 9 down- regulated genes in the metastatic gastric cancer, such as PKM2, FKBPIA, KRT8, TMSB4X, GAPD, ATP5A1, PTMA, CALM2, NET1 are shown to be able to be useful markers of the metastatic gastric cancer.
  • Example 4 Diagnosis for Gastric Cancer or Metastatic Gastric Cancer by Quantitative analysis of up- or down-regulated genes in Gastric Cancer or by Quantitative analysis of up- or down-regulated genes in Metastatic Gastric Cancer in Patient Samples
  • the expression levels for gastric cancer-related marker genes were identified in the 4 pairs of patient samples (376454, 663593, 668217, 670500) which consist of test tissues/ normal tissues (Tl ⁇ T4 and Nl ⁇ N4, respectively) taken from 4 patients with gastric cancer from the College of Medicine, Chungnam National University (Korea).
  • the expression levels of the genes which comprise JUN, GSTPl, LMNA, CD44 genes randomly selected by up-regulated genes in metastatic gastric cancer and PKM2, FKBPIA, GAPD, ATP5A1 genes randomly selected by down- regulated genes in metastatic gastric cancer, were identified in the patient samples, which were directly taken from 10 patients (E1HE10) suffering the primary gastric cancer and 7 patients (A1 ⁇ A7) suffering the metastatic gastric cancer from the College of Medicine, Chungnam National University (Korea).
  • RNAs Isolation of total RNAs and Reaction of Reverse Transcriptase Total RNAs were isolated by the same method as Example 1, and a reaction of reverse transcription was performed using 5 ⁇ g oi total RNA at 42 "C for 60 min to produce 8 kinds of 1st cDNA from the patient samples of gastric cancer and 17 of 1st cDNA from the patient samples of the metastatic gastric cancer. Then, cDNA construction was completed by the reaction on the heating block at 70 ° C for 15min.
  • the used primers are as seen from Table 5 and Table 6.
  • an electrophoresis was performed, for all PCR solution, on 2% agarose gel at 100 V for 30 min, and PCR products were quantitatively analyzed using TotalLab vl.O program (NonLinear Dynamix Ltd.) as described in 3)-a) of Example 3.
  • TotalLab vl.O program NonLinear Dynamix Ltd.
  • the amount of competitive RT-PCR products of up-regulated genes such as FKBPIA, LDHA, HSPCB, and TUBA6, in gastric cancer was higher in most tested cancer tissues than those of normal tissues collected from the same patient, and the amount of competitive RT-PCR products of down- regulated genes, such as SNC73, IGKC, LOC131177 (FAM3D), and CD74, in gastric cancer was low in most tested cancer tissues than those of normal tissues.
  • Four tested tissues (T1XT4) were diagnosed to be gastric cancer, and such result meets the result of clinical test for gastric cancer according to prior art (Tl; gastric cancer stage IV; T2: gastric cancer stage IDA; T3 and T4: gastric cancer stage II).
  • the PCR condition was 94 °C (30sec), 55 ° C (lmin), 72 °C (lmin) and was conducted for 25 cycles.
  • the used primers are as seen from Table 7.
  • an electrophoresis was performed, for all PCR solution, on 2% agarose gel at 100V for 30 min, and PCR products were quantitatively analyzed using TotalLab vl.O program (NonLinear Dynamix Ltd.) as described in 3)-a) of Example 3.
  • TotalLab vl.O program NonLinear Dynamix Ltd.
  • the present invention provides 6 down-regulated genes and 26 up-regulated genes in gastric cancer compared to the normal gastric tissues, as the marker of tumor very available for diagnosis of gastric cancer, which marker can perform the quantification sensitively and quickly in the tissues of patients. Further, the present invention provides 9 low-regulated genes and 9 high- regulated genes in the metastatic gastric cancer compared to the primary gastric cancers, as the marker very available for diagnosis for the metastasis of malignant gastric cancer, which marker can perform the quantification sensitively and quickly in the tissues of patients to diagnose metastatic gastric cancer.

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Abstract

L'invention concerne un nécessaire destiné à diagnostiquer un cancer gastrique et un cancer gastrique métastatique, notamment un nécessaire de diagnostic destiné à détecter un cancer gastrique, conçu et développer de manière à détecter des niveaux d'expression du gène régulé à la hausse ou à la baisse dans le cancer gastrique afin de déterminer si l'échantillon gastrique testé est un cancer gastrique ou non. L'invention concerne également un nécessaire de diagnostic destiné à détecter le cancer gastrique métastatique, conçu et développé de manière à détecter l'expression de niveaux de gène régulé à la hausse et à la baisse dans un cancer gastrique métastatique afin de diagnostiquer si l'échantillon de cancer gastrique testé est un cancer métastatique ou non.
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CN102844435A (zh) * 2010-02-22 2012-12-26 库尔纳公司 通过抑制吡咯啉-5-羧酸还原酶1(pycr1)的天然反义转录物而治疗pycr1相关疾病
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WO2011108626A1 (fr) 2010-03-03 2011-09-09 東レ株式会社 Marqueur de cancer gastrique et méthode de détection de cancer gastrique
WO2011108628A1 (fr) 2010-03-03 2011-09-09 東レ株式会社 Marqueur de cancer gastrique et procédé de détection de cancer gastrique
US10648035B2 (en) 2012-11-26 2020-05-12 The Johns Hopkins University Methods and compositions for diagnosing and treating gastric cancer
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CN103884812A (zh) * 2014-03-26 2014-06-25 昆山洛丹伦生物科技有限公司 一种电子元器件塑料部件中多氯化萘的检测方法
WO2016181979A1 (fr) * 2015-05-13 2016-11-17 国立大学法人名古屋大学 Procédé d'utilisation des niveaux d'expression de syt7, mfsd4, et etnk2 pour détecter des métastases de cancer gastrique dans le foie, kit de détection, procédé de criblage d'agents thérapeutiques ciblés moléculaires, et composition pharmaceutique
CN106093429A (zh) * 2016-06-02 2016-11-09 滨州医学院 一种检测胃癌组织的试剂盒
CN108728539A (zh) * 2018-06-05 2018-11-02 浙江大学 一种HoxD10基因在胃癌中的应用
CN113466457A (zh) * 2020-03-30 2021-10-01 韩国原子力医学院 用于预测由微塑料暴露诱发的癌恶性病变预后的生物标志物组合
CN112522412A (zh) * 2020-12-30 2021-03-19 北京泱深生物信息技术有限公司 检测生物标志物的试剂、产品及其在疾病中的应用
CN113265462A (zh) * 2020-12-30 2021-08-17 北京泱深生物信息技术有限公司 与胃癌相关的基因及其应用
CN113278694A (zh) * 2020-12-30 2021-08-20 北京泱深生物信息技术有限公司 一种以生物标志物作为检测靶标的产品及其应用
CN116516008A (zh) * 2023-05-04 2023-08-01 中国中医科学院望京医院(中国中医科学院骨伤科研究所) 胃粘膜肠上皮化生标志物jun及其应用
CN116516008B (zh) * 2023-05-04 2024-05-07 中国中医科学院望京医院(中国中医科学院骨伤科研究所) 胃粘膜肠上皮化生标志物jun及其应用

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