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Volumn 133, Issue 8, 2013, Pages 1803-1812

Knockout of the tetraspanin Cd9 in the TRAMP model of de novo prostate cancer increases spontaneous metastases in an organ-specific manner

Author keywords

cancer; CD9; metastasis; prostate; tetraspanin

Indexed keywords

TETRASPANIN;

EID: 84881551872     PISSN: 00207136     EISSN: 10970215     Source Type: Journal    
DOI: 10.1002/ijc.28204     Document Type: Article
Times cited : (19)

References (51)
  • 2
    • 80054686286 scopus 로고    scopus 로고
    • Tumor metastasis: Molecular insights and evolving paradigms
    • Valastyan S, Weinberg Robert A,. Tumor metastasis: molecular insights and evolving paradigms. Cell 2011; 147: 275-92.
    • (2011) Cell , vol.147 , pp. 275-292
    • Valastyan, S.1    Weinberg Robert, A.2
  • 3
    • 28444441957 scopus 로고    scopus 로고
    • Tetraspanin functions and associated microdomains
    • Hemler ME,. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 2005; 6: 801-11.
    • (2005) Nat Rev Mol Cell Biol , vol.6 , pp. 801-811
    • Hemler, M.E.1
  • 4
    • 57749169272 scopus 로고    scopus 로고
    • Tetraspanins: Push and pull in suppressing and promoting metastasis
    • Zoller M,. Tetraspanins: push and pull in suppressing and promoting metastasis. Nat Rev Cancer 2009; 9: 40-55.
    • (2009) Nat Rev Cancer , vol.9 , pp. 40-55
    • Zoller, M.1
  • 6
    • 0030975429 scopus 로고    scopus 로고
    • Localization of the transmembrane 4 superfamily (TM4SF) member PETA-3 (CD151) in normal human tissues: Comparison with CD9, CD63, and alpha5 beta1 integrin
    • Sincock PM, Mayrhofer G, Ashman LK,. Localization of the transmembrane 4 superfamily (TM4SF) member PETA-3 (CD151) in normal human tissues: comparison with CD9, CD63, and alpha5 beta1 integrin. J Histochem Cytochem 1997; 45: 515-26.
    • (1997) J Histochem Cytochem , vol.45 , pp. 515-526
    • Sincock, P.M.1    Mayrhofer, G.2    Ashman, L.K.3
  • 8
    • 34247886067 scopus 로고    scopus 로고
    • Down-regulation of CD9 expression during prostate carcinoma progression is associated with CD9 mRNA modifications
    • Wang J-C, Begin LR, Berube NG, et al. Down-regulation of CD9 expression during prostate carcinoma progression is associated with CD9 mRNA modifications. Clin Cancer Res 2007; 13: 2354-61.
    • (2007) Clin Cancer Res , vol.13 , pp. 2354-2361
    • Wang, J.-C.1    Begin, L.R.2    Berube, N.G.3
  • 9
    • 24944543203 scopus 로고    scopus 로고
    • Androgens induce CD-9 in human prostate tissue
    • Chuan Y, Pang S, Bergh A, et al. Androgens induce CD-9 in human prostate tissue. Int J Androl 2005; 28: 291-6.
    • (2005) Int J Androl , vol.28 , pp. 291-296
    • Chuan, Y.1    Pang, S.2    Bergh, A.3
  • 10
    • 0029876559 scopus 로고    scopus 로고
    • Motility related protein-1 (MRP-1/CD9) reduction as a factor of poor prognosis in breast cancer
    • Miyake M, Nakano K, Itoi S, et al. Motility related protein-1 (MRP-1/CD9) reduction as a factor of poor prognosis in breast cancer. Cancer Res 1996; 56: 1244-9.
    • (1996) Cancer Res , vol.56 , pp. 1244-1249
    • Miyake, M.1    Nakano, K.2    Itoi, S.3
  • 11
    • 0029087933 scopus 로고
    • Motility related protein 1 (MRP-1/CD9) expression: Inverse correlation with metastases in breast cancer
    • Miyake M, Nakano K, Ieki Y, et al. Motility related protein 1 (MRP-1/CD9) expression: inverse correlation with metastases in breast cancer. Cancer Res 1995; 55: 4127-31.
    • (1995) Cancer Res , vol.55 , pp. 4127-4131
    • Miyake, M.1    Nakano, K.2    Ieki, Y.3
  • 12
    • 0030972183 scopus 로고    scopus 로고
    • Immunohistochemically detected expression of motility-related protein-1 (MRP-1/CD9) in lung adenocarcinoma and its relation to prognosis
    • Higashiyama M, Doi O, Kodama K, et al. Immunohistochemically detected expression of motility-related protein-1 (MRP-1/CD9) in lung adenocarcinoma and its relation to prognosis. Int J Cancer 1997; 74: 205-11.
    • (1997) Int J Cancer , vol.74 , pp. 205-211
    • Higashiyama, M.1    Doi, O.2    Kodama, K.3
  • 13
    • 0028803507 scopus 로고
    • Reduced motility related protein-1 (MRP-1/CD9) gene expression as a factor of poor prognosis in non-small cell lung cancer
    • Higashiyama M, Taki T, Ieki Y, et al. Reduced motility related protein-1 (MRP-1/CD9) gene expression as a factor of poor prognosis in non-small cell lung cancer. Cancer Res 1995; 55: 6040-4.
    • (1995) Cancer Res , vol.55 , pp. 6040-6044
    • Higashiyama, M.1    Taki, T.2    Ieki, Y.3
  • 14
    • 0030834148 scopus 로고    scopus 로고
    • Differential display cloning identifies motility-related protein (MRP1/CD9) as highly expressed in primary compared to metastatic human colon carcinoma cells
    • Cajot J, Sordat I, Silvestre T, et al. Differential display cloning identifies motility-related protein (MRP1/CD9) as highly expressed in primary compared to metastatic human colon carcinoma cells. Cancer Res 1997; 57: 2593-7.
    • (1997) Cancer Res , vol.57 , pp. 2593-2597
    • Cajot, J.1    Sordat, I.2    Silvestre, T.3
  • 15
    • 0036462439 scopus 로고    scopus 로고
    • Integrin a3 expression as a prognostic factor in colon cancer: Association with MRP-1/CD9 and KAI1/CD82
    • Hashida H, Takabayashi A, Tokuhara T, et al. Integrin a3 expression as a prognostic factor in colon cancer:association with MRP-1/CD9 and KAI1/CD82. Int J Cancer 2002; 97: 518-25.
    • (2002) Int J Cancer , vol.97 , pp. 518-525
    • Hashida, H.1    Takabayashi, A.2    Tokuhara, T.3
  • 16
    • 0031748466 scopus 로고    scopus 로고
    • Motility related protein 1 (MRP1/CD9) expression in colon cancer
    • Mori M, Mimori K, Shiraishi T, et al. Motility related protein 1 (MRP1/CD9) expression in colon cancer. Clin Cancer Res 1998; 4: 1507-10.
    • (1998) Clin Cancer Res , vol.4 , pp. 1507-1510
    • Mori, M.1    Mimori, K.2    Shiraishi, T.3
  • 17
    • 0035139331 scopus 로고    scopus 로고
    • Reduced expression of CD9 in oral squamous cell carcinoma: CD9 expression inversely related to high prevalence of lymph node metastasis
    • Kusukawa J, Ryu F, Kameyama T, et al. Reduced expression of CD9 in oral squamous cell carcinoma: CD9 expression inversely related to high prevalence of lymph node metastasis. J Oral Pathol Med 2001; 30: 73-9.
    • (2001) J Oral Pathol Med , vol.30 , pp. 73-79
    • Kusukawa, J.1    Ryu, F.2    Kameyama, T.3
  • 18
    • 1342280438 scopus 로고    scopus 로고
    • Motility-related protein-1 (MRP-1/CD9) expression can predict disease-free survival in patients with squamous cell carcinoma of the head and neck
    • Mhawech P, Dulguerov P, Tschanz E, et al. Motility-related protein-1 (MRP-1/CD9) expression can predict disease-free survival in patients with squamous cell carcinoma of the head and neck. Br J Cancer 2004; 90: 471-5.
    • (2004) Br J Cancer , vol.90 , pp. 471-475
    • Mhawech, P.1    Dulguerov, P.2    Tschanz, E.3
  • 19
    • 0141815835 scopus 로고    scopus 로고
    • Motility-related protein-1/CD9 expression in head and neck squamous cell carcinoma
    • Erovic BM, Pammer J, Hollemann D, et al. Motility-related protein-1/CD9 expression in head and neck squamous cell carcinoma. Head Neck 2003; 25: 848-57.
    • (2003) Head Neck , vol.25 , pp. 848-857
    • Erovic, B.M.1    Pammer, J.2    Hollemann, D.3
  • 20
    • 0141889277 scopus 로고    scopus 로고
    • Motility-related protein 1 (MRP-1/CD9) expression in urothelial bladder carcinoma and its relation to tumor recurrence and progression
    • Mhawech P, Herrmann F, Coassin M, et al. Motility-related protein 1 (MRP-1/CD9) expression in urothelial bladder carcinoma and its relation to tumor recurrence and progression. Cancer 2003; 98: 1649-57.
    • (2003) Cancer , vol.98 , pp. 1649-1657
    • Mhawech, P.1    Herrmann, F.2    Coassin, M.3
  • 21
    • 49649122294 scopus 로고    scopus 로고
    • Epigenetic silencing of the tetraspanin CD9 during disease progression in multiple myeloma cells and correlation with survival
    • De, et al
    • De, Bruyne E, Bos TJ, Asosingh K, et al. Epigenetic silencing of the tetraspanin CD9 during disease progression in multiple myeloma cells and correlation with survival. Clin Cancer Res 2008; 14: 2918-26.
    • (2008) Clin Cancer Res , vol.14 , pp. 2918-2926
    • Bruyne, E.1    Bos, T.J.2    Asosingh, K.3
  • 22
    • 84861215687 scopus 로고    scopus 로고
    • Expression levels of HMGA2 and CD9 and its clinicopathological significances in the benign and malignant lesions of the gallbladder
    • Zou Q, Xiong L, Yang Z, et al. Expression levels of HMGA2 and CD9 and its clinicopathological significances in the benign and malignant lesions of the gallbladder. World J Surg Oncol 2012; 10: 92.
    • (2012) World J Surg Oncol , vol.10 , pp. 92
    • Zou, Q.1    Xiong, L.2    Yang, Z.3
  • 23
    • 0346333256 scopus 로고    scopus 로고
    • Progression of cervical carcinomas is associated with down-regulation of CD9 but strong local re-expression at sites of transendothelial invasion
    • Sauer G, Windisch J, Kurzeder C, et al. Progression of cervical carcinomas is associated with down-regulation of CD9 but strong local re-expression at sites of transendothelial invasion. Clin Cancer Res 2003; 9: 6426-31.
    • (2003) Clin Cancer Res , vol.9 , pp. 6426-6431
    • Sauer, G.1    Windisch, J.2    Kurzeder, C.3
  • 24
    • 77956011418 scopus 로고    scopus 로고
    • Prognostic significance of CD9 expression in locally advanced gastric cancer treated with surgery and adjuvant chemoradiotherapy
    • Soyuer S, Soyuer I, Unal D, et al. Prognostic significance of CD9 expression in locally advanced gastric cancer treated with surgery and adjuvant chemoradiotherapy. Pathol Res Pract 2010; 206: 607-10.
    • (2010) Pathol Res Pract , vol.206 , pp. 607-610
    • Soyuer, S.1    Soyuer, I.2    Unal, D.3
  • 25
    • 1642314100 scopus 로고    scopus 로고
    • CD9 expression in gastric cancer and its significance
    • Hori H, Yano S, Koufuji K, et al. CD9 expression in gastric cancer and its significance. J Surg Res 2004; 117: 208-15.
    • (2004) J Surg Res , vol.117 , pp. 208-215
    • Hori, H.1    Yano, S.2    Koufuji, K.3
  • 26
    • 2442626887 scopus 로고    scopus 로고
    • CD9 expression is not a prognostic factor in human osteosarcoma
    • Kubista B, Erovic BM, Klinger H, et al. CD9 expression is not a prognostic factor in human osteosarcoma. Cancer Lett 2004; 209: 105-10.
    • (2004) Cancer Lett , vol.209 , pp. 105-110
    • Kubista, B.1    Erovic, B.M.2    Klinger, H.3
  • 27
    • 84856116959 scopus 로고    scopus 로고
    • CD9 Is critical for cutaneous wound healing through JNK signaling
    • Zhang J, Dong J, Gu H, et al. CD9 Is critical for cutaneous wound healing through JNK signaling. J Invest Dermatol 2012; 132: 226-36.
    • (2012) J Invest Dermatol , vol.132 , pp. 226-236
    • Zhang, J.1    Dong, J.2    Gu, H.3
  • 28
    • 26444513618 scopus 로고    scopus 로고
    • Over-expression of CD9 does not affect in vivo tumorigenic or metastatic properties of human prostate cancer cells
    • Zvieriev V, Wang J-C, Chevrette M,. Over-expression of CD9 does not affect in vivo tumorigenic or metastatic properties of human prostate cancer cells. Biochem Biophys Res Commun 2005; 337: 498-504.
    • (2005) Biochem Biophys Res Commun , vol.337 , pp. 498-504
    • Zvieriev, V.1    Wang, J.-C.2    Chevrette, M.3
  • 29
    • 0033964768 scopus 로고    scopus 로고
    • Severely reduced female fertility in CD9-deficient mice
    • Le Naour F, Rubinstein E, Jasmin C, et al. Severely reduced female fertility in CD9-deficient mice. Science 2000; 287: 319-21.
    • (2000) Science , vol.287 , pp. 319-321
    • Le Naour, F.1    Rubinstein, E.2    Jasmin, C.3
  • 30
    • 31544471680 scopus 로고    scopus 로고
    • Reduced fertility of female mice lacking CD81
    • Rubinstein E, Ziyyat A, Prenant M, et al. Reduced fertility of female mice lacking CD81. Dev Biol 2006; 290: 351-8.
    • (2006) Dev Biol , vol.290 , pp. 351-358
    • Rubinstein, E.1    Ziyyat, A.2    Prenant, M.3
  • 31
    • 65449166493 scopus 로고    scopus 로고
    • CD9 negatively regulates integrin αiIbβ3 activation and could thus prevent excessive platelet recruitment at sites of vascular injury
    • Mangin PH, Kleitz L, Boucheix C, et al. CD9 negatively regulates integrin αIIbβ3 activation and could thus prevent excessive platelet recruitment at sites of vascular injury. J Thromb Haemost 2009; 7: 900-2.
    • (2009) J Thromb Haemost , vol.7 , pp. 900-902
    • Mangin, P.H.1    Kleitz, L.2    Boucheix, C.3
  • 32
    • 75149154876 scopus 로고    scopus 로고
    • Tetraspanin CD9 negatively regulates lipopolysaccharide-induced macrophage activation and lung inflammation
    • Suzuki M, Tachibana I, Takeda Y, et al. Tetraspanin CD9 negatively regulates lipopolysaccharide-induced macrophage activation and lung inflammation. J Immunol 2009; 182: 6485-93.
    • (2009) J Immunol , vol.182 , pp. 6485-6493
    • Suzuki, M.1    Tachibana, I.2    Takeda, Y.3
  • 34
    • 0029832290 scopus 로고    scopus 로고
    • Metastatic prostate cancer in a transgenic mouse
    • Gingrich JR, Barrios RJ, Morton RA, et al. Metastatic prostate cancer in a transgenic mouse. Cancer Res 1996; 56: 4096-102.
    • (1996) Cancer Res , vol.56 , pp. 4096-4102
    • Gingrich, J.R.1    Barrios, R.J.2    Morton, R.A.3
  • 35
    • 0038415024 scopus 로고    scopus 로고
    • Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model
    • Kaplan-Lefko PJ, Chen TM, Ittmann MM, et al. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 2003; 55: 219-37.
    • (2003) Prostate , vol.55 , pp. 219-237
    • Kaplan-Lefko, P.J.1    Chen, T.M.2    Ittmann, M.M.3
  • 36
    • 84873049293 scopus 로고    scopus 로고
    • Genetic ablation of the tetraspanin CD151 reduces spontaneous metastatic spread of prostate cancer in the TRAMP model
    • Copeland BT, Bowman MJ, Ashman LK,. Genetic ablation of the tetraspanin CD151 reduces spontaneous metastatic spread of prostate cancer in the TRAMP model. Mol Cancer Res 2013; 11: 95-105.
    • (2013) Mol Cancer Res , vol.11 , pp. 95-105
    • Copeland, B.T.1    Bowman, M.J.2    Ashman, L.K.3
  • 37
    • 38749142915 scopus 로고    scopus 로고
    • Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer
    • Chiaverotti T, Couto SS, Donjacour A, et al. Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. Am J Pathol 2008; 172: 236-47.
    • (2008) Am J Pathol , vol.172 , pp. 236-247
    • Chiaverotti, T.1    Couto, S.S.2    Donjacour, A.3
  • 38
    • 36048989332 scopus 로고    scopus 로고
    • Origin of androgen-insensitive poorly differentiated tumors in the transgenic adenocarcinoma of mouse prostate model
    • Huss WJ, Grayy DR, Tavakoli K, et al. Origin of androgen-insensitive poorly differentiated tumors in the transgenic adenocarcinoma of mouse prostate model. Neoplasia 2007; 9: 938-50.
    • (2007) Neoplasia , vol.9 , pp. 938-950
    • Huss, W.J.1    Grayy, D.R.2    Tavakoli, K.3
  • 39
    • 0033049122 scopus 로고    scopus 로고
    • Pathologic progression of autochthonous prostate cancer in the TRAMP model
    • Gingrich J, Barrios R, Foster B, et al. Pathologic progression of autochthonous prostate cancer in the TRAMP model. Prostate Cancer Prostatic Disord 1999; 2: 70-7.
    • (1999) Prostate Cancer Prostatic Disord , vol.2 , pp. 70-77
    • Gingrich, J.1    Barrios, R.2    Foster, B.3
  • 40
    • 0033958932 scopus 로고    scopus 로고
    • Requirement of CD9 on the egg plasma membrane for fertilization
    • Miyado K, Yamada G, Yamada S, et al. Requirement of CD9 on the egg plasma membrane for fertilization. Science 2000; 287: 321-4.
    • (2000) Science , vol.287 , pp. 321-324
    • Miyado, K.1    Yamada, G.2    Yamada, S.3
  • 41
    • 6344284230 scopus 로고    scopus 로고
    • MRP-1/CD9 gene transduction downregulates Wnt signal pathways
    • Huang C-l, Liu D, Masuya D, et al. MRP-1/CD9 gene transduction downregulates Wnt signal pathways. Oncogene 2004; 23: 7475-83.
    • (2004) Oncogene , vol.23 , pp. 7475-7483
    • Huang, C.-L.1    Liu, D.2    Masuya, D.3
  • 42
    • 52649170765 scopus 로고    scopus 로고
    • Tetraspanin family member CD9 inhibits Aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis
    • Nakazawa Y, Sato S, Naito M, et al. Tetraspanin family member CD9 inhibits Aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis. Blood 2008; 112: 1730-9.
    • (2008) Blood , vol.112 , pp. 1730-1739
    • Nakazawa, Y.1    Sato, S.2    Naito, M.3
  • 43
    • 80052867439 scopus 로고    scopus 로고
    • Targeting CD9 produces stimulus-independent antiangiogenic effects predominantly in activated endothelial cells during angiogenesis: A novel antiangiogenic therapy
    • Kamisasanuki T, Tokushige S, Terasaki H, et al. Targeting CD9 produces stimulus-independent antiangiogenic effects predominantly in activated endothelial cells during angiogenesis: a novel antiangiogenic therapy. Biochem Biophys Res Commun 2011; 413: 128-35.
    • (2011) Biochem Biophys Res Commun , vol.413 , pp. 128-135
    • Kamisasanuki, T.1    Tokushige, S.2    Terasaki, H.3
  • 44
    • 0035895069 scopus 로고    scopus 로고
    • Regulatory role of tetraspanin CD9 in tumor-endothelial cell interaction during transendothelial invasion of melanoma cells
    • Longo N, Yáñez-Mõ Ma, Mittelbrunn Ma, et al. Regulatory role of tetraspanin CD9 in tumor-endothelial cell interaction during transendothelial invasion of melanoma cells. Blood 2001; 98: 3717-26.
    • (2001) Blood , vol.98 , pp. 3717-3726
    • Longo, N.1    Yáñez-Mõ, M.2    Mittelbrunn, M.3
  • 45
    • 0027406455 scopus 로고
    • Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA
    • Ikeyama S, Koyama M, Yamaoko M, et al. Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med 1993; 177: 1231-7.
    • (1993) J Exp Med , vol.177 , pp. 1231-1237
    • Ikeyama, S.1    Koyama, M.2    Yamaoko, M.3
  • 46
    • 0034597534 scopus 로고    scopus 로고
    • Suppression of pulmonary metastasis using adenovirally motility related protein-1 (MRP-1/CD9) gene delivery
    • Miyake M, Inufusa H, Adachi M, et al. Suppression of pulmonary metastasis using adenovirally motility related protein-1 (MRP-1/CD9) gene delivery. Oncogene 2000; 19: 5221-6.
    • (2000) Oncogene , vol.19 , pp. 5221-5226
    • Miyake, M.1    Inufusa, H.2    Adachi, M.3
  • 47
    • 33847738889 scopus 로고    scopus 로고
    • Adenoviral transduction of MRP-1/CD9 and KAI1/CD82 inhibits lymph node metastasis in orthotopic lung cancer model
    • Takeda T, Hattori N, Tokuhara T, et al. Adenoviral transduction of MRP-1/CD9 and KAI1/CD82 inhibits lymph node metastasis in orthotopic lung cancer model. Cancer Res 2007; 67: 1744-9.
    • (2007) Cancer Res , vol.67 , pp. 1744-1749
    • Takeda, T.1    Hattori, N.2    Tokuhara, T.3
  • 48
    • 32044452725 scopus 로고    scopus 로고
    • CD9 overexpression suppressed the liver metastasis and malignant ascites via inhibition of proliferation and motility of small-cell lung cancer cells in NK cell-depleted SCID mice
    • Zheng R, Yano S, Zhang H, et al. CD9 overexpression suppressed the liver metastasis and malignant ascites via inhibition of proliferation and motility of small-cell lung cancer cells in NK cell-depleted SCID mice. Oncol Res 2005; 15: 365-72.
    • (2005) Oncol Res , vol.15 , pp. 365-372
    • Zheng, R.1    Yano, S.2    Zhang, H.3
  • 49
    • 70349652241 scopus 로고    scopus 로고
    • A novel therapeutic strategy with anti-CD9 antibody in gastric cancers
    • Nakamoto T, Murayama Y, Oritani K, et al. A novel therapeutic strategy with anti-CD9 antibody in gastric cancers. J Gastroenterol 2009; 44: 889-96.
    • (2009) J Gastroenterol , vol.44 , pp. 889-896
    • Nakamoto, T.1    Murayama, Y.2    Oritani, K.3
  • 50
    • 79953201597 scopus 로고    scopus 로고
    • The complexity of tetraspanins
    • Rubinstein E,. The complexity of tetraspanins. Biochem Soc Trans 2011; 39: 501-5.
    • (2011) Biochem Soc Trans , vol.39 , pp. 501-505
    • Rubinstein, E.1
  • 51
    • 77955022593 scopus 로고    scopus 로고
    • Tetraspanin CD151 regulates transforming growth factor beta signaling: Implication in tumor metastasis
    • Sadej R, Romanska H, Kavanagh D, et al. Tetraspanin CD151 regulates transforming growth factor beta signaling: implication in tumor metastasis. Cancer Res 2010; 70: 6059-70.
    • (2010) Cancer Res , vol.70 , pp. 6059-6070
    • Sadej, R.1    Romanska, H.2    Kavanagh, D.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.