메뉴 건너뛰기




Volumn 177, Issue 1, 2010, Pages 387-403

Metastatic outgrowth encompasses COL-I, FN1, and POSTN up-regulation and assembly to fibrillar networks regulating cell adhesion, migration, and growth

Author keywords

[No Author keywords available]

Indexed keywords

COLLAGEN TYPE 1; FIBRONECTIN; SCLEROPROTEIN; SHORT HAIRPIN RNA; TRANSCRIPTION FACTOR RUNX2; TRANSFORMING GROWTH FACTOR BETA; VERSICAN;

EID: 77954565543     PISSN: 00029440     EISSN: 15252191     Source Type: Journal    
DOI: 10.2353/ajpath.2010.090748     Document Type: Article
Times cited : (117)

References (68)
  • 1
    • 0036674501 scopus 로고    scopus 로고
    • Dissemination and growth of cancer cells in metastatic sites
    • DOI 10.1038/nrc865
    • Chambers AF, Groom AC, MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002, 2:563-572 (Pubitemid 37328923)
    • (2002) Nature Reviews Cancer , vol.2 , Issue.8 , pp. 563-572
    • Chambers, A.F.1    Groom, A.C.2    MacDonald, I.C.3
  • 2
    • 33746851956 scopus 로고    scopus 로고
    • Tumor metastasis: Mechanistic insights and clinical challenges
    • DOI 10.1038/nm1469, PII NM1469
    • Steeg PS: Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006, 12:895-904 (Pubitemid 44175140)
    • (2006) Nature Medicine , vol.12 , Issue.8 , pp. 895-904
    • Steeg, P.S.1
  • 3
    • 33751252276 scopus 로고    scopus 로고
    • Cancer metastasis: Building a framework
    • Gupta GP, Massague J: Cancer metastasis: building a framework. Cell 2006, 127:679-695
    • (2006) Cell , vol.127 , pp. 679-695
    • Gupta, G.P.1    Massague, J.2
  • 4
    • 34247521438 scopus 로고    scopus 로고
    • Priming the 'soil' for breast cancer metastasis: The pre-metastatic niche
    • Psaila B, Kaplan RN, Port ER, Lyden D: Priming the 'soil' for breast cancer metastasis: the pre-metastatic niche. Breast Dis 2006, 26:65-74
    • (2006) Breast Dis , vol.26 , pp. 65-74
    • Psaila, B.1    Kaplan, R.N.2    Port, E.R.3    Lyden, D.4
  • 5
    • 67649881870 scopus 로고    scopus 로고
    • From tumor lymphangiogenesis to lymphvascular niche
    • Hirakawa S: From tumor lymphangiogenesis to lymphvascular niche. Cancer Sci 2009, 100:983-989
    • (2009) Cancer Sci , vol.100 , pp. 983-989
    • Hirakawa, S.1
  • 6
    • 0038481970 scopus 로고    scopus 로고
    • The pathogenesis of cancer metastasis: The 'seed and soil' hypothesis revisited
    • Fidler IJ: The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 2003, 3:453-458
    • (2003) Nat Rev Cancer , vol.3 , pp. 453-458
    • Fidler, I.J.1
  • 7
    • 49849091679 scopus 로고    scopus 로고
    • Micromanagers of malignancy: Role of microRNAs in regulating metastasis
    • Ma L, Weinberg RA: Micromanagers of malignancy: role of microRNAs in regulating metastasis. Trends Genet 2008, 24:448-456
    • (2008) Trends Genet , vol.24 , pp. 448-456
    • Ma, L.1    Weinberg, R.A.2
  • 8
    • 2942538264 scopus 로고    scopus 로고
    • Dissecting the metastatic cascade
    • Pantel K, Brakenhoff RH: Dissecting the metastatic cascade. Nat Rev Cancer 2004, 4:448-456
    • (2004) Nat Rev Cancer , vol.4 , pp. 448-456
    • Pantel, K.1    Brakenhoff, R.H.2
  • 10
    • 0041784818 scopus 로고    scopus 로고
    • The amount of metastatic melanoma in a sentinel lymph node: Does it have prognostic significance?
    • Carlson GW, Murray DR, Lyles RH, Staley CA, Hestley A, Cohen C: The amount of metastatic melanoma in a sentinel lymph node: does it have prognostic significance? Ann Surg Oncol 2003, 10:575-581
    • (2003) Ann Surg Oncol , vol.10 , pp. 575-581
    • Carlson, G.W.1    Murray, D.R.2    Lyles, R.H.3    Staley, C.A.4    Hestley, A.5    Cohen, C.6
  • 14
    • 0037316303 scopus 로고    scopus 로고
    • A comparison of normalization methods for high density oligonucleotide array data based on variance and bias
    • DOI 10.1093/bioinformatics/19.2.185
    • Bolstad BM, Irizarry RA, Astrand M, Speed TP: A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 2003, 19:185-193 (Pubitemid 36181903)
    • (2003) Bioinformatics , vol.19 , Issue.2 , pp. 185-193
    • Bolstad, B.M.1    Irizarry, R.A.2    Astrand, M.3    Speed, T.P.4
  • 15
    • 0035942271 scopus 로고    scopus 로고
    • Significance analysis of microarrays applied to the ionizing radiation response
    • Tusher VG, Tibshirani R, Chu G: Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA: 2001, 98:5116-5121
    • (2001) Proc Natl Acad Sci USA , vol.98 , pp. 5116-5121
    • Tusher, V.G.1    Tibshirani, R.2    Chu, G.3
  • 18
    • 0032775514 scopus 로고    scopus 로고
    • FGF expression allows nevus cells to survive in three-dimensional collagen gel under conditions that induce apoptosis in normal human melanocytes
    • DOI 10.1046/j.1523-1747.1999.00636.x
    • Alanko T, Rosenberg M, Saksela O: FGF expression allows nevus cells to survive in three-dimensional collagen gel under conditions that induce apoptosis in normal human melanocytes. J Invest Dermatol 1999, 113:111-116 (Pubitemid 29328168)
    • (1999) Journal of Investigative Dermatology , vol.113 , Issue.1 , pp. 111-116
    • Alanko, T.1    Rosenberg, M.2    Saksela, O.3
  • 19
    • 10844291804 scopus 로고    scopus 로고
    • Cysteine cathepsins are central contributors of invasion by cultured adenosylmethionine decarboxylase-transformed rodent fibroblasts
    • DOI 10.1158/0008-5472.CAN-03-2993
    • Ravanko K, Jarvinen K, Helin J, Kalkkinen N, Holtta E: Cysteine cathepsins are central contributors of invasion by cultured adenosyl-methionine decarboxylase-transformed rodent fibroblasts. Cancer Res 2004, 64:8831-8838 (Pubitemid 39665486)
    • (2004) Cancer Research , vol.64 , Issue.24 , pp. 8831-8838
    • Ravanko, K.1    Jarvinen, K.2    Helin, J.3    Kalkkinen, N.4    Holtta, E.5
  • 20
    • 2942511574 scopus 로고    scopus 로고
    • Role of osteopontin in tumour progression
    • Rittling SR, Chambers AF: Role of osteopontin in tumour progression. Br J Cancer 2004, 90:1877-1881
    • (2004) Br J Cancer , vol.90 , pp. 1877-1881
    • Rittling, S.R.1    Chambers, A.F.2
  • 24
    • 39149122855 scopus 로고    scopus 로고
    • Capturing pluripotency
    • Silva J, Smith A: Capturing pluripotency. Cell 2008, 132:532-536
    • (2008) Cell , vol.132 , pp. 532-536
    • Silva, J.1    Smith, A.2
  • 25
    • 45549100605 scopus 로고    scopus 로고
    • Melanoma stem cells: The dark seed of melanoma
    • Zabierowski SE, Herlyn M: Melanoma stem cells: the dark seed of melanoma. J Clin Oncol 2008, 26:2890-2894
    • (2008) J Clin Oncol , vol.26 , pp. 2890-2894
    • Zabierowski, S.E.1    Herlyn, M.2
  • 26
    • 41149157649 scopus 로고    scopus 로고
    • TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4
    • Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massague J: TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008, 133:66-77
    • (2008) Cell , vol.133 , pp. 66-77
    • Padua, D.1    Zhang, X.H.2    Wang, Q.3    Nadal, C.4    Gerald, W.L.5    Gomis, R.R.6    Massague, J.7
  • 28
    • 0035907240 scopus 로고    scopus 로고
    • Identification of Novel TGF-beta/Smad Gene Targets in Dermal Fibroblasts using a Combined cDNA Microarray/Promoter Transactivation Approach
    • DOI 10.1074/jbc.M100754200
    • Verrecchia F, Chu ML, Mauviel A: Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem 2001, 276:17058-17062 (Pubitemid 37411506)
    • (2001) Journal of Biological Chemistry , vol.276 , Issue.20 , pp. 17058-17062
    • Verrecchia, F.1    Chu, M.-L.2    Mauviel, A.3
  • 29
    • 0032973197 scopus 로고    scopus 로고
    • Identification and characterization of a novel protein, periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor beta
    • Horiuchi K, Amizuka N, Takeshita S, Takamatsu H, Katsuura M, Ozawa H, Toyama Y, Bonewald LF, Kudo A: Identification and characterization of a novel protein, periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor beta. J Bone Miner Res 1999, 14:1239-1249
    • (1999) J Bone Miner Res , vol.14 , pp. 1239-1249
    • Horiuchi, K.1    Amizuka, N.2    Takeshita, S.3    Takamatsu, H.4    Katsuura, M.5    Ozawa, H.6    Toyama, Y.7    Bonewald, L.F.8    Kudo, A.9
  • 30
    • 0023654923 scopus 로고
    • Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-beta
    • Ignotz RA, Endo T, Massague J: Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-beta. J Biol Chem 1987, 262:6443-6446
    • (1987) J Biol Chem , vol.262 , pp. 6443-6446
    • Ignotz, R.A.1    Endo, T.2    Massague, J.3
  • 31
    • 0033104505 scopus 로고    scopus 로고
    • TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent Smad4-independent pathway
    • Hocevar BA, Brown TL, Howe PH: TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent Smad4-independent pathway. EMBO J 1999, 18:1345-1356
    • (1999) EMBO J , vol.18 , pp. 1345-1356
    • Hocevar, B.A.1    Brown, T.L.2    Howe, P.H.3
  • 32
    • 35548936833 scopus 로고    scopus 로고
    • Models, mechanisms and clinical evidence for cancer dormancy
    • DOI 10.1038/nrc2256, PII NRC2256
    • Aguirre-Ghiso JA: Models, mechanisms, and clinical evidence for cancer dormancy. Nat Rev Cancer 2007, 7:834-846 (Pubitemid 350006258)
    • (2007) Nature Reviews Cancer , vol.7 , Issue.11 , pp. 834-846
    • Aguirre-Ghiso, J.A.1
  • 33
    • 63049090100 scopus 로고    scopus 로고
    • Metastasis: From dissemination to organ-specific colonization
    • Nguyen DX, Bos PD, Massague J: Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 2009, 9:274-284
    • (2009) Nat Rev Cancer , vol.9 , pp. 274-284
    • Nguyen, D.X.1    Bos, P.D.2    Massague, J.3
  • 34
    • 33749065143 scopus 로고    scopus 로고
    • Switch to an invasive growth phase in melanoma is associated with tenascin-C, fibronectin, and procollagen-I forming specific channel structures for invasion
    • Kaariainen E, Nummela P, Soikkeli J, Yin M, Lukk M, Jahkola T, Virolainen S, Ora A, Ukkonen E, Saksela O, Holtta E: Switch to an invasive growth phase in melanoma is associated with tenascin-C, fibronectin, and procollagen-I forming specific channel structures for invasion. J Pathol 2006, 210:181-191
    • (2006) J Pathol , vol.210 , pp. 181-191
    • Kaariainen, E.1    Nummela, P.2    Soikkeli, J.3    Yin, M.4    Lukk, M.5    Jahkola, T.6    Virolainen, S.7    Ora, A.8    Ukkonen, E.9    Saksela, O.10    Holtta, E.11
  • 35
    • 34948854409 scopus 로고    scopus 로고
    • A major fraction of fibronectin present in the extracellular matrix of tissues is plasma-derived
    • DOI 10.1074/jbc.M611315200
    • Moretti FA, Chauhan AK, Iaconcig A, Porro F, Baralle FE, Muro AF: A major fraction of fibronectin present in the extracellular matrix of tissues is plasma-derived. J Biol Chem 2007, 282:28057-28062 (Pubitemid 47529518)
    • (2007) Journal of Biological Chemistry , vol.282 , Issue.38 , pp. 28057-28062
    • Moretti, F.A.1    Chauhan, A.K.2    Iaconcig, A.3    Porro, F.4    Baralle, F.E.5    Muro, A.F.6
  • 36
    • 67650763823 scopus 로고    scopus 로고
    • Fibronectins in vascular morphogenesis
    • Astrof S, Hynes RO: Fibronectins in vascular morphogenesis. Angio-genesis 2009, 12:165-175
    • (2009) Angio-genesis , vol.12 , pp. 165-175
    • Astrof, S.1    Hynes, R.O.2
  • 37
    • 33845455093 scopus 로고    scopus 로고
    • Stromal Cell Networks Regulate Lymphocyte Entry, Migration, and Territoriality in Lymph Nodes
    • DOI 10.1016/j.immuni.2006.10.011, PII S1074761306004833
    • Bajenoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N, Germain RN: Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 2006, 25:989-1001 (Pubitemid 44914055)
    • (2006) Immunity , vol.25 , Issue.6 , pp. 989-1001
    • Bajenoff, M.1    Egen, J.G.2    Koo, L.Y.3    Laugier, J.4    Brau, F.5    Glaichenhaus, N.6    Germain, R.N.7
  • 38
    • 0042887252 scopus 로고    scopus 로고
    • The ins and outs of fibronectin matrix assembly
    • DOI 10.1242/jcs.00670
    • Wierzbicka-Patynowski I, Schwarzbauer JE: The ins and outs of fibronectin matrix assembly. J Cell Sci 2003, 116:3269-3276 (Pubitemid 37038975)
    • (2003) Journal of Cell Science , vol.116 , Issue.16 , pp. 3269-3276
    • Wierzbicka-Patynowski, I.1    Schwarzbauer, J.E.2
  • 39
    • 3142655415 scopus 로고    scopus 로고
    • Localization of a cryptic binding site for tenascin on fibronectin
    • Ingham KC, Brew SA, Erickson HP: Localization of a cryptic binding site for tenascin on fibronectin. J Biol Chem 2004, 279:28132-28135
    • (2004) J Biol Chem , vol.279 , pp. 28132-28135
    • Ingham, K.C.1    Brew, S.A.2    Erickson, H.P.3
  • 40
    • 50849145156 scopus 로고    scopus 로고
    • Collagen fibrillogenesis: Fibronectin, integrins, and minor collagens as organizers and nucleators
    • Kadler KE, Hill A, Canty-Laird EG: Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators. Curr Opin Cell Biol 2008, 20:495-501
    • (2008) Curr Opin Cell Biol , vol.20 , pp. 495-501
    • Kadler, K.E.1    Hill, A.2    Canty-Laird, E.G.3
  • 42
    • 0037107551 scopus 로고    scopus 로고
    • Fibronectin at a glance
    • Pankov R, Yamada KM: Fibronectin at a glance. J Cell Sci 2002, 115:3861-3863
    • (2002) J Cell Sci , vol.115 , pp. 3861-3863
    • Pankov, R.1    Yamada, K.M.2
  • 43
    • 0022168434 scopus 로고
    • Molecular biology of fibronectin
    • Hynes R: Molecular biology of fibronectin. Annu Rev Cell Biol 1985, 1:67-90
    • (1985) Annu Rev Cell Biol , vol.1 , pp. 67-90
    • Hynes, R.1
  • 45
    • 0037317272 scopus 로고    scopus 로고
    • Novel fold revealed by the structure of a FAS1 domain pair from the insect cell adhesion molecule fasciclin I
    • Clout NJ, Tisi D, Hohenester E: Novel fold revealed by the structure of a FAS1 domain pair from the insect cell adhesion molecule fasciclin I. Structure 2003, 11:197-203
    • (2003) Structure , vol.11 , pp. 197-203
    • Clout, N.J.1    Tisi, D.2    Hohenester, E.3
  • 47
    • 0036775241 scopus 로고    scopus 로고
    • Versican: A versatile extracellular matrix proteoglycan in cell biology
    • Wight TN: Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol 2002, 14:617-623
    • (2002) Curr Opin Cell Biol , vol.14 , pp. 617-623
    • Wight, T.N.1
  • 48
    • 24344498285 scopus 로고    scopus 로고
    • Periostin is down-regulated in high grade human bladder cancers and suppresses in vitro cell invasiveness and in vivo metastasis of cancer cells
    • Kim CJ, Yoshioka N, Tambe Y, Kushima R, Okada Y, Inoue H: Periostin is down-regulated in high grade human bladder cancers and suppresses in vitro cell invasiveness and in vivo metastasis of cancer cells. Int J Cancer 2005, 117:51-58
    • (2005) Int J Cancer , vol.117 , pp. 51-58
    • Kim, C.J.1    Yoshioka, N.2    Tambe, Y.3    Kushima, R.4    Okada, Y.5    Inoue, H.6
  • 50
    • 33751416666 scopus 로고    scopus 로고
    • A chemical proteomics approach for the identification of accessible antigens expressed in human kidney cancer
    • Castronovo V, Waltregny D, Kischel P, Roesli C, Elia G, Rybak JN, Neri D: A chemical proteomics approach for the identification of accessible antigens expressed in human kidney cancer. Mol Cell Proteomics 2006, 5:2083-2091
    • (2006) Mol Cell Proteomics , vol.5 , pp. 2083-2091
    • Castronovo, V.1    Waltregny, D.2    Kischel, P.3    Roesli, C.4    Elia, G.5    Rybak, J.N.6    Neri, D.7
  • 51
    • 19844383074 scopus 로고    scopus 로고
    • Periostin induction in tumor cell line explants and inhibition of in vitro cell growth by anti-periostin antibodies
    • Tai IT, Dai M, Chen LB: Periostin induction in tumor cell line explants and inhibition of in vitro cell growth by anti-periostin antibodies. Carcinogenesis 2005, 26:908-915
    • (2005) Carcinogenesis , vol.26 , pp. 908-915
    • Tai, I.T.1    Dai, M.2    Chen, L.B.3
  • 52
    • 0037898286 scopus 로고    scopus 로고
    • The divergent expression of periostin mRNA in the periodontal ligament during experimental tooth movement
    • Wilde J, Yokozeki M, Terai K, Kudo A, Moriyama K: The divergent expression of periostin mRNA in the periodontal ligament during experimental tooth movement. Cell Tissue Res 2003, 312:345-351
    • (2003) Cell Tissue Res , vol.312 , pp. 345-351
    • Wilde, J.1    Yokozeki, M.2    Terai, K.3    Kudo, A.4    Moriyama, K.5
  • 55
    • 38949201642 scopus 로고    scopus 로고
    • Human periostin gene expression in normal tissues, tumors and melanoma: Evidences for periostin production by both stromal and melanoma cells
    • Tilman G, Mattiussi M, Brasseur F, van Baren N, Decottignies A: Human periostin gene expression in normal tissues, tumors and melanoma: evidences for periostin production by both stromal and melanoma cells. Mol Cancer 2007, 6:80
    • (2007) Mol Cancer , vol.6 , pp. 80
    • Tilman, G.1    Mattiussi, M.2    Brasseur, F.3    Van Baren, N.4    Decottignies, A.5
  • 56
    • 0035902141 scopus 로고    scopus 로고
    • The microenvironment of the tumour-host interface
    • Liotta LA, Kohn EC: The microenvironment of the tumour-host interface. Nature 2001, 411:375-379
    • (2001) Nature , vol.411 , pp. 375-379
    • Liotta, L.A.1    Kohn, E.C.2
  • 59
    • 36749013537 scopus 로고    scopus 로고
    • Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells
    • Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, Sahai E: Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 2007, 9:1392-1400
    • (2007) Nat Cell Biol , vol.9 , pp. 1392-1400
    • Gaggioli, C.1    Hooper, S.2    Hidalgo-Carcedo, C.3    Grosse, R.4    Marshall, J.F.5    Harrington, K.6    Sahai, E.7
  • 60
    • 0034534561 scopus 로고    scopus 로고
    • Fibronectin polymerization stimulates cell growth by RGD-dependent and -independent mechanisms
    • Sottile J, Hocking DC, Langenbach KJ: Fibronectin polymerization stimulates cell growth by RGD-dependent and -independent mechanisms. J Cell Sci 2000, 113 Pt 23:4287-4299
    • (2000) J Cell Sci , vol.113 , Issue.PART 23 , pp. 4287-4299
    • Sottile, J.1    Hocking, D.C.2    Langenbach, K.J.3
  • 64
    • 11144240041 scopus 로고    scopus 로고
    • Vascular injury induces expression of periostin: Implications for vascular cell differentiation and migration
    • Lindner V, Wang Q, Conley BA, Friesel RE, Vary CP: Vascular injury induces expression of periostin: implications for vascular cell differentiation and migration. Arterioscler Thromb Vasc Biol 2005, 25:77-83
    • (2005) Arterioscler Thromb Vasc Biol , vol.25 , pp. 77-83
    • Lindner, V.1    Wang, Q.2    Conley, B.A.3    Friesel, R.E.4    Vary, C.P.5
  • 66
    • 1942422179 scopus 로고    scopus 로고
    • Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression
    • Shao R, Bao S, Bai X, Blanchette C, Anderson RM, Dang T, Gishizky ML, Marks JR, Wang XF: Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression. Mol Cell Biol 2004, 24:3992-4003
    • (2004) Mol Cell Biol , vol.24 , pp. 3992-4003
    • Shao, R.1    Bao, S.2    Bai, X.3    Blanchette, C.4    Anderson, R.M.5    Dang, T.6    Gishizky, M.L.7    Marks, J.R.8    Wang, X.F.9
  • 67
    • 36348980599 scopus 로고    scopus 로고
    • The extra-domain A of fibronectin is a vascular marker of solid tumors and metastases
    • Rybak JN, Roesli C, Kaspar M, Villa A, Neri D: The extra-domain A of fibronectin is a vascular marker of solid tumors and metastases. Cancer Res 2007, 67:10948-10957
    • (2007) Cancer Res , vol.67 , pp. 10948-10957
    • Rybak, J.N.1    Roesli, C.2    Kaspar, M.3    Villa, A.4    Neri, D.5


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.