메뉴 건너뛰기




Volumn 10, Issue 7, 1996, Pages 673-682

Analysis of liver development, regeneration, and carcinogenesis by genetic marking studies

Author keywords

oval cell; retroviral vector; stem cell; transgenic mice

Indexed keywords

CYTOKERATIN; VIRUS VECTOR;

EID: 0029953814     PISSN: 08926638     EISSN: None     Source Type: Journal    
DOI: 10.1096/fasebj.10.7.8635684     Document Type: Review
Times cited : (69)

References (59)
  • 1
    • 0027772191 scopus 로고
    • Hepatic stem cells
    • Thorgeirsson, S. S. (1993) Hepatic stem cells. Am. J. Pathol. 142, 1331-1333
    • (1993) Am. J. Pathol. , vol.142 , pp. 1331-1333
    • Thorgeirsson, S.S.1
  • 2
    • 0023117339 scopus 로고
    • A probabilistic model of mosaicism based on the histological analysis of chimeric rat liver
    • Iannaccone, P. M., Weinberg, W. C., and Berkwits, L. (1987) A probabilistic model of mosaicism based on the histological analysis of chimeric rat liver. Development 99, 187-196
    • (1987) Development , vol.99 , pp. 187-196
    • Iannaccone, P.M.1    Weinberg, W.C.2    Berkwits, L.3
  • 3
    • 0026001002 scopus 로고
    • Use of transgenic mice to infer the biological properties of small intestinal stem cells and to examine the lineage relationships of their descendants
    • Roth, K. A., Hermiston, M. L., and Gordon, J. I. (1991) Use of transgenic mice to infer the biological properties of small intestinal stem cells and to examine the lineage relationships of their descendants. Proc. Natl. Acad. Sci. USA 88, 9407-9411
    • (1991) Proc. Natl. Acad. Sci. USA , vol.88 , pp. 9407-9411
    • Roth, K.A.1    Hermiston, M.L.2    Gordon, J.I.3
  • 4
    • 0022498494 scopus 로고
    • Tissue-specific expression in transgenic mice of a fused gene containing RSV terminal sequence
    • Overbeek, P. A., Lai, S. P., Van Quill, K. R., and Westphal, H. (1986) Tissue-specific expression in transgenic mice of a fused gene containing RSV terminal sequence. Science 231, 1574-1577
    • (1986) Science , vol.231 , pp. 1574-1577
    • Overbeek, P.A.1    Lai, S.P.2    Van Quill, K.R.3    Westphal, H.4
  • 6
    • 0028285183 scopus 로고
    • Cell lineage study in the liver using retroviral mediated gene transfer
    • Bralet, M.-P., Branchereau, S., Brechot, C., and Ferry, N. (1994) Cell lineage study in the liver using retroviral mediated gene transfer. Am. J. Pathol. 144, 896-905
    • (1994) Am. J. Pathol. , vol.144 , pp. 896-905
    • Bralet, M.-P.1    Branchereau, S.2    Brechot, C.3    Ferry, N.4
  • 7
    • 0028860883 scopus 로고
    • Ras-transduced diethynitrosamine-treated hepatocytes develop into cancers of mixed phenotype in vivo
    • Lin, Y.-Z., Brunt, E., Bowling, W., Hafenrichter, D. G., Kennedy, S., Flye, M. W., and Ponder, K. P. (1995) Ras-transduced diethynitrosamine-treated hepatocytes develop into cancers of mixed phenotype in vivo. Cancer Res. 55, 5242-5250
    • (1995) Cancer Res. , vol.55 , pp. 5242-5250
    • Lin, Y.-Z.1    Brunt, E.2    Bowling, W.3    Hafenrichter, D.G.4    Kennedy, S.5    Flye, M.W.6    Ponder, K.P.7
  • 8
    • 0025343853 scopus 로고
    • Isolation, culture, and transplantation of intrahepatic biliary epithelial cells and oval cells
    • Sirica, A. E., Mathis, G. A., Sano, N., and Elmore, L. W. (1990) Isolation, culture, and transplantation of intrahepatic biliary epithelial cells and oval cells. Pathobiology 58, 44-64
    • (1990) Pathobiology , vol.58 , pp. 44-64
    • Sirica, A.E.1    Mathis, G.A.2    Sano, N.3    Elmore, L.W.4
  • 9
    • 0026544368 scopus 로고
    • The stem cells of the liver: A selective review
    • Aterman, K. (1992) The stem cells of the liver: a selective review. J. Cancer Res. Clin. Oncol. 118, 87-115
    • (1992) J. Cancer Res. Clin. Oncol. , vol.118 , pp. 87-115
    • Aterman, K.1
  • 10
    • 0027488689 scopus 로고
    • Cell lineages in hepatic development and the identification of progenitor cells in normal and injured liver
    • Fausto, N., Lemire, J. M., and Shiojiri, N. (1993) Cell lineages in hepatic development and the identification of progenitor cells in normal and injured liver. Proc. Soc. Exp. Biol. Med. 204, 237-241
    • (1993) Proc. Soc. Exp. Biol. Med. , vol.204 , pp. 237-241
    • Fausto, N.1    Lemire, J.M.2    Shiojiri, N.3
  • 12
    • 0025306467 scopus 로고
    • Cell lineages and differentiation programs in epidermal, urothelial, and hepatic tissues and their neoplasms
    • Marceau, N. (1990) Cell lineages and differentiation programs in epidermal, urothelial, and hepatic tissues and their neoplasms. Lab. Invest. 63, 4-20
    • (1990) Lab. Invest. , vol.63 , pp. 4-20
    • Marceau, N.1
  • 13
    • 0028310594 scopus 로고
    • Liver stem cells
    • Sell, S. (1994) Liver stem cells. Modern Pathol. 7, 105-112
    • (1994) Modern Pathol. , vol.7 , pp. 105-112
    • Sell, S.1
  • 14
    • 0028217537 scopus 로고
    • Migration of hepatocytes along hepatic plates and stem cell-fed hepatocyte lineages
    • Grisham, J. W. (1994) Migration of hepatocytes along hepatic plates and stem cell-fed hepatocyte lineages. Am. J. Pathol. 144, 849-854
    • (1994) Am. J. Pathol. , vol.144 , pp. 849-854
    • Grisham, J.W.1
  • 15
    • 0025814562 scopus 로고
    • Cell lineages and oval cell progenitors in rat liver development
    • Shiojiri, N., Lemire, J. M., and Fausto, N. (1991) Cell lineages and oval cell progenitors in rat liver development. Cancer Res. 51, 2611-2620
    • (1991) Cancer Res. , vol.51 , pp. 2611-2620
    • Shiojiri, N.1    Lemire, J.M.2    Fausto, N.3
  • 17
    • 0021213136 scopus 로고
    • Isolation and partial characterization of oval and hyperplastic bile ductular cell-enriched populations from the livers of carcinogen and noncarcinogen-treated rats
    • Sirica, A. E., and Cihla, H. P. (1984) Isolation and partial characterization of oval and hyperplastic bile ductular cell-enriched populations from the livers of carcinogen and noncarcinogen-treated rats. Cancer Res. 44, 3454-3466
    • (1984) Cancer Res. , vol.44 , pp. 3454-3466
    • Sirica, A.E.1    Cihla, H.P.2
  • 18
    • 0025873457 scopus 로고
    • Oval cell proliferation of small hepatocytes in liver injury induced by D-galactosamine
    • Lemire, J., Shiojiri, N., and Fausto, N. (1991) Oval cell proliferation of small hepatocytes in liver injury induced by D-galactosamine. Am. J. Pathol. 139, 535-552
    • (1991) Am. J. Pathol. , vol.139 , pp. 535-552
    • Lemire, J.1    Shiojiri, N.2    Fausto, N.3
  • 20
    • 0024312850 scopus 로고
    • Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma
    • Sell, A., and Dunsford, H. (1989) Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma. Am. J. Pathol. 134, 1347-1363
    • (1989) Am. J. Pathol. , vol.134 , pp. 1347-1363
    • Sell, A.1    Dunsford, H.2
  • 21
    • 0023746797 scopus 로고
    • Biliary epithelial and hepatocyte cell lineage relationship in embryonic rat liver as determined by the differential expression of cytokeratins, alpha-fetoprotein, and cell surface-exposed components
    • Germain, L., Blouin, M. J., and Marceau, N. (1988) Biliary epithelial and hepatocyte cell lineage relationship in embryonic rat liver as determined by the differential expression of cytokeratins, alpha-fetoprotein, and cell surface-exposed components. Cancer. Res. 48, 4909-4918
    • (1988) Cancer. Res. , vol.48 , pp. 4909-4918
    • Germain, L.1    Blouin, M.J.2    Marceau, N.3
  • 22
    • 0023867734 scopus 로고
    • Promotion and differentiation of rat ductular oval cells in primary culture
    • Germain, L., Noel, M., Gourdeau, H., and Marceau, N. (1988) Promotion and differentiation of rat ductular oval cells in primary culture. Cancer Res. 48, 368-378
    • (1988) Cancer Res. , vol.48 , pp. 368-378
    • Germain, L.1    Noel, M.2    Gourdeau, H.3    Marceau, N.4
  • 23
    • 0014121745 scopus 로고
    • Significance of the so-called oval cell proliferation during azo-dye hepatocarcinogenesis
    • Inaoka, Y. (1967) Significance of the so-called oval cell proliferation during azo-dye hepatocarcinogenesis. Gann 58, 355-366
    • (1967) Gann , vol.58 , pp. 355-366
    • Inaoka, Y.1
  • 25
    • 0021990270 scopus 로고
    • Combined hepatocellular-cholangiocarcinoma: A histologic and immunohistochemical study
    • Goodman, Z. D., Ishak, K. G., Langloss, J. M., Sesterhenn, I. A., and Rabin, L. (1985) Combined hepatocellular-cholangiocarcinoma: a histologic and immunohistochemical study. Cancer 55, 124-135
    • (1985) Cancer , vol.55 , pp. 124-135
    • Goodman, Z.D.1    Ishak, K.G.2    Langloss, J.M.3    Sesterhenn, I.A.4    Rabin, L.5
  • 28
    • 0022318864 scopus 로고
    • The streaming liver
    • Zajicek, G., Oren, R., and Weinreb, M. (1985) The streaming liver. Liver 5, 293-300
    • (1985) Liver , vol.5 , pp. 293-300
    • Zajicek, G.1    Oren, R.2    Weinreb, M.3
  • 29
    • 0023947191 scopus 로고
    • The streaming liver II. Hepatocyte life history
    • Arber, N., Zajicek, G., and Ariel, I. (1988) The streaming liver II. Hepatocyte life history. Liver 8, 80-87
    • (1988) Liver , vol.8 , pp. 80-87
    • Arber, N.1    Zajicek, G.2    Ariel, I.3
  • 30
    • 0017656829 scopus 로고
    • Cell kinetics in the liver of rats under normal and abnormal dietary conditions
    • Blikkendaal-Lieftinck, L. F., Kooij, M., Kramer, M. F., and Den Otter, W. (1977) Cell kinetics in the liver of rats under normal and abnormal dietary conditions. Exp. Mol. Pathol. 26, 184-192
    • (1977) Exp. Mol. Pathol. , vol.26 , pp. 184-192
    • Blikkendaal-Lieftinck, L.F.1    Kooij, M.2    Kramer, M.F.3    Den Otter, W.4
  • 32
    • 0001639106 scopus 로고
    • 3-thymidine into cells of the rat and mouse
    • 3-thymidine into cells of the rat and mouse. Science 131, 737-738
    • (1960) Science , vol.131 , pp. 737-738
    • Schultze, B.1    Oehlert, W.2
  • 33
    • 0011488172 scopus 로고
    • Lifespan of liver cells
    • MacDonald, R. A. (1961) Lifespan of liver cells. Arch. Int. Med. 107, 79-87
    • (1961) Arch. Int. Med. , vol.107 , pp. 79-87
    • MacDonald, R.A.1
  • 34
    • 0014264985 scopus 로고
    • The kinetics of cellular proliferation in regenerating liver
    • Fabrikant, J. I. (1968) The kinetics of cellular proliferation in regenerating liver. J. Cell Biol. 36, 551-565
    • (1968) J. Cell Biol. , vol.36 , pp. 551-565
    • Fabrikant, J.I.1
  • 36
    • 0001824639 scopus 로고
    • Cellular proliferation in the liver. Recent results
    • Grisham, J. W. (1969) Cellular proliferation in the liver. Recent results. Cancer Res. 17, 28-43
    • (1969) Cancer Res. , vol.17 , pp. 28-43
    • Grisham, J.W.1
  • 37
    • 0029152221 scopus 로고
    • Experiments in transgenic mice demonstrate that hepatocytes are the source for postnatal liver growth and do not stream
    • Kennedy, S. C., Rettinger, S. D., Flye, M. W., and Ponder, K. P. (1995) Experiments in transgenic mice demonstrate that hepatocytes are the source for postnatal liver growth and do not stream. Hepatology 22, 160-168
    • (1995) Hepatology , vol.22 , pp. 160-168
    • Kennedy, S.C.1    Rettinger, S.D.2    Flye, M.W.3    Ponder, K.P.4
  • 38
    • 0028158811 scopus 로고
    • Liver-directed gene therapy: Quantitative evaluation of promoter elements using in vivo retroviral transduction
    • Rettinger, S., Kennedy, S., Wu, X., Flye, W., and Ponder, K. P. (1994) Liver-directed gene therapy: Quantitative evaluation of promoter elements using in vivo retroviral transduction. Proc. Natl. Acad. Sci. USA 91, 1460-1464
    • (1994) Proc. Natl. Acad. Sci. USA , vol.91 , pp. 1460-1464
    • Rettinger, S.1    Kennedy, S.2    Wu, X.3    Flye, W.4    Ponder, K.P.5
  • 40
    • 0028353410 scopus 로고
    • Replacement of diseased mouse liver by hepatic cell transplantation
    • Rhim, J. A., Sandgren, E. P., Degen, J. L., Palmiter, R. D., and Brinster, R. L. (1994) Replacement of diseased mouse liver by hepatic cell transplantation. Science 263, 1149-1152
    • (1994) Science , vol.263 , pp. 1149-1152
    • Rhim, J.A.1    Sandgren, E.P.2    Degen, J.L.3    Palmiter, R.D.4    Brinster, R.L.5
  • 42
    • 0027892512 scopus 로고
    • Cellular origin of cancer: Dedifferentiation or stem cell maturation arrest?
    • Sell, S. (1993) Cellular origin of cancer: dedifferentiation or stem cell maturation arrest? Environ. Health Persp. 101, 15-26
    • (1993) Environ. Health Persp. , vol.101 , pp. 15-26
    • Sell, S.1
  • 43
    • 0027743351 scopus 로고
    • Oval cell proliferation in early stages of hepatocarcinogenesis in Simian virus-40 large T-transgenic mice
    • Bennoun, M., Rissel, M., Engelhardt, N., Guillouzo, A., Briant, P., and Weber-Benarous, A. (1993) Oval cell proliferation in early stages of hepatocarcinogenesis in Simian virus-40 large T-transgenic mice. Am. J. Pathol. 143, 1326-1336
    • (1993) Am. J. Pathol. , vol.143 , pp. 1326-1336
    • Bennoun, M.1    Rissel, M.2    Engelhardt, N.3    Guillouzo, A.4    Briant, P.5    Weber-Benarous, A.6
  • 44
    • 0025766290 scopus 로고
    • Selective amplification of periportal transitional cells precedes formation of hepatocellular carcinoma in SV40 large tag transgenic mice
    • Schirmacher, P., Held, W. A., Yang, D., Biempica, L., and Rogler, C. E. (1991) Selective amplification of periportal transitional cells precedes formation of hepatocellular carcinoma in SV40 large tag transgenic mice. Am. J. Pathol. 139, 231-241
    • (1991) Am. J. Pathol. , vol.139 , pp. 231-241
    • Schirmacher, P.1    Held, W.A.2    Yang, D.3    Biempica, L.4    Rogler, C.E.5
  • 45
    • 0025069255 scopus 로고
    • Altered hepatic foci: Their role in murine hepatocarcinogenesis
    • Pilot, H. C. (1990) Altered hepatic foci: their role in murine hepatocarcinogenesis. Annu. Rev. Pharmacol. Toxicol. 30, 465-500
    • (1990) Annu. Rev. Pharmacol. Toxicol. , vol.30 , pp. 465-500
    • Pilot, H.C.1
  • 46
    • 0017692938 scopus 로고
    • Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogens
    • Solt, D. B., Medline, A., and Farber, E. (1977) Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogens. Am. J. Pathol. 88, 595-618
    • (1977) Am. J. Pathol. , vol.88 , pp. 595-618
    • Solt, D.B.1    Medline, A.2    Farber, E.3
  • 47
    • 0017110066 scopus 로고
    • Cancer, retrodifferentiation, and the myth of Faust
    • Uriel, J. (1976) Cancer, retrodifferentiation, and the myth of Faust. Cancer Res. 36, 4269-4275
    • (1976) Cancer Res. , vol.36 , pp. 4269-4275
    • Uriel, J.1
  • 48
    • 0023199292 scopus 로고
    • Growth in culture and tumorigenicity after transfection with the ras oncogene of liver epithelial cells from carcinogen-treated rats
    • Braun, L., Goyette, M., Yaswen, P., Thompson, N. L., and Fausto, N. (1987) Growth in culture and tumorigenicity after transfection with the ras oncogene of liver epithelial cells from carcinogen-treated rats. Cancer Res. 47, 4116-4124
    • (1987) Cancer Res. , vol.47 , pp. 4116-4124
    • Braun, L.1    Goyette, M.2    Yaswen, P.3    Thompson, N.L.4    Fausto, N.5
  • 49
    • 0025297612 scopus 로고
    • Expression of hepatocyte and oval cell antigens in hepatocellular carcinomas produced by oncogene-transfected liver epithelial cells
    • Goyette, M., Faris, R., Braun, L., Hixson, D., and Fausto, N. (1990) Expression of hepatocyte and oval cell antigens in hepatocellular carcinomas produced by oncogene-transfected liver epithelial cells. Cancer Res. 50, 4809-4817
    • (1990) Cancer Res. , vol.50 , pp. 4809-4817
    • Goyette, M.1    Faris, R.2    Braun, L.3    Hixson, D.4    Fausto, N.5
  • 50
    • 0024241798 scopus 로고
    • Neoplastic transformation and lineage switching of rat liver epithelial cells by retrovirus-associated oncogenes
    • Garfield, S., Huber, B. E., Nagy, P., Cordingley, M. G., and Thorgeirsson, S. S. (1988) Neoplastic transformation and lineage switching of rat liver epithelial cells by retrovirus-associated oncogenes. Mol. Carcinogen. 1., 189-195
    • (1988) Mol. Carcinogen. , vol.1 , pp. 189-195
    • Garfield, S.1    Huber, B.E.2    Nagy, P.3    Cordingley, M.G.4    Thorgeirsson, S.S.5
  • 51
    • 0028149501 scopus 로고
    • Oval cell lines OC/CDE 6 and OC/CDE 22 give rise to cholangio-cellular and undifferentiated carcinomas after transformation
    • Steinberg, P., Steinbrecher, R., Radaeva, S., Shirmacher, P., Dienes, H. P., Oesch, F., and Bannasch, P. (1995) Oval cell lines OC/CDE 6 and OC/CDE 22 give rise to cholangio-cellular and undifferentiated carcinomas after transformation. Lab. Invest. 71, 700-709
    • (1995) Lab. Invest. , vol.71 , pp. 700-709
    • Steinberg, P.1    Steinbrecher, R.2    Radaeva, S.3    Shirmacher, P.4    Dienes, H.P.5    Oesch, F.6    Bannasch, P.7
  • 52
    • 0023217079 scopus 로고
    • Hepatocarcinomas, cholangiocarcinomas, and hepatoblastomas produced by chemically transformed cultured rat liver epithelial cells
    • Tsao, M.-S., and Grisham, J. W. (1987) Hepatocarcinomas, cholangiocarcinomas, and hepatoblastomas produced by chemically transformed cultured rat liver epithelial cells. Am. J. Pathol. 127, 168-181
    • (1987) Am. J. Pathol. , vol.127 , pp. 168-181
    • Tsao, M.-S.1    Grisham, J.W.2
  • 53
    • 0025156630 scopus 로고
    • Oval cells and liver carcinogenesis: An analysis of celllineages in hepatic tumors using oncogene transfection techniques. Mouse liver caroinogenesis: mechanisms and species comparisons
    • Fausto, N. (1990) Oval cells and liver carcinogenesis: an analysis of celllineages in hepatic tumors using oncogene transfection techniques. Mouse liver caroinogenesis: mechanisms and species comparisons. Prog. Clin. Biol. Res. 331, 325-334
    • (1990) Prog. Clin. Biol. Res. , vol.331 , pp. 325-334
    • Fausto, N.1
  • 54
    • 0023715118 scopus 로고
    • Tumorigenicity of simian virus 40-hepatocyte cell lines: Effect of in vitro and in vivo passage on expression of liver-specific genes and oncogenes
    • Woodworth, C. D., Kreider, J. W., Mengel, L., and Isom, H. (1988) Tumorigenicity of simian virus 40-hepatocyte cell lines: effect of in vitro and in vivo passage on expression of liver-specific genes and oncogenes. Mol. Cell. Biol. 8, 4492-4501
    • (1988) Mol. Cell. Biol. , vol.8 , pp. 4492-4501
    • Woodworth, C.D.1    Kreider, J.W.2    Mengel, L.3    Isom, H.4
  • 55
    • 0026533082 scopus 로고
    • Introduction of the ras oncogene transforms a SV40 immortalized hepatocyte cell line without loss of expression of albumin and other liver-specific genes
    • Isom, H. C., Woodworth, C. D., Meng, Y., Kreider, J., Miller, T., and Mengel, L. (1992) Introduction of the ras oncogene transforms a SV40 immortalized hepatocyte cell line without loss of expression of albumin and other liver-specific genes. Cancer Res. 52, 940-948
    • (1992) Cancer Res. , vol.52 , pp. 940-948
    • Isom, H.C.1    Woodworth, C.D.2    Meng, Y.3    Kreider, J.4    Miller, T.5    Mengel, L.6
  • 56
    • 0026533045 scopus 로고
    • Ras transformation of simian virus 40-immortalized rat hepatocytes: An in vitro model of hepatocarcinogenesis
    • Fang, X.-J., Flowers, M., Keating, A., Cameron, R., and Sherman, M. (1992) Ras transformation of simian virus 40-immortalized rat hepatocytes: an in vitro model of hepatocarcinogenesis. Cancer Res. 52, 173-180
    • (1992) Cancer Res. , vol.52 , pp. 173-180
    • Fang, X.-J.1    Flowers, M.2    Keating, A.3    Cameron, R.4    Sherman, M.5
  • 57
    • 0027231678 scopus 로고
    • The v-raf oncogene enhances tumorigenicity and suppressed differentiation in vivo in a rat hepatocyte cell line
    • Fang, X.-J., Keating, A., Flowers, M., Liew, C.-C., Gupta, H., Mills, G. B., and Sherman, M. (1993) The v-raf oncogene enhances tumorigenicity and suppressed differentiation in vivo in a rat hepatocyte cell line. Carcinogenesis 14, 669-674
    • (1993) Carcinogenesis , vol.14 , pp. 669-674
    • Fang, X.-J.1    Keating, A.2    Flowers, M.3    Liew, C.-C.4    Gupta, H.5    Mills, G.B.6    Sherman, M.7
  • 58
    • 0027494387 scopus 로고
    • Hepatic gene therapy: Present and future
    • Ledley, F. R. (1993) Hepatic gene therapy: present and future. Hepatology 18, 1263-1273
    • (1993) Hepatology , vol.18 , pp. 1263-1273
    • Ledley, F.R.1
  • 59
    • 0027746111 scopus 로고
    • Regulation of the differentiation of diploid and some aneuploid rat liver epithelial (stemlike) cells by the hepatic microenvironment
    • Coleman, W. B., Wennerger, A. E., Smith, G. J., and Grisham, J. W. (1993) Regulation of the differentiation of diploid and some aneuploid rat liver epithelial (stemlike) cells by the hepatic microenvironment. Am. J. Pathol. 142, 1373-1382
    • (1993) Am. J. Pathol. , vol.142 , pp. 1373-1382
    • Coleman, W.B.1    Wennerger, A.E.2    Smith, G.J.3    Grisham, J.W.4


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.