메뉴 건너뛰기




Volumn 16, Issue 7, 2011, Pages 683-695

Trichostatin A sensitizes HBx-expressing liver cancer cells to etoposide treatment

Author keywords

Apoptosis; Bid; Etoposide; HBx; TSA

Indexed keywords

CASPASE 3; CASPASE 8; ETOPOSIDE; HEPATITIS B VIRUS X PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN BID; PROTEIN P53; TRICHOSTATIN A;

EID: 80051547554     PISSN: 13608185     EISSN: 1573675X     Source Type: Journal    
DOI: 10.1007/s10495-011-0597-x     Document Type: Article
Times cited : (20)

References (47)
  • 1
    • 1642544603 scopus 로고    scopus 로고
    • Focus on hepatocellular carcinoma
    • DOI 10.1016/S1535-6108(04)00058-3, PII S1535610804000583
    • Bruix J, Boix L, Sala M, Llovet JM (2004) Focus on hepatocellular carcinoma. Cancer Cell 5(3):215-219 (Pubitemid 38402113)
    • (2004) Cancer Cell , vol.5 , Issue.3 , pp. 215-219
    • Bruix, J.1    Boix, L.2    Sala, M.3    Llovet, J.M.4
  • 2
    • 74249096643 scopus 로고    scopus 로고
    • Hepatocellular carcinoma and evidence-based surgery
    • Braillon A (2009) Hepatocellular carcinoma and evidence-based surgery. World J Gastroenterol 15(42):5371
    • (2009) World J Gastroenterol , vol.15 , Issue.42 , pp. 5371
    • Braillon, A.1
  • 4
    • 69449106391 scopus 로고    scopus 로고
    • Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma
    • Lee JO, Lee KW, Oh DY, Kim JH, Im SA, Kim TY, Bang YJ (2009) Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma. Ann Oncol 20(8):1402-1407
    • (2009) Ann Oncol , vol.20 , Issue.8 , pp. 1402-1407
    • Lee, J.O.1    Lee, K.W.2    Oh, D.Y.3    Kim, J.H.4    Im, S.A.5    Kim, T.Y.6    Bang, Y.J.7
  • 5
    • 48049120897 scopus 로고    scopus 로고
    • Chemotherapy with etoposide, doxorubicin, cisplatin, 5-fluorouracil, and leucovorin for patients with advanced hepatocellular carcinoma
    • Yuan JN, Chao Y, Lee WP, Li CP, Lee RC, Chang FY, Yen SH, Lee SD, Whang-Peng J (2008) Chemotherapy with etoposide, doxorubicin, cisplatin, 5-fluorouracil, and leucovorin for patients with advanced hepatocellular carcinoma. Med Oncol 25(2):201-206
    • (2008) Med Oncol , vol.25 , Issue.2 , pp. 201-206
    • Yuan, J.N.1    Chao, Y.2    Lee, W.P.3    Li, C.P.4    Lee, R.C.5    Chang, F.Y.6    Yen, S.H.7    Lee, S.D.8    Whang-Peng, J.9
  • 6
    • 0034954277 scopus 로고    scopus 로고
    • X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis
    • DOI 10.1016/S1359-6101(00)00034-4, PII S1359610100000344
    • Diao J, Garces R, Richardson CD (2001) X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev 12(2-3): 189-205 (Pubitemid 32588145)
    • (2001) Cytokine and Growth Factor Reviews , vol.12 , Issue.2-3 , pp. 189-205
    • Diao, J.1    Garces, R.2    Richardson, C.D.3
  • 7
    • 57749106581 scopus 로고    scopus 로고
    • Premature cell cycle entry induced by hepatitis B virus regulatory HBx protein during compensatory liver regeneration
    • Hodgson AJ, Keasler VV, Slagle BL (2008) Premature cell cycle entry induced by hepatitis B virus regulatory HBx protein during compensatory liver regeneration. Cancer Res 68(24):10341-10348
    • (2008) Cancer Res , vol.68 , Issue.24 , pp. 10341-10348
    • Hodgson, A.J.1    Keasler, V.V.2    Slagle, B.L.3
  • 8
    • 54449091313 scopus 로고    scopus 로고
    • Hepatitis B virus X protein via the p38MAPK pathway induces E2F1 release and ATR kinase activation mediating p53 apoptosis
    • Wang WH, Hullinger RL, Andrisani OM (2008) Hepatitis B virus X protein via the p38MAPK pathway induces E2F1 release and ATR kinase activation mediating p53 apoptosis. J Biol Chem 283(37):25455-25467
    • (2008) J Biol Chem , vol.283 , Issue.37 , pp. 25455-25467
    • Wang, W.H.1    Hullinger, R.L.2    Andrisani, O.M.3
  • 9
    • 70449394392 scopus 로고    scopus 로고
    • Hepatitis B virus X protein (HBx) induces G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase
    • Cheng P, Li Y, Yang L, Wen Y, Shi W, Mao Y, Chen P, Lv H, Tang Q, Wei Y (2009) Hepatitis B virus X protein (HBx) induces G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase. Oncol Rep 22(5):1101-1107
    • (2009) Oncol Rep , vol.22 , Issue.5 , pp. 1101-1107
    • Cheng, P.1    Li, Y.2    Yang, L.3    Wen, Y.4    Shi, W.5    Mao, Y.6    Chen, P.7    Lv, H.8    Tang, Q.9    Wei, Y.10
  • 10
    • 34249901562 scopus 로고    scopus 로고
    • RNA interference targeting HBx suppresses tumor growth and enhances cisplatin chemosensitivity in human hepatocellular carcinoma
    • DOI 10.1016/j.canlet.2007.01.004, PII S0304383507000109
    • Cheng AS, Wong N, Tse AM, Chan KY, Chan KK, Sung JJ, Chan HL (2007) RNA interference targeting HBx suppresses tumor growth and enhances cisplatin chemosensitivity in human hepatocellular carcinoma. Cancer Lett 253(1):43-52 (Pubitemid 46874725)
    • (2007) Cancer Letters , vol.253 , Issue.1 , pp. 43-52
    • Cheng, A.S.L.1    Wong, N.2    Tse, A.M.Y.3    Chan, K.Y.Y.4    Chan, K.K.5    Sung, J.J.Y.6    Chan, H.L.Y.7
  • 11
    • 48549099121 scopus 로고    scopus 로고
    • COX-2 mediates hepatitis B virus X protein abrogation of p53-induced apoptosis
    • Cheng AS, Yu J, Lai PB, Chan HL, Sung JJ (2008) COX-2 mediates hepatitis B virus X protein abrogation of p53-induced apoptosis. Biochem Biophys Res Commun 374(2):175-180
    • (2008) Biochem Biophys Res Commun , vol.374 , Issue.2 , pp. 175-180
    • Cheng, A.S.1    Yu, J.2    Lai, P.B.3    Chan, H.L.4    Sung, J.J.5
  • 12
    • 77955655051 scopus 로고    scopus 로고
    • Hepatitis B virus X protein prevents apoptosis of hepatocellular carcinoma cells by upregulating SATB1 and HURP expression
    • Kuo TC, Chao CC (2010) Hepatitis B virus X protein prevents apoptosis of hepatocellular carcinoma cells by upregulating SATB1 and HURP expression. Biochem Pharmacol 80(7):1093-1102
    • (2010) Biochem Pharmacol , vol.80 , Issue.7 , pp. 1093-1102
    • Kuo, T.C.1    Chao, C.C.2
  • 13
    • 7744229935 scopus 로고    scopus 로고
    • Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: Involvement of invasive potential
    • Chung TW, Lee YC, Kim CH (2004) Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB J 18(10):1123-1125
    • (2004) FASEB J , vol.18 , Issue.10 , pp. 1123-1125
    • Chung, T.W.1    Lee, Y.C.2    Kim, C.H.3
  • 14
    • 67649595826 scopus 로고    scopus 로고
    • Apoptosis and cancer: The genesis of a research field
    • Cotter TG (2009) Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer 9(7):501-507
    • (2009) Nat Rev Cancer , vol.9 , Issue.7 , pp. 501-507
    • Cotter, T.G.1
  • 15
    • 33646846666 scopus 로고    scopus 로고
    • Mcl-1 interacts with truncated bid and inhibits its induction of cytochrome c release and its role in receptor-mediated apoptosis
    • DOI 10.1074/jbc.M505688200
    • Clohessy JG, Zhuang J, de Boer J, Gil-Gomez G, Brady HJ (2006) Mcl-1 interacts with truncated Bid and inhibits its induction of cytochrome c release and its role in receptor-mediated apoptosis. J Biol Chem 281(9):5750-5759 (Pubitemid 43847674)
    • (2006) Journal of Biological Chemistry , vol.281 , Issue.9 , pp. 5750-5759
    • Clohessy, J.G.1    Zhuang, J.2    De Boer, J.3    Gil-Gomez, G.4    Brady, H.J.M.5
  • 16
    • 33646838466 scopus 로고    scopus 로고
    • Real time single cell analysis of bid cleavage and bid translocation during caspase-dependent and neuronal caspase-independent apoptosis
    • DOI 10.1074/jbc.M511562200
    • Ward MW, Rehm M, Duessmann H, Kacmar S, Concannon CG, Prehn JH (2006) Real time single cell analysis of Bid cleavage and Bid translocation during caspase-dependent and neuronal caspase-independent apoptosis. J Biol Chem 281(9):5837-5844 (Pubitemid 43847683)
    • (2006) Journal of Biological Chemistry , vol.281 , Issue.9 , pp. 5837-5844
    • Ward, M.W.1    Rehm, M.2    Duessmann, H.3    Kacmar, S.4    Concannon, C.G.5    Prehn, J.H.M.6
  • 17
    • 24744445352 scopus 로고    scopus 로고
    • Histone deacetylase inhibitors for treatment of hepatocellular carcinoma
    • DOI 10.1111/j.1745-7254.2005.00195.x
    • Coradini D, Speranza A (2005) Histone deacetylase inhibitors for treatment of hepatocellular carcinoma. Acta Pharmacol Sin 26(9):1025-1033 (Pubitemid 41296939)
    • (2005) Acta Pharmacologica Sinica , vol.26 , Issue.9 , pp. 1025-1033
    • Coradini, D.1    Speranza, A.2
  • 19
    • 34447574853 scopus 로고    scopus 로고
    • Topoisomerase II-drug interaction domains: Identification of substituents on etoposide that interact with the enzyme
    • DOI 10.1021/bi700272u
    • Wilstermann AM, Bender RP, Godfrey M, Choi S, Anklin C, Berkowitz DB, Osheroff N, Graves DE (2007) Topoisomerase II-drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Biochemistry 46(28): 8217-8225 (Pubitemid 47075961)
    • (2007) Biochemistry , vol.46 , Issue.28 , pp. 8217-8225
    • Wilstermann, A.M.1    Bender, R.P.2    Godfrey, M.3    Choi, S.4    Anklin, C.5    Berkowitz, D.B.6    Osheroff, N.7    Graves, D.E.8
  • 20
    • 34547617889 scopus 로고    scopus 로고
    • BRCA1- and BRCA2-deficient cells are sensitive to etoposide-induced DNA double-strand breaks via topoisomerase II
    • DOI 10.1158/0008-5472.CAN-07-0601
    • Treszezamsky AD, Kachnic LA, Feng Z, Zhang J, Tokadjian C, Powell SN (2007) BRCA1- and BRCA2-deficient cells are sensitive to etoposide-induced DNA double-strand breaks via topoisomerase II. Cancer Res 67(15):7078-7081 (Pubitemid 47206532)
    • (2007) Cancer Research , vol.67 , Issue.15 , pp. 7078-7081
    • Treszezamsky, A.D.1    Kachnic, L.A.2    Feng, Z.3    Zhang, J.4    Tokadjian, C.5    Powell, S.N.6
  • 22
    • 21244469091 scopus 로고    scopus 로고
    • Etoposide (VP-16) sensitizes p53-deficient human non-small cell lung cancer cells to caspase-7-mediated apoptosis
    • DOI 10.1007/s10495-005-1898-8
    • Chiu CC, Lin CH, Fang K (2005) Etoposide (VP-16) sensitizes p53-deficient human non-small cell lung cancer cells to caspase- 7-mediated apoptosis. Apoptosis 10(3):643-650 (Pubitemid 40896669)
    • (2005) Apoptosis , vol.10 , Issue.3 , pp. 643-650
    • Chiu, C.-C.1    Lin, C.-H.M.Y.2    Fang, K.3
  • 23
    • 0033862298 scopus 로고    scopus 로고
    • Wild-type p53-dependent etoposide-induced apoptosis mediated by caspase- 3 activation in human glioma cells
    • Yin D, Tamaki N, Kokunai T (2000) Wild-type p53-dependent etoposide-induced apoptosis mediated by caspase-3 activation in human glioma cells. J Neurosurg 93(2):289-297 (Pubitemid 30604872)
    • (2000) Journal of Neurosurgery , vol.93 , Issue.2 , pp. 289-297
    • Yin, D.1    Tamaki, N.2    Kokunai, T.3
  • 26
    • 0038485588 scopus 로고    scopus 로고
    • Role of caspases, Bid, and p53 in the apoptotic response triggered by histone deacetylase inhibitors trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA)
    • DOI 10.1074/jbc.M213093200
    • Henderson C, Mizzau M, Paroni G, Maestro R, Schneider C, Brancolini C (2003) Role of caspases, Bid, and p53 in the apoptotic response triggered by histone deacetylase inhibitors trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA). J Biol Chem 278(14):12579-12589 (Pubitemid 36800248)
    • (2003) Journal of Biological Chemistry , vol.278 , Issue.14 , pp. 12579-12589
    • Henderson, C.1    Mizzau, M.2    Paroni, G.3    Maestro, R.4    Schneider, C.5    Brancolini, C.6
  • 27
    • 49849092584 scopus 로고    scopus 로고
    • Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells
    • Muscolini M, Cianfrocca R, Sajeva A, Mozzetti S, Ferrandina G, Costanzo A, Tuosto L (2008) Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells. Mol Cancer Ther 7(6):1410-1419
    • (2008) Mol Cancer Ther , vol.7 , Issue.6 , pp. 1410-1419
    • Muscolini, M.1    Cianfrocca, R.2    Sajeva, A.3    Mozzetti, S.4    Ferrandina, G.5    Costanzo, A.6    Tuosto, L.7
  • 28
    • 43749087604 scopus 로고    scopus 로고
    • Combinatorial action of the HDAC inhibitor trichostatin A and etoposide induces caspase-mediated AIF-dependent apoptotic cell death in non-small cell lung carcinoma cells
    • DOI 10.1038/sj.onc.1210976, PII 1210976
    • Hajji N, Wallenborg K, Vlachos P, Nyman U, Hermanson O, Joseph B (2008) Combinatorial action of the HDAC inhibitor trichostatin A and etoposide induces caspase-mediated AIFdependent apoptotic cell death in non-small cell lung carcinoma cells. Oncogene 27(22):3134-3144 (Pubitemid 351693171)
    • (2008) Oncogene , vol.27 , Issue.22 , pp. 3134-3144
    • Hajji, N.1    Wallenborg, K.2    Vlachos, P.3    Nyman, U.4    Hermanson, O.5    Joseph, B.6
  • 29
    • 33744963542 scopus 로고    scopus 로고
    • p53 is cleaved by caspases generating fragments localizing to mitochondria
    • DOI 10.1074/jbc.M512467200
    • Sayan BS, Sayan AE, Knight RA, Melino G, Cohen GM (2006) p53 is cleaved by caspases generating fragments localizing to mitochondria. J Biol Chem 281(19):13566-13573 (Pubitemid 43855270)
    • (2006) Journal of Biological Chemistry , vol.281 , Issue.19 , pp. 13566-13573
    • Sayan, B.S.1    Sayan, A.E.2    Knight, R.A.3    Melino, G.4    Cohen, G.M.5
  • 30
    • 72849108742 scopus 로고    scopus 로고
    • Association of p53 with Bid induces cell death in response to etoposide treatment in hepatocellular carcinoma
    • Song G, Chen GG, Yun JP, Lai PB (2009) Association of p53 with Bid induces cell death in response to etoposide treatment in hepatocellular carcinoma. Curr Cancer Drug Targets 9(7):871-880
    • (2009) Curr Cancer Drug Targets , vol.9 , Issue.7 , pp. 871-880
    • Song, G.1    Chen, G.G.2    Yun, J.P.3    Lai, P.B.4
  • 31
    • 58949098335 scopus 로고    scopus 로고
    • Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression
    • Tang H, Da L, Mao Y, Li Y, Li D, Xu Z, Li F, Wang Y, Tiollais P, Li T, Zhao M (2009) Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression. Hepatology 49(1):60-71
    • (2009) Hepatology , vol.49 , Issue.1 , pp. 60-71
    • Tang, H.1    Da, L.2    Mao, Y.3    Li, Y.4    Li, D.5    Xu, Z.6    Li, F.7    Wang, Y.8    Tiollais, P.9    Li, T.10    Zhao, M.11
  • 32
    • 48849116019 scopus 로고    scopus 로고
    • Hepatitis B virus X protein induces apoptosis by enhancing translocation of Bax to mitochondria
    • Kim HJ, Kim SY, Kim J, Lee H, Choi M, Kim JK, Ahn JK (2008) Hepatitis B virus X protein induces apoptosis by enhancing translocation of Bax to mitochondria. IUBMB Life 60(7):473-480
    • (2008) IUBMB Life , vol.60 , Issue.7 , pp. 473-480
    • Kim, H.J.1    Kim, S.Y.2    Kim, J.3    Lee, H.4    Choi, M.5    Kim, J.K.6    Ahn, J.K.7
  • 35
    • 17644383750 scopus 로고    scopus 로고
    • Human hepatitis B virus X protein promotes cell proliferation and inhibits cell apoptosis through interacting with a serine protease Hepsin
    • DOI 10.1007/s00705-004-0446-0
    • Zhang JL, Zhao WG,WuKL, Wang K, Zhang X, Gu CF, Li Y, Zhu Y, Wu JG (2005) Human hepatitis B virus X protein promotes cell proliferation and inhibits cell apoptosis through interacting with a serine protease Hepsin. Arch Virol 150(4):721-741 (Pubitemid 40560821)
    • (2005) Archives of Virology , vol.150 , Issue.4 , pp. 721-741
    • Zhang, J.-L.1    Zhao, W.-G.2    Wu, K.-L.3    Wang, K.4    Zhang, X.5    Gu, C.-F.6    Li, Y.7    Zhu, Y.8    Wu, J.-G.9
  • 36
    • 0035907311 scopus 로고    scopus 로고
    • The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade
    • Lee YI, Kang-Park S, Do SI (2001) The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. J Biol Chem 276(20):16969-16977
    • (2001) J Biol Chem , vol.276 , Issue.20 , pp. 16969-16977
    • Lee, Y.I.1    Kang-Park, S.2    Do, S.I.3
  • 39
    • 0034785734 scopus 로고    scopus 로고
    • Sustained activation of mitogen-activated protein kinases and activator protein 1 by the hepatitis B virus X protein in mouse hepatocytes in vivo
    • DOI 10.1128/JVI.75.21.10348-10358.2001
    • Nijhara R, Jana SS, Goswami SK, Rana A, Majumdar SS, Kumar V, Sarkar DP (2001) Sustained activation of mitogen-activated protein kinases and activator protein 1 by the hepatitis B virus X protein in mouse hepatocytes in vivo. J Virol 75(21):10348-10358 (Pubitemid 32948065)
    • (2001) Journal of Virology , vol.75 , Issue.21 , pp. 10348-10358
    • Nijhara, R.1    Jana, S.S.2    Goswami, S.K.3    Rana, A.4    Majumdar, S.S.5    Kumar, V.6    Sarkar, D.P.7
  • 41
    • 0028855276 scopus 로고
    • Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response elementdirected transactivation
    • Truant R, Antunovic J, Greenblatt J, Prives C, Cromlish JA (1995) Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response elementdirected transactivation. J Virol 69(3):1851-1859
    • (1995) J Virol , vol.69 , Issue.3 , pp. 1851-1859
    • Truant, R.1    Antunovic, J.2    Greenblatt, J.3    Prives, C.4    Cromlish, J.A.5
  • 42
    • 43649102599 scopus 로고    scopus 로고
    • Reactivation of p53 in cells expressing hepatitis B virus X-protein involves p53 phosphorylation and a reduction of Hdm2
    • DOI 10.1111/j.1349-7006.2008.00754.x
    • Wang JH, Yun C, Kim S, Chae S, Lee YI, Kim WH, Lee JH, Kim W, Cho H (2008) Reactivation of p53 in cells expressing hepatitis B virus X-protein involves p53 phosphorylation and a reduction of Hdm2. Cancer Sci 99(5):888-893 (Pubitemid 351997589)
    • (2008) Cancer Science , vol.99 , Issue.5 , pp. 888-893
    • Wang, J.-H.1    Yun, C.2    Kim, S.3    Chae, S.4    Lee, Y.I.5    Kim, W.-H.6    Lee, J.-H.7    Kim, W.8    Cho, H.9
  • 43
    • 0030826733 scopus 로고    scopus 로고
    • Induced N- and C-terminal cleavage of p53: A core fragment of p53, generated by interaction with damaged DNA, promotes cleavage of the N-terminus of full-length p53, whereas ssDNA induces C-terminal cleavage of p53
    • DOI 10.1093/emboj/16.19.6008
    • Okorokov AL, Ponchel F, Milner J (1997) Induced N- and C-terminal cleavage of p53: a core fragment of p53, generated by interaction with damaged DNA, promotes cleavage of the N-terminus of full-length p53, whereas ssDNA induces C-terminal cleavage of p53. EMBO J 16(19):6008-6017 (Pubitemid 27427296)
    • (1997) EMBO Journal , vol.16 , Issue.19 , pp. 6008-6017
    • Okorokov, A.L.1    Ponchel, F.2    Milner, J.3
  • 44
    • 38449114690 scopus 로고    scopus 로고
    • The combination of the histone-deacetylase inhibitor trichostatin A and gemcitabine induces inhibition of proliferation and increased apoptosis in pancreatic carcinoma cells
    • Gahr S, Ocker M, Ganslmayer M, Zopf S, Okamoto K, Hartl A, Leitner S, Hahn EG, Herold C (2007) The combination of the histone-deacetylase inhibitor trichostatin A and gemcitabine induces inhibition of proliferation and increased apoptosis in pancreatic carcinoma cells. Int J Oncol 31(3):567-576
    • (2007) Int J Oncol , vol.31 , Issue.3 , pp. 567-576
    • Gahr, S.1    Ocker, M.2    Ganslmayer, M.3    Zopf, S.4    Okamoto, K.5    Hartl, A.6    Leitner, S.7    Hahn, E.G.8    Herold, C.9


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.