The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Cyclophilin A as a New Therapeutic Target for Hepatitis C Virus-induced Hepatocellular Carcinoma

  • Lee, Jinhwa (Department of Clinical Lab Science, School of Health Science, Dongseo University)
  • Received : 2013.03.28
  • Accepted : 2013.09.23
  • Published : 2013.10.30
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Abstract

Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is thought to account for more than 80% of primary liver cancers. Both HBV and HCV can establish chronic liver inflammatory infections, altering hepatocyte and liver physiology with potential liver disease progression and HCC development. Cyclophilin A (CypA) has been identified as an essential host factor for the HCV replication by physically interacting with the HCV non structural protein NS5A that in turn interacts with RNA-dependent RNA polymerase NS5B. CypA, a cytosolic binding protein of the immunosuppressive drug cyclosporine A, is overexpressed in many cancer types and often associated with malignant transformation. Therefore, CypA can be a good target for molecular cancer therapy. Because of antiviral activity, the CypA inhibitors have been tested for the treatment of chronic hepatitis C. Nonimmunosuppressive Cyp inhibitors such as NIM811, SCY-635, and Alisporivir have attracted more interests for appropriating CypA for antiviral chemotherapeutic target on HCV infection. This review describes CypA inhibitors as a potential HCC treatment tool that is contrived by their obstructing chronic HCV infection and summarizes roles of CypA in cancer development.

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References

  1. Friedman J, Weissman I. Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA. Cell. 1991;66:799-806. https://doi.org/10.1016/0092-8674(91)90123-G
  2. Rush DN. Cyclosporine toxicity to organs other than the kidney. Clin Biochem. 1991;24:101-105. https://doi.org/10.1016/0009-9120(91)90399-Y
  3. Luban J. Absconding with the chaperone: essential cyclophilin-Gag interaction in HIV-1 virions. Cell. 1996;87:1157-1159. https://doi.org/10.1016/S0092-8674(00)81811-5
  4. Klappa P, Freedman RB, Zimmermann R. Protein disulphide isomerase and a lumenal cyclophilin-type peptidyl prolyl cistrans isomerase are in transient contact with secretory proteins during late stages of translocation. Eur J Biochem. 1995;232:755-764. https://doi.org/10.1111/j.1432-1033.1995.tb20870.x
  5. Naylor DJ, Hoogenraad NJ, Hoj PB. Characterisation of several Hsp70 interacting proteins from mammalian organelles. Biochim Biophys Acta. 1999;1431:443-450. https://doi.org/10.1016/S0167-4838(99)00070-9
  6. Castro AP, Carvalho TM, Moussatche N, Damaso CR. Redistribution of cyclophilin A to viral factories during vaccinia virus infection and its incorporation into mature particles. J Virol. 2003;77:9052-9068. https://doi.org/10.1128/JVI.77.16.9052-9068.2003
  7. Steinmann B, Bruckner P, Superti-Furga A. Cyclosporin A slows collagen triple-helix formation in vivo: indirect evidence for a physiologic role of peptidyl-prolyl cis-trans-isomerase. J Biol Chem. 1991;266:1299-1303.
  8. Kruse M, Brunke M, Escher A, Szalay AA, Tropschug M, Zimmermann R. Enzyme assembly after de novo synthesis in rabbit reticulocyte lysate involves molecular chaperones and immunophilins. J Biol Chem. 1995;270:2588-2594. https://doi.org/10.1074/jbc.270.6.2588
  9. Craig EA, Gambill BD, Nelson RJ. Heat shock proteins: molecular chaperones of protein biogenesis. Microbiol Rev. 1993;57:402-414.
  10. Parsell DA, Lindquist S. The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu Rev Genet. 1993;27:437-496. https://doi.org/10.1146/annurev.ge.27.120193.002253
  11. Hong F, Lee J, Song JW, Lee SJ, Ahn H, Cho JJ, Ha J, Kim SS. Cyclosporin A blocks muscle differentiation by inducing oxidative stress and inhibiting the peptidyl-prolyl-cis-trans isomerase activity of cyclophilin A: cyclophilin A protects myoblasts from cyclosporin A-induced cytotoxicity. FASEB J. 2002;16:1633-1635. https://doi.org/10.1096/fj.02-0060fje
  12. Wiederrecht G, Lam E, Hung S, Martin M, Sigal N. The mechanism of action of FK-506 and cyclosporin A. Ann N Y Acad Sci. 1993;696:9-19.
  13. Bauer K, Kretzschmar AK, Cvijic H, Blumert C, Loffler D, Brocke-Heidrich K, Schiene-Fischer C, Fischer G, Sinz A, Clevenger CV, Horn F. Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells. Oncogene. 2009;28:2784-2795. https://doi.org/10.1038/onc.2009.142
  14. Haworth RA, Hunter DR. Allosteric inhibition of the $Ca^{2+}$-activated hydrophilic channel of the mitochondrial inner membrane by nucleotides. J Membr Biol. 1980;54:231-236. https://doi.org/10.1007/BF01870239
  15. Halestrap AP, Davidson AM. Inhibition of $Ca^{2+}$-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem J. 1990;268:153-160. https://doi.org/10.1042/bj2680153
  16. Bhattacharyya T, Karnezis AN, Murphy SP, Hoang T, Freeman BC, Phillips B, Morimoto RI. Cloning and subcellular localization of human mitochondrial hsp70. J Biol Chem. 1995;270:1705-1710. https://doi.org/10.1074/jbc.270.4.1705
  17. Thomas PJ, Qu BH, Pedersen PL. Defective protein folding as a basis of human disease. Trends Biochem Sci. 1995;20:456-459. https://doi.org/10.1016/S0968-0004(00)89100-8
  18. Price ER, Zydowsky LD, Jin MJ, Baker CH, McKeon FD, Walsh CT. Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Proc Natl Acad Sci USA. 1991;88:1903-1907. https://doi.org/10.1073/pnas.88.5.1903
  19. Sherry B, Yarlett N, Strupp A, Cerami A. Identification of cyclophilin as a proinflammatory secretory product of lipopolysaccharide-activated macrophages. Proc Natl Acad Sci USA. 1992;89:3511-3515. https://doi.org/10.1073/pnas.89.8.3511
  20. Yurchenko V, Zybarth G, O'Connor M, Dai WW, Franchin G, Hao T, Guo H, Hung HC, Toole B, Gallay P, Sherry B, Bukrinsky M. Active site residues of cyclophilin A are crucial for its signaling activity via CD147. J Biol Chem. 2002;277:22959-22965. https://doi.org/10.1074/jbc.M201593200
  21. Sherry B, Zybarth G, Alfano M, Dubrovsky L, Mitchell R, Rich D, Ulrich P, Bucala R, Cerami A, Bukrinsky M. Role of cyclophilin A in the uptake of HIV-1 by macrophages and T lymphocytes. Proc Natl Acad Sci U S A. 1998;95:1758-1763. https://doi.org/10.1073/pnas.95.4.1758
  22. Jin ZG, Melaragno MG, Liao DF, Yan C, Haendeler J, Suh YA, Lambeth JD, Berk BC. Cyclophilin A is a secreted growth factor induced by oxidative stress. Circ Res. 2000;87:789-796. https://doi.org/10.1161/01.RES.87.9.789
  23. Yurchenko V, O'Connor M, Dai WW, Guo H, Toole B, Sherry B, Bukrinsky M. CD147 is a signaling receptor for cyclophilin B. Biochem Biophys Res Commun. 2001;288:786-788. https://doi.org/10.1006/bbrc.2001.5847
  24. Konttinen YT, Li TF, Mandelin J, Liljestrom M, Sorsa T, Santavirta S, Virtanen I. Increased expression of extracellular matrix metalloproteinase inducer in rheumatoid synovium. Arthritis Rheum. 2000;43:275-280. https://doi.org/10.1002/1529-0131(200002)43:2<275::AID-ANR6>3.0.CO;2-#
  25. Jin ZG, Melaragno MG, Liao DF, Yan C, Haendeler J, Suh YA, Lambeth JD, Berk BC. Cyclophilin A is a secreted growth factor induced by oxidative stress. Circ Res. 2000;87:789-796. https://doi.org/10.1161/01.RES.87.9.789
  26. Sarris AH, Harding MW, Jiang TR, Aftab D, Handschumacher RE. Immunofluorescent localization and immunochemical determination of cyclophilin-A with specific rabbit antisera. Transplantation. 1992;54:904-910. https://doi.org/10.1097/00007890-199211000-00026
  27. Zhu C, Wang X, Deinum J, Huang Z, Gao J, Modjtahedi N, Neagu MR, Nilsson M, Eriksson PS, Hagberg H, Luban J, Kroemer G, Blomgren K. Cyclophilin A participates in the nuclear translocation of apoptosis-inducing factor in neurons after cerebral hypoxia-ischemia. J Exp Med. 2007;204:1741-1748. https://doi.org/10.1084/jem.20070193
  28. Krummrei U, Bang R, Schmidtchen R, Brune K, Bang H. Cyclophilin-A is a zinc-dependent DNA binding protein in macrophages. FEBS Lett. 1995;371:47-51. https://doi.org/10.1016/0014-5793(95)00815-Q
  29. Satoh K, Shimokawa H, Berk BC. Cyclophilin A: promising new target in cardiovascular therapy. Circ J. 2010;74:2249-2256. https://doi.org/10.1253/circj.CJ-10-0904
  30. Obchoei S, Wongkhan S, Wongkham C, Li M, Yao Q, Chen C. Cyclophilin A: potential functions and therapeutic target for human cancer. Med Sci Monit. 2009;15:RA221-232.
  31. Towers GJ, Hatziioannou T, Cowan S, Goff SP, Luban J, Bieniasz PD. Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Nat Med. 2003;9:1138-1143. https://doi.org/10.1038/nm910
  32. Wohlfarth C, Efferth T. Natural products as promising drug candidates for the treatment of hepatitis B and C. Acta Pharmacol Sin. 2009;30:25-30. https://doi.org/10.1038/aps.2008.5
  33. Satoh K, Nigro P, Berk BC. Oxidative stress and vascular smooth muscle cell growth: a mechanistic linkage by cyclophilin A. Antioxid Redox Signal. 2010;12:675-682. https://doi.org/10.1089/ars.2009.2875
  34. Sherry B, Zybarth G, Alfano M, Dubrovsky L, Mitchell R, Rich D, Ulrich P, Bucala R, Cerami A, Bukrinsky M. Role of cyclophilin A in the uptake of HIV-1 by macrophages and T lymphocytes. Proc Natl Acad Sci USA. 1998;95:1758-1763. https://doi.org/10.1073/pnas.95.4.1758
  35. Heitman J, Cullen BR. Cyclophilin B escorts the hepatitis C virus RNA polymerase: a viral achilles heel? Mol Cell. 2005;19:145-146. https://doi.org/10.1016/j.molcel.2005.07.001
  36. Membreno FE, Espinales JC, Lawitz EJ. Cyclophilin inhibitors for hepatitis C therapy. Clin Liver Dis. 2013;17:129-139. https://doi.org/10.1016/j.cld.2012.09.008
  37. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264-1273. https://doi.org/10.1053/j.gastro.2011.12.061
  38. Bouchard MJ, Navas-Martin S. Hepatitis B and C virus hepatocarcinogenesis: lessons learned and future challenges. Cancer Lett. 2011;305:123-143. https://doi.org/10.1016/j.canlet.2010.11.014
  39. Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis. 2005;25:143-154. https://doi.org/10.1055/s-2005-871194
  40. Roberts LR, Gores GJ. Hepatocellular carcinoma: molecular pathways and new therapeutic targets. Semin Liver Dis. 2005;25:212-225. https://doi.org/10.1055/s-2005-871200
  41. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557-2576. https://doi.org/10.1053/j.gastro.2007.04.061
  42. Suzuki T, Aizaki H, Murakami K, Shoji I, Wakita T. Molecular biology of hepatitis C virus. J Gastroenterol. 2007;42:411-423. https://doi.org/10.1007/s00535-007-2030-3
  43. Dustin LB, Rice CM. Flying under the radar: the immunobiology of hepatitis C. Annu Rev Immunol. 2007;25:71-99. https://doi.org/10.1146/annurev.immunol.25.022106.141602
  44. Ura S, Honda M, Yamashita T, Ueda T, Takatori H, Nishino R, Sunakozaka H, Sakai Y, Horimoto K, Kaneko S. Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma. Hepatology. 2009;49:1098-1112. https://doi.org/10.1002/hep.22749
  45. Nieto N. Oxidative-stress and IL-6 mediate the fibrogenic effects of Kupffer cells on stellate cells. Hepatology. 2006;44:1487-1501. https://doi.org/10.1002/hep.21427
  46. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215-233. https://doi.org/10.1016/j.cell.2009.01.002
  47. Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M. MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology. 2008;47:1223-1232.
  48. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liverspecific MicroRNA. Science. 2005;309:1577-1581. https://doi.org/10.1126/science.1113329
  49. Kutay H, Bai S, Datta J, Motiwala T, Pogribny I, Frankel W, Jacob ST, Ghoshal K. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem. 2006; 99:671-678. https://doi.org/10.1002/jcb.20982
  50. Jopling CL, Norman KL, Sarnow P. Positive and negative modulation of viral and cellular mRNAs by liver-specific microRNA miR-122. Cold Spring Harb Symp Quant Biol. 2006; 71:369-376. https://doi.org/10.1101/sqb.2006.71.022
  51. Randall G, Panis M, Cooper JD, Tellinghuisen TL, Sukhodolets KE, Pfeffer S, Landthaler M, Landgraf P, Kan S, Lindenbach BD, Chien M, Weir DB, Russo JJ, Ju J, Brownstein MJ, Sheridan R, Sander C, Zavolan M, Tuschl T, Rice CM. Cellular cofactors affecting hepatitis C virus infection and replication. Proc Natl Acad Sci U S A. 2007;104:12884-12889. https://doi.org/10.1073/pnas.0704894104
  52. Nunnari G, Schnell MJ. MicroRNA-122: a therapeutic target for hepatitis C virus (HCV) infection. Front Biosci (Schol Ed). 2011;3:1032-1037.
  53. Gao P, Wong CC, Tung EK, Lee JM, Wong CM, Ng IO. Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesis. J Hepatol. 2011;54:1177-1184. https://doi.org/10.1016/j.jhep.2010.09.023
  54. Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, Ambs S, Chen Y, Meltzer PS, Croce CM, Qin LX, Man K, Lo CM, Lee J, Ng IO, Fan J, Tang ZY, Sun HC, Wang XW. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med. 2009;361:1437-1447. https://doi.org/10.1056/NEJMoa0901282
  55. McGivern DR, Lemon SM. Tumor suppressors, chromosomal instability, and hepatitis C virus-associated liver cancer. Annu Rev Pathol. 2009;4:399-415. https://doi.org/10.1146/annurev.pathol.4.110807.092202
  56. Finch CE, Crimmins EM. Inflammatory exposure and historical changes in human life-spans. Science. 2004;305:1736-1739. https://doi.org/10.1126/science.1092556
  57. Brechot C, Jaffredo F, Lagorce D, Gerken G, Meyer zum Buschenfelde K, Papakonstontinou A, Hadziyannis S, Romeo R, Colombo M, Rodes J, Bruix J, Williams R, Naoumov N. Impact of HBV, HCV and GBV-C/HGV on hepatocellular carcinomas in Europe: results of a European concerted action. J Hepatol. 1998;29:173-183. https://doi.org/10.1016/S0168-8278(98)80001-9
  58. Wang YY, Lo GH, Lai KH, Cheng JS, Lin CK, Hsu PI. Increased serum concentrations of tumor necrosis factoralpha are associated with disease progression and malnutrition in hepatocellular carcinoma. J Chin Med Assoc. 2003;66:593-598.
  59. Mondelli MU, Barnaba V. Viral and host immune regulatory mechanisms in hepatitis C virus infection. Eur J Gastroenterol Hepatol. 2006;18:327-331. https://doi.org/10.1097/00042737-200604000-00004
  60. Tsai JF, Jeng JE, Ho MS, Chang WY, Lin ZY, Tsai JH. Hepatitis B and C virus infection as risk factors for hepatocellular carcinoma in Chinese: a case-control study. Int J Cancer. 1994;56:619-621. https://doi.org/10.1002/ijc.2910560502
  61. Stroffolini T, Chiaramonte M, Tiribelli C, Villa E, Simonetti RG, Rapicetta M, Stazi MA, Bertin T, Croce SL, Trande P, et al. Hepatitis C virus infection, HBsAg carrier state and hepatocellular carcinoma: relative risk and population attributable risk from a case-control study in Italy. J Hepatol. 1992;16:360-363. https://doi.org/10.1016/S0168-8278(05)80670-1
  62. Wheelhouse NM, Chan YS, Gillies SE, Caldwell H, Ross JA, Harrison DJ, Prost S. TNF-alpha induced DNA damage in primary murine hepatocytes. Int J Mol Med. 2003;12:889-894.
  63. Rehermann B. Intrahepatic T cells in hepatitis B: viral control versus liver cell injury. J Exp Med. 2000;191:1263-1268. https://doi.org/10.1084/jem.191.8.1263
  64. Freeman AJ, Marinos G, Ffrench RA, Lloyd AR. Immunopathogenesis of hepatitis C virus infection. Immunol Cell Biol. 2001;79:515-536. https://doi.org/10.1046/j.1440-1711.2001.01036.x
  65. Rapicetta M, Ferrari C, Levrero M. Viral determinants and host immune responses in the pathogenesis of HBV infection. J Med Virol. 2002;67:454-457. https://doi.org/10.1002/jmv.10096
  66. Akiba J, Yano H, Ogasawara S, Higaki K, Kojiro M. Expression and function of interleukin-8 in human hepatocellular carcinoma. Int J Oncol. 2001;18:257-264.
  67. Ishido S, Fujita T, Hotta H. Complex formation of NS5B with NS3 and NS4A proteins of hepatitis C virus. Biochem Biophys Res Commun. 1998;244:35-40. https://doi.org/10.1006/bbrc.1998.8202
  68. Zekri AR, Ashour MS, Hassan A, Alam El-Din HM, El-Shehaby AM, Abu-Shady MA. Cytokine profile in Egyptian hepatitis C virus genotype-4 in relation to liver disease progression. World J Gastroenterol. 2005;11:6624-6630. https://doi.org/10.3748/wjg.v11.i42.6624
  69. Brady MT, MacDonald AJ, Rowan AG, Mills KH. Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes. Eur J Immunol. 2003;33:3448-3457. https://doi.org/10.1002/eji.200324251
  70. Sun B, Karin M. Obesity, inflammation, and liver cancer. J Hepatol. 2012;56:704-713. https://doi.org/10.1016/j.jhep.2011.09.020
  71. Zekri AR, Bahnassy AA, Abdel-Wahab SA, Khafagy MM, Loutfy SA, Radwan H, Shaarawy SM. Expression of pro- and anti-inflammatory cytokines in relation to apoptotic genes in Egyptian liver disease patients associated with HCV-genotype- 4. J Gastroenterol Hepatol. 2009;24:416-428. https://doi.org/10.1111/j.1440-1746.2008.05699.x
  72. Ait-Goughoulte M, Banerjee A, Meyer K, Mazumdar B, Saito K, Ray RB, Ray R. Hepatitis C virus core protein interacts with fibrinogen-beta and attenuates cytokine stimulated acute- phase response. Hepatology. 2010;51:1505-1513. https://doi.org/10.1002/hep.23502
  73. Tilg H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G, Huber C. Serum levels of cytokines in chronic liver diseases. Gastroenterology. 1992;103:264-274. https://doi.org/10.1016/0016-5085(92)91122-K
  74. Torre D, Zeroli C, Giola M, Ferrario G, Fiori GP, Bonetta G, Tambini R. Serum levels of interleukin-1 alpha, interleukin-1 beta, interleukin-6, and tumor necrosis factor in patients with acute viral hepatitis. Clin Infect Dis. 1994;18:194-198. https://doi.org/10.1093/clinids/18.2.194
  75. Taniguchi H, Kato N, Otsuka M, Goto T, Yoshida H, Shiratori Y, Omata M. Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription. J Med Virol. 2004;72:52-59. https://doi.org/10.1002/jmv.10545
  76. Shin JY, Hur W, Wang JS, Jang JW, Kim CW, Bae SH, Jang SK, Yang SH, Sung YC, Kwon OJ, Yoon SK. HCV core protein promotes liver fibrogenesis via up-regulation of CTGF with TGF-beta1. Exp Mol Med. 2005;37:138-145. https://doi.org/10.1038/emm.2005.19
  77. Battaglia S, Benzoubir N, Nobilet S, Charneau P, Samuel D, Zignego AL, Atfi A, Brechot C, Bourgeade MF. Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition. PLoS One. 2009;4:e4355. https://doi.org/10.1371/journal.pone.0004355
  78. Large MK, Kittlesen DJ, Hahn YS. Suppression of host immune response by the core protein of hepatitis C virus: possible implications for hepatitis C virus persistence. J Immunol. 1999;162:931-938.
  79. You LR, Chen CM, Lee YH. Hepatitis C virus core protein enhances NF-kappaB signal pathway triggering by lymphotoxin-beta receptor ligand and tumor necrosis factor alpha. J Virol. 1999;73:1672-1681.
  80. Soguero C, Joo M, Chianese-Bullock KA, Nguyen DT, Tung K, Hahn YS. Hepatitis C virus core protein leads to immune suppression and liver damage in a transgenic murine model. J Virol. 2002;76:9345-9354. https://doi.org/10.1128/JVI.76.18.9345-9354.2002
  81. Chan-Fook C, Jiang WR, Clarke BE, Zitzmann N, Maidens C, McKeating JA, Jones IM. Hepatitis C virus glycoprotein E2 binding to CD81: the role of E1E2 cleavage and protein glycosylation in bioactivity. Virology. 2000;273:60-66. https://doi.org/10.1006/viro.2000.0407
  82. Reyes GR. The nonstructural NS5A protein of hepatitis C virus: an expanding, multifunctional role in enhancing hepatitis C virus pathogenesis. J Biomed Sci. 2002;9:187-197. https://doi.org/10.1007/BF02256065
  83. Kitaoka S, Shiota G, Kawasaki H. Serum levels of interleukin-10, interleukin-12 and soluble interleukin-2 receptor in chronic liver disease type C. Hepatogastroenterology. 2003;50:1569-1574.
  84. Chia CS, Ban K, Ithnin H, Singh H, Krishnan R, Mokhtar S, Malihan N, Seow HF. Expression of interleukin-18, interferon- gamma and interleukin-10 in hepatocellular carcinoma. Immunol Lett. 2002;84:163-172. https://doi.org/10.1016/S0165-2478(02)00176-1
  85. Kakumu S, Okumura A, Ishikawa T, Yano M, Enomoto A, Nishimura H, Yoshioka K, Yoshika Y. Serum levels of IL-10, IL-15 and soluble tumour necrosis factor-alpha (TNF-alpha) receptors in type C chronic liver disease. Clin Exp Immunol. 1997;109:458-463. https://doi.org/10.1046/j.1365-2249.1997.4861382.x
  86. Zekri AR, Ashour MS, Hassan A, Alam El-Din HM, El-Shehaby AM, Abu-Shady MA. Cytokine profile in Egyptian hepatitis C virus genotype-4 in relation to liver disease progression. World J Gastroenterol. 2005;11:6624-6630. https://doi.org/10.3748/wjg.v11.i42.6624
  87. Beckebaum S, Zhang X, Chen X, Yu Z, Frilling A, Dworacki G, Grosse-Wilde H, Broelsch CE, Gerken G, Cicinnati VR. Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. Clin Cancer Res. 2004;10:7260-7269. https://doi.org/10.1158/1078-0432.CCR-04-0872
  88. Huang YS, Hwang SJ, Chan CY, Wu JC, Chao Y, Chang FY, Lee SD. Serum levels of cytokines in hepatitis C-related liver disease: a longitudinal study. Zhonghua Yi Xue Za Zhi (Taipei). 1999;62:327-333.
  89. Nakazaki H. Preoperative and postoperative cytokines in patients with cancer. Cancer. 1992;70:709-713. https://doi.org/10.1002/1097-0142(19920801)70:3<709::AID-CNCR2820700328>3.0.CO;2-O
  90. Ikeguchi M, Hirooka Y. Interleukin-2 gene expression is a new biological prognostic marker in hepatocellular carcinomas. Onkologie. 2005;28:255-259. https://doi.org/10.1159/000084695
  91. Aroucha DC, do Carmo RF, Moura P, Silva JL, Vasconcelos LR, Cavalcanti MS, Muniz MT, Aroucha ML, Siqueira ER, Cahu GG, Pereira LM, Coelho MR. High tumor necrosis factor-${\alpha}$/interleukin-10 ratio is associated with hepatocellular carcinoma in patients with chronic hepatitis C. Cytokine. 2013;62: 421-425. https://doi.org/10.1016/j.cyto.2013.03.024
  92. Bartosch B, Thimme R, Blum HE, Zoulim F. Hepatitis C virus-induced hepatocarcinogenesis. J Hepatol. 2009;51:810-820. https://doi.org/10.1016/j.jhep.2009.05.008
  93. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol. 2004;78:12725-12734. https://doi.org/10.1128/JVI.78.23.12725-12734.2004
  94. Corton JC, Moreno ES, Merritt A, Bocos C, Cattley RC. Cloning genes responsive to a hepatocarcinogenic peroxisome proliferator chemical reveals novel targets of regulation. Cancer Lett. 1998;134:61-71. https://doi.org/10.1016/S0304-3835(98)00241-9
  95. Lim SO, Park SJ, Kim W, Park SG, Kim HJ, Kim YI, Sohn TS, Noh JH, Jung G. Proteome analysis of hepatocellular carcinoma. Biochem Biophys Res Commun. 2002;291:1031-1037. https://doi.org/10.1006/bbrc.2002.6547
  96. Yang H, Chen J, Yang J, Qiao S, Zhao S, Yu L. Cyclophilin A is upregulated in small cell lung cancer and activates ERK1/2 signal. Biochem Biophys Res Commun. 2007;361:763-767. https://doi.org/10.1016/j.bbrc.2007.07.085
  97. Campa MJ, Wang MZ, Howard B, Fitzgerald MC, Patz EF Jr. Protein expression profiling identifies macrophage migration inhibitory factor and cyclophilin a as potential molecular targets in non-small cell lung cancer. Cancer Res. 2003;63:1652- 1656.
  98. Cecconi D, Astner H, Donadelli M, Palmieri M, Missiaglia E, Hamdan M, Scarpa A, Righetti PG. Proteomic analysis of pancreatic ductal carcinoma cells treated with 5-aza-2'-deoxycytidine. Electrophoresis. 2003;24:4291-4303. https://doi.org/10.1002/elps.200305724
  99. Shen J, Person MD, Zhu J, Abbruzzese JL, Li D. Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry. Cancer Res. 2004;64:9018-9026. https://doi.org/10.1158/0008-5472.CAN-04-3262
  100. Li M, Wang H, Li F, Fisher WE, Chen C, Yao Q. Effect of cyclophilin A on gene expression in human pancreatic cancer cells. Am J Surg. 2005;190:739-745. https://doi.org/10.1016/j.amjsurg.2005.07.013
  101. Mikuriya K, Kuramitsu Y, Ryozawa S, Fujimoto M, Mori S, Oka M, Hamano K, Okita K, Sakaida I, Nakamura K. Expression of glycolytic enzymes is increased in pancreatic cancerous tissues as evidenced by proteomic profiling by two-dimensional electrophoresis and liquid chromatographymass spectrometry/mass spectrometry. Int J Oncol. 2007;30:849-855.
  102. Zheng J, Koblinski JE, Dutson LV, Feeney YB, Clevenger CV. Prolyl isomerase cyclophilin A regulation of Janus-activated kinase 2 and the progression of human breast cancer. Cancer Res. 2008;68:7769-7778. https://doi.org/10.1158/0008-5472.CAN-08-0639
  103. Hathout Y, Riordan K, Gehrmann M, Fenselau C. Differential protein expression in the cytosol fraction of an MCF-7 breast cancer cell line selected for resistance toward melphalan. J Proteome Res. 2002;1:435-442. https://doi.org/10.1021/pr020006i
  104. Melle C, Osterloh D, Ernst G, Schimmel B, Bleul A, von Eggeling F. Identification of proteins from colorectal cancer tissue by two-dimensional gel electrophoresis and SELDI mass spectrometry. Int J Mol Med. 2005;16:11-17.
  105. Lou J, Fatima N, Xiao Z, Stauffer S, Smythers G, Greenwald P, Ali IU. Proteomic profiling identifies cyclooxygenase-2-independent global proteomic changes by celecoxib in colorectal cancer cells. Cancer Epidemiol Biomarkers Prev. 2006;15:1598-1606. https://doi.org/10.1158/1055-9965.EPI-06-0216
  106. Wong CS, Wong VW, Chan CM, Ma BB, Hui EP, Wong MC, Lam MY, Au TC, Chan WH, Cheuk W, Chan AT. Identification of 5-fluorouracil response proteins in colorectal carcinoma cell line SW480 by two-dimensional electrophoresis and MALDI-TOF mass spectrometry. Oncol Rep. 2008;20:89-98.
  107. Chen J, He QY, Yuen AP, Chiu JF. Proteomics of buccal squamous cell carcinoma: the involvement of multiple pathways in tumorigenesis. Proteomics. 2004;4:2465-2475. https://doi.org/10.1002/pmic.200300762
  108. Qi YJ, He QY, Ma YF, Du YW, Liu GC, Li YJ, Tsao GS, Ngai SM, Chiu JF. Proteomic identification of malignant transformation-related proteins in esophageal squamous cell carcinoma. J Cell Biochem. 2008;104:1625-1635. https://doi.org/10.1002/jcb.21727
  109. Al-Ghoul M, Bruck TB, Lauer-Fields JL, Asirvatham VS, Zapata C, Kerr RG, Fields GB. Comparative proteomic analysis of matched primary and metastatic melanoma cell lines. J Proteome Res. 2008;7:4107-4118. https://doi.org/10.1021/pr800174k
  110. Han X, Yoon SH, Ding Y, Choi TG, Choi WJ, Kim YH, Kim YJ, Huh YB, Ha J, Kim SS. Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells. Oncol Rep. 2010;23:1053-1062.
  111. Howard BA, Zheng Z, Campa MJ, Wang MZ, Sharma A, Haura E, Herndon JE 2nd, Fitzgerald MC, Bepler G, Patz EF Jr. Translating biomarkers into clinical practice: prognostic implications of cyclophilin A and macrophage migratory inhibitory factor identified from protein expression profiles in non-small cell lung cancer. Lung Cancer. 2004;46:313-323. https://doi.org/10.1016/j.lungcan.2004.05.013
  112. Howard BA, Furumai R, Campa MJ, Rabbani ZN, Vujaskovic Z, Wang XF, Patz EF Jr. Stable RNA interference-mediated suppression of cyclophilin A diminishes non-small-cell lung tumor growth in vivo. Cancer Res. 2005;65:8853-8860. https://doi.org/10.1158/0008-5472.CAN-05-1219
  113. Choi KJ, Piao YJ, Lim MJ, Kim JH, Ha J, Choe W, Kim SS. Overexpressed cyclophilin A in cancer cells renders resistance to hypoxia- and cisplatin-induced cell death. Cancer Res. 2007;67:3654-3662. https://doi.org/10.1158/0008-5472.CAN-06-1759
  114. Gu S, Liu Z, Pan S, Jiang Z, Lu H, Amit O, Bradbury EM, Hu CA, Chen X. Global investigation of p53-induced apoptosis through quantitative proteomic profiling using comparative amino acid-coded tagging. Mol Cell Proteomics. 2004;3:998-1008. https://doi.org/10.1074/mcp.M400033-MCP200
  115. Yu X, Harris SL, Levine AJ. The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res. 2006;66:4795-4801. https://doi.org/10.1158/0008-5472.CAN-05-4579
  116. Tong MJ, Reddy KR, Lee WM, Pockros PJ, Hoefs JC, Keeffe EB, Hollinger FB, Hathcote EJ, White H, Foust RT, Jensen DM, Krawitt EL, Fromm H, Black M, Blatt LM, Klein M, Lubina J. Treatment of chronic hepatitis C with consensus interferon: a multicenter, randomized, controlled trial. Consensus Interferon Study Group. Hepatology. 1997;26:747-754. https://doi.org/10.1002/hep.510260330
  117. Cross TJ, Antoniades CG, Harrison PM. Current and future management of chronic hepatitis C infection. Postgrad Med J. 2008;84:172-176. https://doi.org/10.1136/pgmj.2008.068205
  118. Simmonds P, Bukh J, Combet C, Deleage G, Enomoto N, Feinstone S, Halfon P, Inchauspe G, Kuiken C, Maertens G, Mizokami M, Murphy DG, Okamoto H, Pawlotsky JM, Penin F, Sablon E, Shin-I T, Stuyver LJ, Thiel HJ, Viazov S, Weiner AJ, Widell A. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology. 2005;42:962-973. https://doi.org/10.1002/hep.20819
  119. Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications. Gut. 2006;55:1350-1359. https://doi.org/10.1136/gut.2005.076646
  120. Fernandes F, Poole DS, Hoover S, Middleton R, Andrei AC, Gerstner J, Striker R. Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B. Hepatology. 2007;46:1026-1033.
  121. Chatterji U, Lim P, Bobardt MD, Wieland S, Cordek DG, Vuagniaux G, Chisari F, Cameron CE, Targett-Adams P, Parkinson T, Gallay PA. HCV resistance to cyclosporin A does not correlate with a resistance of the NS5A-cyclophilin A interaction to cyclophilin inhibitors. J Hepatol. 2010;53:50-56. https://doi.org/10.1016/j.jhep.2010.01.041
  122. Coelmont L, Hanoulle X, Chatterji U, Berger C, Snoeck J, Bobardt M, Lim P, Vliegen I, Paeshuyse J, Vuagniaux G, Vandamme AM, Bartenschlager R, Gallay P, Lippens G, Neyts J. DEB025 (Alisporivir) inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerisation in domain II of NS5A. PLoS One. 2010;5:e13687. https://doi.org/10.1371/journal.pone.0013687
  123. Fernandes F, Ansari IU, Striker R. Cyclosporine inhibits a direct interaction between cyclophilins and hepatitis C NS5A. PLoS One. 2010;5:e9815. https://doi.org/10.1371/journal.pone.0009815
  124. Yang F, Robotham JM, Grise H, Frausto S, Madan V, Zayas M, Bartenschlager R, Robinson M, Greenstein AE, Nag A, Logan TM, Bienkiewicz E, Tang H. A major determinant of cyclophilin dependence and cyclosporine susceptibility of hepatitis C virus identified by a genetic approach. PLoS Pathog. 2010;6:e1001118. https://doi.org/10.1371/journal.ppat.1001118
  125. Hanoulle X, Badillo A, Wieruszeski JM, Verdegem D, Landrieu I, Bartenschlager R, Penin F, Lippens G. Hepatitis C virus NS5A protein is a substrate for the peptidyl-prolyl cis/trans isomerase activity of cyclophilins A and B. J Biol Chem. 2009;284:13589-13601. https://doi.org/10.1074/jbc.M809244200
  126. Verdegem D, Badillo A, Wieruszeski JM, Landrieu I, Leroy A, Bartenschlager R, Penin F, Lippens G, Hanoulle X. Domain 3 of NS5A protein from the hepatitis C virus has intrinsic alpha-helical propensity and is a substrate of cyclophilin A. J Biol Chem. 2011;286:20441-20454. https://doi.org/10.1074/jbc.M110.182436
  127. Gregory MA, Bobardt M, Obeid S, Chatterji U, Coates NJ, Foster T, Gallay P, Leyssen P, Moss SJ, Neyts J, Nur-e-Alam M, Paeshuyse J, Piraee M, Suthar D, Warneck T, Zhang MQ, Wilkinson B. Preclinical characterization of naturally occurring polyketide cyclophilin inhibitors from the sanglifehrin family. Antimicrob Agents Chemother. 2011;55:1975-1981. https://doi.org/10.1128/AAC.01627-10
  128. Foster TL, Gallay P, Stonehouse NJ, Harris M. Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner. J Virol. 2011;85:7460-7464. https://doi.org/10.1128/JVI.00393-11
  129. Inoue K, Sekiyama K, Yamada M, Watanabe T, Yasuda H, Yoshiba M. Combined interferon alpha2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial. J Gastroenterol. 2003;38:567-572.
  130. Inoue K, Yoshiba M. Interferon combined with cyclosporine treatment as an effective countermeasure against hepatitis C virus recurrence in liver transplant patients with end-stage hepatitis C virus related disease. Transplant Proc. 2005; 37:1233-1234. https://doi.org/10.1016/j.transproceed.2004.11.041
  131. Jang YY, Han ES, Lee CS, Kim YK, Song JH, Shin YK. Enhancement of cyclosporine-induced oxidative damage of kidney mitochondria by iron. Korean J Physiol Pharmacol. 1999;3:631-640.
  132. Paeshuyse J, Kaul A, De Clercq E, Rosenwirth B, Dumont JM, Scalfaro P, Bartenschlager R, Neyts J. The nonimmunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology. 2006;43:761-770. https://doi.org/10.1002/hep.21102
  133. Hopkins S, Scorneaux B, Huang Z, Murray MG, Wring S, Smitley C, Harris R, Erdmann F, Fischer G, Ribeill Y. SCY-635, a novel nonimmunosuppressive analog of cyclosporine that exhibits potent inhibition of hepatitis C virus RNA replication in vitro. Antimicrob Agents Chemother. 2010;54:660-672. https://doi.org/10.1128/AAC.00660-09
  134. Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature. 2005;436:967-972. https://doi.org/10.1038/nature04082
  135. Puyang X, Poulin DL, Mathy JE, Anderson LJ, Ma S, Fang Z, Zhu S, Lin K, Fujimoto R, Compton T, Wiedmann B. Mechanism of resistance of hepatitis C virus replicons to structurally distinct cyclophilin inhibitors. Antimicrob Agents Chemother. 2010;54:1981-1987. https://doi.org/10.1128/AAC.01236-09
  136. Chatterji U, Bobardt M, Selvarajah S, Yang F, Tang H, Sakamoto N, Vuagniaux G, Parkinson T, Gallay P. The isomerase active site of cyclophilin A is critical for hepatitis C virus replication. J Biol Chem. 2009;284:16998-17005. https://doi.org/10.1074/jbc.M109.007625
  137. Liu Z, Yang F, Robotham JM, Tang H. Critical role of cyclophilin A and its prolyl-peptidyl isomerase activity in the structure and function of the hepatitis C virus replication complex. J Virol. 2009;83:6554-6565. https://doi.org/10.1128/JVI.02550-08
  138. Ke HM, Zydowsky LD, Liu J, Walsh CT. Crystal structure of recombinant human T-cell cyclophilin A at 2.5 A resolution. Proc Natl Acad Sci USA. 1991;88:9483-9487. https://doi.org/10.1073/pnas.88.21.9483
  139. Hanoulle X, Badillo A, Wieruszeski JM, Verdegem D, Landrieu I, Bartenschlager R, Penin F, Lippens G. Hepatitis C virus NS5A protein is a substrate for the peptidyl-prolyl cis/trans isomerase activity of cyclophilins A and B. J Biol Chem. 2009;284:13589-13601. https://doi.org/10.1074/jbc.M809244200
  140. Fernandes F, Ansari IU, Striker R. Cyclosporine inhibits a direct interaction between cyclophilins and hepatitis C NS5A. PLoS One. 2010;5:e9815. https://doi.org/10.1371/journal.pone.0009815
  141. Ross-Thriepland D, Amako Y, Harris M. The C terminus of NS5A domain II is a key determinant of hepatitis C virus genome replication, but is not required for virion assembly and release. J Gen Virol. 2013;94:1009-1018. https://doi.org/10.1099/vir.0.050633-0
  142. Coelmont L, Hanoulle X, Chatterji U, Berger C, Snoeck J, Bobardt M, Lim P, Vliegen I, Paeshuyse J, Vuagniaux G, Vandamme AM, Bartenschlager R, Gallay P, Lippens G, Neyts J. DEB025 (Alisporivir) inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerisation in domain II of NS5A. PLoS One. 2010;5:e13687. https://doi.org/10.1371/journal.pone.0013687
  143. Waller H, Chatterji U, Gallay P, Parkinson T, Targett-Adams P. The use of AlphaLISA technology to detect interaction between hepatitis C virus-encoded NS5A and cyclophilin A. J Virol Methods. 2010;165:202-210. https://doi.org/10.1016/j.jviromet.2010.01.020
  144. Yang F, Robotham JM, Grise H, Frausto S, Madan V, Zayas M, Bartenschlager R, Robinson M, Greenstein AE, Nag A, Logan TM, Bienkiewicz E, Tang H. A major determinant of cyclophilin dependence and cyclosporine susceptibility of hepatitis C virus identified by a genetic approach. PLoS Pathog. 2010;6:e1001118. https://doi.org/10.1371/journal.ppat.1001118
  145. Watashi K, Ishii N, Hijikata M, Inoue D, Murata T, Miyanari Y, Shimotohno K. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell. 2005;19:111-122. https://doi.org/10.1016/j.molcel.2005.05.014
  146. Weng L, Tian X, Gao Y, Watashi K, Shimotohno K, Wakita T, Kohara M, Toyoda T. Different mechanisms of hepatitis C virus RNA polymerase activation by cyclophilin A and B in vitro. Biochim Biophys Acta. 2012;1820:1886-1892. https://doi.org/10.1016/j.bbagen.2012.08.017
  147. Paeshuyse J, Kaul A, De Clercq E, Rosenwirth B, Dumont JM, Scalfaro P, Bartenschlager R, Neyts J. The nonimmunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology. 2006;43:761-770. https://doi.org/10.1002/hep.21102
  148. Delang L, Vliegen I, Froeyen M, Neyts J. Comparative study of the genetic barriers and pathways towards resistance of selective inhibitors of hepatitis C virus replication. Antimicrob Agents Chemother. 2011;55:4103-4113. https://doi.org/10.1128/AAC.00294-11
  149. Flisiak R, Horban A, Gallay P, Bobardt M, Selvarajah S, Wiercinska-Drapalo A, Siwak E, Cielniak I, Higersberger J, Kierkus J, Aeschlimann C, Grosgurin P, Nicolas-Metral V, Dumont JM, Porchet H, Crabbe R, Scalfaro P. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology. 2008;47:817-826. https://doi.org/10.1002/hep.22131
  150. Pawlotsky JM, Sarin SK, Foster GR, Peng CY, Rasenack J, Flisiak R, Piratvisuth T, Wedemeyer H, Chuang WL, Zhang WM, Naoumov NV. Alisporivir plus ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-G2 or G3 patients: SVR12 results from VITAL-1 Phase 2b study. J Hepatol. 2012;56:1405.
  151. Coelmont L, Kaptein S, Paeshuyse J, Vliegen I, Dumont JM, Vuagniaux G, Neyts J. Debio 025, a cyclophilin binding molecule, is highly efficient in clearing hepatitis C virus (HCV) replicon-containing cells when used alone or in combination with specifically targeted antiviral therapy for HCV (STAT-C) inhibitors. Antimicrob Agents Chemother. 2009;53:967-976. https://doi.org/10.1128/AAC.00939-08
  152. Kovacs SJ, Ke J, Dabovic K, Barve A, et al. Therapeutic dose effects of the Cyclophilin Inhibitor Alisporivir (ALV) on circulating bilirubin concentrations in healthy subjects. Gastroenterology. 2012;142:S964.
  153. Griffel LH, Bao W, Orsenigo R, Guo V, Wu M, Zhang W, Avila C. Interferon (IFN)-free Alisporivir (DEB025) treatment in the VITAL-1 study has a more beneficial overall safety profile vs IFN-containing treatment. Hepatology. 2012;56:792.
  154. Hopkins S, Scorneaux B, Huang Z, Murray MG, Wring S, Smitley C, Harris R, Erdmann F, Fischer G, Ribeill Y. SCY-635, a novel nonimmunosuppressive analog of cyclosporine that exhibits potent inhibition of hepatitis C virus RNA replication in vitro. Antimicrob Agents Chemother. 2010;54:660-672. https://doi.org/10.1128/AAC.00660-09

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