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International Journal of Genomics
Volume 2015, Article ID 179528, 16 pages
http://dx.doi.org/10.1155/2015/179528
Review Article

An Omics Perspective on Molecular Biomarkers for Diagnosis, Prognosis, and Therapeutics of Cholangiocarcinoma

1Department of Biology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
2Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand

Received 18 March 2015; Accepted 9 August 2015

Academic Editor: Giulia Piaggio

Copyright © 2015 Pattaya Seeree et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. J.-N. Vauthey and L. H. Blumgart, “Recent advances in the management of cholangiocarcinomas,” Seminars in Liver Disease, vol. 14, no. 2, pp. 109–114, 1994. View at Publisher · View at Google Scholar · View at Scopus
  2. B. Blechacz and G. J. Gores, “Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment,” Hepatology, vol. 48, no. 1, pp. 308–321, 2008. View at Publisher · View at Google Scholar · View at Scopus
  3. S. A. Khan, B. R. Davidson, R. Goldin et al., “Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document,” Gut, vol. 51, supplement 6, pp. vi1–vi9, 2002. View at Google Scholar
  4. Y. Shaib and H. B. El-Serag, “The epidemiology of cholangiocarcinoma,” Seminars in Liver Disease, vol. 24, no. 2, pp. 115–125, 2004. View at Publisher · View at Google Scholar
  5. B. Sripa and C. Pairojkul, “Cholangiocarcinoma: lessons from Thailand,” Current Opinion in Gastroenterology, vol. 24, no. 3, pp. 349–356, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. J. E. Everhart and C. E. Ruhl, “Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas,” Gastroenterology, vol. 136, no. 4, pp. 1134–1144, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. N. Razumilava and G. J. Gores, “Cholangiocarcinoma,” The Lancet, vol. 383, no. 9935, pp. 2168–2179, 2014. View at Publisher · View at Google Scholar · View at Scopus
  8. T. M. Welzel, B. I. Graubard, S. Zeuzem, H. B. El-Serag, J. A. Davila, and K. A. Mcglynn, “Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-medicare database,” Hepatology, vol. 54, no. 2, pp. 463–471, 2011. View at Publisher · View at Google Scholar · View at Scopus
  9. T. Nakagohri, T. Kinoshita, M. Konishi, S. Takahashi, and N. Gotohda, “Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma,” World Journal of Surgery, vol. 32, no. 12, pp. 2675–2680, 2008. View at Publisher · View at Google Scholar · View at Scopus
  10. C. B. Rosen, J. K. Heimbach, and G. J. Gores, “Liver transplantation for cholangiocarcinoma,” Transplant International, vol. 23, no. 7, pp. 692–697, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. C.-Y. Chen, S.-C. Shiesh, H.-C. Tsao, and X.-Z. Lin, “The assessment of biliary CA 125, CA 19-9 and CEA in diagnosing cholangiocarcinoma—the influence of sampling time and hepatolithiasis,” Hepato-Gastroenterology, vol. 49, no. 45, pp. 616–620, 2002. View at Google Scholar · View at Scopus
  12. Y. Nakanuma and M. Sasaki, “Expression of blood group-related antigens in the intrahepatic biliary tree and hepatocytes in normal livers and various hepatobiliary diseases,” Hepatology, vol. 10, no. 2, pp. 174–178, 1989. View at Publisher · View at Google Scholar · View at Scopus
  13. A. Nakeeb, P. A. Lipsett, K. D. Lillemoe et al., “Biliary carcinoembryonic antigen levels are a marker for cholangiocarcinoma,” The American Journal of Surgery, vol. 171, no. 1, pp. 147–152, 1996. View at Publisher · View at Google Scholar · View at Scopus
  14. R. P. Horgan and L. C. Kenny, “‘Omic’ technologies: genomics, transcriptomics, proteomics and metabolomics,” The Obstetrician & Gynaecologist, vol. 13, no. 3, pp. 189–195, 2011. View at Publisher · View at Google Scholar
  15. E. F. Petricoin, K. C. Zoon, E. C. Kohn, J. C. Barrett, and L. A. Liotta, “Clinical proteomics: translating benchside promise into bedside reality,” Nature Reviews Drug Discovery, vol. 1, no. 9, pp. 683–695, 2002. View at Publisher · View at Google Scholar · View at Scopus
  16. D. Theodorescu and H. Mischak, “Mass spectrometry based proteomics in urine biomarker discovery,” World Journal of Urology, vol. 25, no. 5, pp. 435–443, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. W. P. Blackstock and M. P. Weir, “Proteomics: quantitative and physical mapping of cellular proteins,” Trends in Biotechnology, vol. 17, no. 3, pp. 121–127, 1999. View at Publisher · View at Google Scholar · View at Scopus
  18. J. R. Cantor and D. M. Sabatini, “Cancer cell metabolism: one hallmark, many faces,” Cancer Discovery, vol. 2, no. 10, pp. 881–898, 2012. View at Publisher · View at Google Scholar · View at Scopus
  19. C. V. Dang, “Links between metabolism and cancer,” Genes & Development, vol. 26, no. 9, pp. 877–890, 2012. View at Publisher · View at Google Scholar · View at Scopus
  20. M. G. Vander Heiden, “Targeting cancer metabolism: a therapeutic window opens,” Nature Reviews Drug Discovery, vol. 10, no. 9, pp. 671–684, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. P. S. Ward and C. B. Thompson, “Signaling in control of cell growth and metabolism,” Cold Spring Harbor Perspectives in Biology, vol. 4, no. 7, Article ID a006783, 2012. View at Publisher · View at Google Scholar · View at Scopus
  22. E. G. B. Fritcher, B. R. Kipp, K. C. Halling et al., “A multivariable model using advanced cytologic methods for the evaluation of indeterminate pancreatobiliary strictures,” Gastroenterology, vol. 136, no. 7, pp. 2180–2186, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. G. J. Gores, “Cholangiocarcinoma: current concepts and insights,” Hepatology, vol. 37, no. 5, pp. 961–969, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. H. Malhi and G. J. Gores, “Review article: the modern diagnosis and therapy of cholangiocarcinoma,” Alimentary Pharmacology and Therapeutics, vol. 23, no. 9, pp. 1287–1296, 2006. View at Publisher · View at Google Scholar · View at Scopus
  25. K. Homayounfar, B. Gunawan, S. Cameron et al., “Pattern of chromosomal aberrations in primary liver cancers identified by comparative genomic hybridization,” Human Pathology, vol. 40, no. 6, pp. 834–842, 2009. View at Publisher · View at Google Scholar · View at Scopus
  26. S. C. McKay, K. Unger, S. Pericleous et al., “Array comparative genomic hybridization identifies novel potential therapeutic targets in cholangiocarcinoma,” HPB, vol. 13, no. 5, pp. 309–319, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. G. Miller, N. D. Socci, D. Dhall et al., “Genome wide analysis and clinical correlation of chromosomal and transcriptional mutations in cancers of the biliary tract,” Journal of Experimental and Clinical Cancer Research, vol. 28, article 62, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. S. H. Koo, C. H. Ihm, K. C. Kwon, J. W. Park, J. M. Kim, and G. Kong, “Genetic alterations in hepatocellular carcinoma and intrahepatic cholangiocarcinoma,” Cancer Genetics and Cytogenetics, vol. 130, no. 1, pp. 22–28, 2001. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Tsuda, S. Satarug, V. Bhudhisawasdi, T. Kihana, T. Sugimura, and S. Hirohashi, “Cholangiocarcinomas in Japanese and Thai patients: difference in etiology and incidence of point mutation of the c-KI-ras proto-oncogene,” Molecular Carcinogenesis, vol. 6, no. 4, pp. 266–269, 1992. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Yoshida, T. Todoroki, Y. Ichikawa et al., “Mutations of p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in biliary tract cancers,” Cancer Research, vol. 55, no. 13, pp. 2756–2760, 1995. View at Google Scholar
  31. S. Dachrut, S. Banthaisong, M. Sripa et al., “DNA copy-number loss on 1p36.1 harboring runx3 with promoter hypermethylation and associated loss of runx3 expression in liver fluke-associated intrahepatic cholangiocarcinoma,” Asian Pacific Journal of Cancer Prevention, vol. 10, no. 4, pp. 575–582, 2009. View at Google Scholar · View at Scopus
  32. T. Limpaiboon, S. Tapdara, P. Jearanaikoon, B. Sripa, and V. Bhudhisawasdi, “Prognostic significance of microsatellite alterations at 1p36 in cholangiocarcinoma,” World Journal of Gastroenterology, vol. 12, no. 27, pp. 4377–4382, 2006. View at Google Scholar · View at Scopus
  33. K. Muenphon, T. Limpaiboon, P. Jearanaikoon, C. Pairojkul, B. Sripa, and V. Bhudhisawasdi, “Amplification of chromosome 21q22.3 harboring trefoil factor family genes in liver fluke related cholangiocarcinoma is associated with poor prognosis,” World Journal of Gastroenterology, vol. 12, no. 26, pp. 4143–4148, 2006. View at Google Scholar · View at Scopus
  34. M.-A. Seol, I.-S. Chu, M.-J. Lee et al., “Genome-wide expression patterns associated with oncogenesis and sarcomatous transdifferentation of cholangiocarcinoma,” BMC Cancer, vol. 11, article 78, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. N. Harada, T. Mizoi, M. Kinouchi et al., “Introduction of antisense CD44s cDNA down-regulates expression of overall CD44 isoforms and inhibits tumor growth and metastasis in highly metastatic colon carcinoma cells,” International Journal of Cancer, vol. 91, no. 1, pp. 67–75, 2001. View at Google Scholar · View at Scopus
  36. H. G. Hass, O. Nehls, J. Jobst, A. Frilling, U. Vogel, and S. Kaiser, “Identification of osteopontin as the most consistently over-expressed gene in intrahepatic cholangiocarcinoma: detection by oligonucleotide microarray and real-time PCR analysis,” World Journal of Gastroenterology, vol. 14, no. 16, pp. 2501–2510, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. M. Tachibana, Y. Tonomoto, R. Hyakudomi et al., “Expression and prognostic significance of EFNB2 and EphB4 genes in patients with oesophageal squamous cell carcinoma,” Digestive and Liver Disease, vol. 39, no. 8, pp. 725–732, 2007. View at Publisher · View at Google Scholar · View at Scopus
  38. T. Kudoh and I. B. Dawid, “Role of the iroquois3 homeobox gene in organizer formation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 14, pp. 7852–7857, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. J. M. Ordway, J. A. Bedell, R. W. Citek et al., “Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets,” Carcinogenesis, vol. 27, no. 12, pp. 2409–2423, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. I. Issemann and S. Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,” Nature, vol. 347, no. 6294, pp. 645–650, 1990. View at Publisher · View at Google Scholar · View at Scopus
  41. B. R. Kipp, E. G. Barr Fritcher, A. C. Clayton et al., “Comparison of KRAS mutation analysis and FISH for detecting pancreatobiliary tract cancer in cytology specimens collected during endoscopic retrograde cholangiopancreatography,” The Journal of Molecular Diagnostics, vol. 12, no. 6, pp. 780–786, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. T. Isa, S. Tomita, A. Nakachi et al., “Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma,” Hepato-Gastroenterology, vol. 49, no. 45, pp. 604–608, 2002. View at Google Scholar · View at Scopus
  43. W. Chan-On, M.-L. Nairismägi, C. K. Ong et al., “Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers,” Nature Genetics, vol. 45, no. 12, pp. 1474–1478, 2013. View at Publisher · View at Google Scholar · View at Scopus
  44. B. R. Kipp, E. G. B. Fritcher, A. C. Clayton et al., “Comparison of KRAS mutation analysis and FISH for detecting pancreatobiliary tract cancer in cytology specimens collected during endoscopic retrograde cholangiopancreatography,” Journal of Molecular Diagnostics, vol. 12, no. 6, pp. 780–786, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. K. Nakazawa, Y. Dobashi, S. Suzuki, H. Fujii, Y. Takeda, and A. Ooi, “Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers,” Journal of Pathology, vol. 206, no. 3, pp. 356–365, 2005. View at Publisher · View at Google Scholar · View at Scopus
  46. R. F. Xu, J. P. Sun, S. R. Zhang et al., “KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients,” Biomedicine and Pharmacotherapy, vol. 65, no. 1, pp. 22–26, 2011. View at Publisher · View at Google Scholar · View at Scopus
  47. H. Prenen, J. de Schutter, B. Jacobs et al., “PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer,” Clinical Cancer Research, vol. 15, no. 9, pp. 3184–3188, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. P. Laurent-Puig, A. Lievre, and H. Blons, “Mutations and response to epidermal growth factor receptor Inhibitors,” Clinical Cancer Research, vol. 15, no. 4, pp. 1133–1139, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. D. Yoshikawa, H. Ojima, A. Kokubu et al., “Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma,” British Journal of Cancer, vol. 100, no. 8, pp. 1257–1266, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. M. R. O'Dell, J. L. Huang, C. L. Whitney-Miller et al., “Kras G12D and p53 mutation cause primary intrahepatic cholangiocarcinoma,” Cancer Research, vol. 72, no. 6, pp. 1557–1567, 2012. View at Publisher · View at Google Scholar · View at Scopus
  51. V. Deshpande, A. Nduaguba, S. M. Zimmerman et al., “Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma,” BMC Cancer, vol. 11, article 60, 2011. View at Publisher · View at Google Scholar · View at Scopus
  52. M.-O. Riener, M. Bawohl, P.-A. Clavien, and W. Jochum, “Rare PIK3CA hotspot mutations in carcinomas of the biliary tract,” Genes Chromosomes and Cancer, vol. 47, no. 5, pp. 363–367, 2008. View at Publisher · View at Google Scholar · View at Scopus
  53. C. Li, W. Shen, S. Shen, and Z. Ai, “Gene expression patterns combined with bioinformatics analysis identify genes associated with cholangiocarcinoma,” Computational Biology and Chemistry, vol. 47, pp. 192–197, 2013. View at Publisher · View at Google Scholar · View at Scopus
  54. R. Rice, D. P. C. Rice, and I. Thesleff, “Foxc1 integrates Fgf and Bmp signalling independently of Twist or Noggin during calvarial bone development,” Developmental Dynamics, vol. 233, no. 3, pp. 847–852, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. P. S. Ray, J. Wang, Y. Qu et al., “FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer,” Cancer Research, vol. 70, no. 10, pp. 3870–3876, 2010. View at Publisher · View at Google Scholar · View at Scopus
  56. C. S. Merzdorf, “Emerging roles for zic genes in early development,” Developmental Dynamics, vol. 236, no. 4, pp. 922–940, 2007. View at Publisher · View at Google Scholar · View at Scopus
  57. L. Sussel, J. Kalamaras, D. J. Hartigan-O'Connor et al., “Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells,” Development, vol. 125, no. 12, pp. 2213–2221, 1998. View at Google Scholar · View at Scopus
  58. M. Price, D. Lazzaro, T. Pohl et al., “Regional expression of the homeobox gene Nkx-2.2 in the developing mammalian forebrain,” Neuron, vol. 8, no. 2, pp. 241–255, 1992. View at Publisher · View at Google Scholar · View at Scopus
  59. L. A. Owen, A. A. Kowalewski, and S. L. Lessnick, “EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing's sarcoma,” PLoS ONE, vol. 3, no. 4, Article ID e1965, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. I. Subrungruang, C. Thawornkuno, C.-P. Porntip, C. Pairojkul, S. Wongkham, and S. Petmitr, “Gene expression profiling of intrahepatic cholangiocarcinoma,” Asian Pacific Journal of Cancer Prevention, vol. 14, no. 1, pp. 557–563, 2013. View at Publisher · View at Google Scholar · View at Scopus
  61. Z. Wu, T. Boonmars, S. Boonjaraspinyo et al., “Candidate genes involving in tumorigenesis of cholangiocarcinoma induced by Opisthorchis viverrini infection,” Parasitology Research, vol. 109, no. 3, pp. 657–673, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. K. Komatsu, Y. Kobune-Fujiwara, A. Andoh et al., “Increased expression of S100A6 at the invading fronts of the primary lesion and liver metastasis in patients with colorectal adenocarcinoma,” British Journal of Cancer, vol. 83, no. 6, pp. 769–774, 2000. View at Publisher · View at Google Scholar · View at Scopus
  63. Y. Dai, “Platelet-derived growth factor receptor tyrosine kinase inhibitors: a review of the recent patent literature,” Expert Opinion on Therapeutic Patents, vol. 20, no. 7, pp. 885–907, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. C.-W. Tong, J.-L. Wang, M.-S. Jiang, C.-H. Hsu, W.-T. Chang, and A.-M. Huang, “Novel genes that mediate nuclear respiratory factor 1-regualted neurite outgrowth in neuroblastoma IMR-32 cells,” Gene, vol. 515, no. 1, pp. 62–70, 2013. View at Publisher · View at Google Scholar · View at Scopus
  65. I. Berger and Y. Shaul, “Structure and function of human jun-D,” Oncogene, vol. 6, no. 4, pp. 561–566, 1991. View at Google Scholar · View at Scopus
  66. T. D. Gilmore, “Introduction to NF-κB: players, pathways, perspectives,” Oncogene, vol. 25, no. 51, pp. 6680–6684, 2006. View at Publisher · View at Google Scholar · View at Scopus
  67. G. Morris-Stiff, M. Teli, N. Jardine, and M. C. A. Puntis, “CA19-9 antigen levels can distinguish between benign and malignant pancreaticobiliary disease,” Hepatobiliary & Pancreatic Diseases International, vol. 8, no. 6, pp. 620–626, 2009. View at Google Scholar · View at Scopus
  68. H.-J. Kim, M.-H. Kim, S.-J. Myung et al., “A new strategy for the application of CA19-9 in the differentiation of pancreaticobiliary cancer: analysis using a receiver operating characteristic curve,” American Journal of Gastroenterology, vol. 94, no. 7, pp. 1941–1946, 1999. View at Publisher · View at Google Scholar · View at Scopus
  69. S. Singh, S.-J. Tang, J. Sreenarasimhaiah, L. F. Lara, and A. Siddiqui, “The clinical utility and limitations of serum carbohydrate antigen (CA19-9) as a diagnostic tool for pancreatic cancer and cholangiocarcinoma,” Digestive Diseases and Sciences, vol. 56, no. 8, pp. 2491–2496, 2011. View at Publisher · View at Google Scholar · View at Scopus
  70. A. H. Patel, D. M. Harnois, G. G. Klee, N. F. Larusso, and G. J. Gores, “The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis,” American Journal of Gastroenterology, vol. 95, no. 1, pp. 204–207, 2000. View at Publisher · View at Google Scholar · View at Scopus
  71. A. Farina, J.-M. Dumonceau, J.-L. Frossard, A. Hadengue, D. F. Hochstrasser, and P. Lescuyer, “Proteomic analysis of human bile from malignant biliary stenosis induced by pancreatic cancer,” Journal of Proteome Research, vol. 8, no. 1, pp. 159–169, 2009. View at Publisher · View at Google Scholar · View at Scopus
  72. T. Janvilisri, K. Leelawat, S. Roytrakul, A. Paemanee, and R. Tohtong, “Novel serum biomarkers to differentiate cholangiocarcinoma from benign biliary tract diseases using a proteomic approach,” Disease Markers, vol. 2015, Article ID 105358, 11 pages, 2015. View at Publisher · View at Google Scholar
  73. J. C. Mertens, C. D. Fingas, J. D. Christensen et al., “Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma,” Cancer Research, vol. 73, no. 2, pp. 897–907, 2013. View at Publisher · View at Google Scholar · View at Scopus
  74. T. O. Lankisch, J. Metzger, A. A. Negm et al., “Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis,” Hepatology, vol. 53, no. 3, pp. 875–884, 2011. View at Publisher · View at Google Scholar · View at Scopus
  75. Q. Wu, C.-Z. Liu, L.-Y. Tao et al., “The clinicopathological and prognostic impact of 14-3-3 protein isoforms expression in human cholangiocarcinoma by immunohistochemistry,” Asian Pacific Journal of Cancer Prevention, vol. 13, no. 4, pp. 1253–1259, 2012. View at Publisher · View at Google Scholar · View at Scopus
  76. H. Hermeking, “The 14-3-3 cancer connection,” Nature Reviews Cancer, vol. 3, no. 12, pp. 931–943, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. Z. Hou, H. Peng, D. E. White et al., “14-3-3 binding sites in the snail protein are essential for snail-mediated transcriptional repression and epithelial-mesenchymal differentiation,” Cancer Research, vol. 70, no. 11, pp. 4385–4393, 2010. View at Publisher · View at Google Scholar
  78. R. Kalluri and E. G. Neilson, “Epithelial-mesenchymal transition and its implications for fibrosis,” Journal of Clinical Investigation, vol. 112, no. 12, pp. 1776–1784, 2003. View at Publisher · View at Google Scholar · View at Scopus
  79. C. Zhang, L.-X. Liu, Z.-R. Dong et al., “Up-regulation of 14-3-3ζ expression in intrahepatic cholangiocarcinoma and its clinical implications,” Tumor Biology, vol. 36, no. 3, pp. 1781–1789, 2015. View at Publisher · View at Google Scholar
  80. Y. Shi, X. Deng, Q. Zhan et al., “A prospective proteomic-based study for identifying potential biomarkers for the diagnosis of cholangiocarcinoma,” Journal of Gastrointestinal Surgery, vol. 17, no. 9, pp. 1584–1591, 2013. View at Publisher · View at Google Scholar · View at Scopus
  81. S. Maeda, T. Morikawa, T. Takadate et al., “Mass spectrometry-based proteomic analysis of formalin-fixed paraffin-embedded extrahepatic cholangiocarcinoma,” Journal of Hepato-Biliary-Pancreatic Sciences, 2015. View at Publisher · View at Google Scholar
  82. D. Kobayashi, S. Koshida, R. Moriai, N. Tsuji, and N. Watanabe, “Olfactomedin 4 promotes S-phase transition in proliferation of pancreatic cancer cells,” Cancer Science, vol. 98, no. 3, pp. 334–340, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. U. Navaneethan, V. Lourdusamy, P. Gk Venkatesh, B. Willard, M. R. Sanaka, and M. Parsi, “Bile proteomics for differentiation of malignant from benign biliary strictures: a pilot study,” Gastroenterology Report (Oxford), vol. 3, no. 2, pp. 136–143, 2015. View at Google Scholar
  84. N. Albiin, I. C. P. Smith, U. Arnelo et al., “Detection of cholangiocarcinoma with magnetic resonance spectroscopy of bile in patients with and without primary sclerosing cholangitis,” Acta Radiologica, vol. 49, no. 8, pp. 855–862, 2008. View at Publisher · View at Google Scholar · View at Scopus
  85. R. M. Kaikaus, N. M. Bass, and R. K. Ockner, “Functions of fatty acid binding proteins,” Experientia, vol. 46, no. 6, pp. 617–630, 1990. View at Publisher · View at Google Scholar · View at Scopus
  86. A. W. Zimmerman and J. H. Veerkamp, “New insights into the structure and function of fatty acid-binding proteins,” Cellular and Molecular Life Sciences, vol. 59, no. 7, pp. 1096–1116, 2002. View at Publisher · View at Google Scholar · View at Scopus
  87. L. True, I. Coleman, S. Hawley et al., “A molecular correlate to the Gleason grading system for prostate adenocarcinoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 29, pp. 10991–10996, 2006. View at Google Scholar
  88. J. B. Andersen and S. S. Thorgeirsson, “Genetic profiling of intrahepatic cholangiocarcinoma,” Current Opinion in Gastroenterology, vol. 28, no. 3, pp. 266–272, 2012. View at Publisher · View at Google Scholar · View at Scopus
  89. K. Wosikowski, D. Schuurhuis, K. Johnson et al., “Identification of epidermal growth factor receptor and c-erbB2 pathway inhibitors by correlation with gene expression patterns,” Journal of the National Cancer Institute, vol. 89, no. 20, pp. 1505–1515, 1997. View at Publisher · View at Google Scholar · View at Scopus
  90. G.-H. Lai, Z. Zhang, X.-N. Shen et al., “erbB-2/neu transformed rat cholangiocytes recapitulate key cellular and molecular features of human bile duct cancer,” Gastroenterology, vol. 129, no. 6, pp. 2047–2057, 2005. View at Publisher · View at Google Scholar · View at Scopus
  91. A. E. Sirica, “Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma,” World Journal of Gastroenterology, vol. 14, no. 46, pp. 7033–7058, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. D. Yoshikawa, H. Ojima, M. Iwasaki et al., “Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma,” British Journal of Cancer, vol. 98, no. 2, pp. 418–425, 2008. View at Publisher · View at Google Scholar · View at Scopus
  93. C. K. Ong, C. Subimerb, C. Pairojkul et al., “Exome sequencing of liver fluke-associated cholangiocarcinoma,” Nature Genetics, vol. 44, no. 6, pp. 690–693, 2012. View at Publisher · View at Google Scholar · View at Scopus
  94. D. G. Kirsch and M. B. Kastan, “Tumor-suppressor p53: implications for tumor development and prognosis,” Journal of Clinical Oncology, vol. 16, no. 9, pp. 3158–3168, 1998. View at Google Scholar · View at Scopus
  95. T. Soussi, “The p53 tumor suppressor gene: from molecular biology to clinical investigation,” Annals of the New York Academy of Sciences, vol. 910, no. 1, pp. 121–139, 2000. View at Google Scholar · View at Scopus
  96. E. Steels, M. Paesmans, T. Berghmans et al., “Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a meta-analysis,” European Respiratory Journal, vol. 18, no. 4, pp. 705–719, 2001. View at Publisher · View at Google Scholar · View at Scopus
  97. J. Wang, X. Wang, S. Xie et al., “P53 status and its prognostic role in extrahepatic bile duct cancer: a meta-analysis of published studies,” Digestive Diseases and Sciences, vol. 56, no. 3, pp. 655–662, 2011. View at Publisher · View at Google Scholar · View at Scopus
  98. S. Levi, A. Urbano-Ispizua, R. Gill et al., “Multiple K-ras codon 12 mutations in cholangiocarcinomas demonstrated with a sensitive polymerase chain reaction technique,” Cancer Research, vol. 51, no. 13, pp. 3497–3502, 1991. View at Google Scholar · View at Scopus
  99. K. Ohashi, M. Tsutsumi, Y. Nakajima, H. Nakano, and Y. Konishi, “Ki-ras point mutations and proliferation activity in biliary tract carcinomas,” British Journal of Cancer, vol. 74, no. 6, pp. 930–935, 1996. View at Publisher · View at Google Scholar · View at Scopus
  100. J. B. Andersen, B. Spee, B. R. Blechacz et al., “Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors,” Gastroenterology, vol. 142, no. 4, pp. 1021–e15, 2012. View at Publisher · View at Google Scholar · View at Scopus
  101. D. Sia, Y. Hoshida, A. Villanueva et al., “Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes,” Gastroenterology, vol. 144, no. 4, pp. 829–840, 2013. View at Publisher · View at Google Scholar · View at Scopus
  102. R. F. Xu, J. P. Sun, S. R. Zhang et al., “KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients,” Biomedicine & Pharmacotherapy, vol. 65, no. 1, pp. 22–26, 2011. View at Publisher · View at Google Scholar · View at Scopus
  103. D. Sia, V. Tovar, A. Moeini, and J. M. Llovet, “Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies,” Oncogene, vol. 32, no. 41, pp. 4861–4870, 2013. View at Publisher · View at Google Scholar · View at Scopus
  104. A. Tannapfel, F. Sommerer, M. Benicke et al., “Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma,” Gut, vol. 52, no. 5, pp. 706–712, 2003. View at Publisher · View at Google Scholar · View at Scopus
  105. M. Miyaki and T. Kuroki, “Role of Smad4 (DPC4) inactivation in human cancer,” Biochemical and Biophysical Research Communications, vol. 306, no. 4, pp. 799–804, 2003. View at Publisher · View at Google Scholar · View at Scopus
  106. X.-Q. Yan, W. Zhang, B.-X. Zhang, H.-F. Liang, W.-G. Zhang, and X.-P. Chen, “Inactivation of Smad4 is a prognostic factor in intrahepatic cholangiocarcinoma,” Chinese Medical Journal, vol. 126, no. 16, pp. 3039–3043, 2013. View at Publisher · View at Google Scholar · View at Scopus
  107. D. R. Borger, K. K. Tanabe, K. C. Fan et al., “Frequent Mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping,” The Oncologist, vol. 17, no. 1, pp. 72–79, 2012. View at Publisher · View at Google Scholar · View at Scopus
  108. B. R. Kipp, J. S. Voss, S. E. Kerr et al., “Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma,” Human Pathology, vol. 43, no. 10, pp. 1552–1558, 2012. View at Publisher · View at Google Scholar · View at Scopus
  109. P. Wang, Q. Dong, C. Zhang et al., “Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas,” Oncogene, vol. 32, no. 25, pp. 3091–3100, 2013. View at Publisher · View at Google Scholar · View at Scopus
  110. C. R. Churi, R. Shroff, Y. Wang et al., “Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications,” PLoS ONE, vol. 9, no. 12, Article ID e115383, 2014. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Miyamoto, H. Ojima, M. Iwasaki et al., “Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma,” British Journal of Cancer, vol. 105, no. 1, pp. 131–138, 2011. View at Publisher · View at Google Scholar · View at Scopus
  112. M. P. Socoteanu, F. Mott, G. Alpini, and A. E. Frankel, “c-Met targeted therapy of cholangiocarcinoma,” World Journal of Gastroenterology, vol. 14, no. 19, pp. 2990–2994, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. T. Terada, Y. Nakanuma, and A. E. Sirica, “Immunohistochemical demonstration of MET overexpression in human intrahepatic cholangiocarcinoma and in hepatolithiasis,” Human Pathology, vol. 29, no. 2, pp. 175–180, 1998. View at Publisher · View at Google Scholar · View at Scopus
  114. J. W. Harbour, M. D. Onken, E. D. O. Roberson et al., “Frequent mutation of BAP1 in metastasizing uveal melanomas,” Science, vol. 330, no. 6009, pp. 1410–1413, 2010. View at Publisher · View at Google Scholar · View at Scopus
  115. T. H. van Essen, S. van Pelt, M. Versluis et al., “Prognostic parameters in uveal melanoma and their association with BAP1 expression,” British Journal of Ophthalmology, vol. 98, no. 12, pp. 1738–1743, 2014. View at Publisher · View at Google Scholar · View at Scopus
  116. C. I. Dumur, D. J. W. Campbell, J. L. DeWitt, R. A. Oyesanya, and A. E. Sirica, “Differential gene expression profiling of cultured neu-transformed versus spontaneously-transformed rat cholangiocytes and of corresponding cholangiocarcinomas,” Experimental and Molecular Pathology, vol. 89, no. 3, pp. 227–235, 2010. View at Publisher · View at Google Scholar · View at Scopus
  117. G. Faa, P. Van Eyken, T. Roskams et al., “Expression of cytokeratin 20 in developing rat liver and in experimental models of ductular and oval cell proliferation,” Journal of Hepatology, vol. 29, no. 4, pp. 628–633, 1998. View at Publisher · View at Google Scholar · View at Scopus
  118. K. Itatsu, Y. Zen, J. Yamaguchi et al., “Expression of matrix metalloproteinase 7 is an unfavorable postoperative prognostic factor in cholangiocarcinoma of the perihilar, hilar, and extrahepatic bile ducts,” Human Pathology, vol. 39, no. 5, pp. 710–719, 2008. View at Publisher · View at Google Scholar · View at Scopus
  119. S. Miwa, S.-I. Miyagawa, J. Soeda, and S. Kawasaki, “Matrix metalloproteinase-7 expression and biologic aggressiveness of cholangiocellular carcinoma,” Cancer, vol. 94, no. 2, pp. 428–434, 2002. View at Publisher · View at Google Scholar · View at Scopus
  120. H.-J. Yoo, B.-R. Yun, J.-H. Kwon et al., “Genetic and expression alterations in association with the sarcomatous change of cholangiocarcinoma cells,” Experimental & Molecular Medicine, vol. 41, no. 2, pp. 102–115, 2009. View at Publisher · View at Google Scholar
  121. M. J. Gu and J. H. Choi, “Epithelial-mesenchymal transition phenotypes are associated with patient survival in intrahepatic cholangiocarcinoma,” Journal of Clinical Pathology, vol. 67, no. 3, pp. 229–234, 2014. View at Publisher · View at Google Scholar · View at Scopus
  122. H. Isomoto, “Epigenetic alterations associated with cholangiocarcinoma (Review),” Oncology Reports, vol. 22, no. 2, pp. 227–232, 2009. View at Publisher · View at Google Scholar · View at Scopus
  123. R. Sriraksa, C. Zeller, W. Dai et al., “Aberrant DNA methylation at genes associated with a stem cell-like phenotype in cholangiocarcinoma tumors,” Cancer Prevention Research, vol. 6, no. 12, pp. 1348–1355, 2013. View at Publisher · View at Google Scholar · View at Scopus
  124. B. Goeppert, C. Konermann, C. R. Schmidt et al., “Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway,” Hepatology, vol. 59, no. 2, pp. 544–554, 2014. View at Publisher · View at Google Scholar · View at Scopus
  125. J. B. Andersen, “Molecular pathogenesis of intrahepatic cholangiocarcinoma,” Journal of Hepato-Biliary-Pancreatic Sciences, vol. 22, no. 2, pp. 101–113, 2015. View at Publisher · View at Google Scholar · View at Scopus
  126. A. Budhu, J. Ji, and X. W. Wang, “The clinical potential of microRNAs,” Journal of Hematology and Oncology, vol. 3, no. 1, article 37, 2010. View at Publisher · View at Google Scholar · View at Scopus
  127. X. W. Wang, N. H. H. Heegaard, and H. Ørum, “MicroRNAs in liver disease,” Gastroenterology, vol. 142, no. 7, pp. 1431–1443, 2012. View at Publisher · View at Google Scholar · View at Scopus
  128. Y. Kawahigashi, T. Mishima, Y. Mizuguchi et al., “microRNA profiling of human intrahepatic cholangiocarcinoma cell lines reveals biliary epithelial cell-specific microRNAs,” Journal of Nippon Medical School, vol. 76, no. 4, pp. 188–197, 2009. View at Publisher · View at Google Scholar · View at Scopus
  129. F. M. Selaru, A. V. Olaru, T. Kan et al., “MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3,” Hepatology, vol. 49, no. 5, pp. 1595–1601, 2009. View at Publisher · View at Google Scholar · View at Scopus
  130. N. Oishi, M. R. Kumar, S. Roessler et al., “Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma,” Hepatology, vol. 56, no. 5, pp. 1792–1803, 2012. View at Publisher · View at Google Scholar · View at Scopus
  131. L. Chen, H.-X. Yan, W. Yang et al., “The role of microRNA expression pattern in human intrahepatic cholangiocarcinoma,” Journal of Hepatology, vol. 50, no. 2, pp. 358–369, 2009. View at Publisher · View at Google Scholar · View at Scopus
  132. Y.-H. Qiu, Y.-P. Wei, N.-J. Shen et al., “miR-204 Inhibits epithelial to mesenchymal transition by targeting slug in intrahepatic cholangiocarcinoma cells,” Cellular Physiology and Biochemistry, vol. 32, no. 5, pp. 1331–1341, 2013. View at Publisher · View at Google Scholar · View at Scopus
  133. I. A. Darby, K. Vuillier-Devillers, É. Pinault et al., “Proteomic analysis of differentially expressed proteins in peripheral cholangiocarcinoma,” Cancer Microenvironment, vol. 4, no. 1, pp. 73–91, 2011. View at Publisher · View at Google Scholar · View at Scopus
  134. T. Tsujino, I. Seshimo, H. Yamamoto et al., “Stromal myofibroblasts predict disease recurrence for colorectal cancer,” Clinical Cancer Research, vol. 13, no. 7, pp. 2082–2090, 2007. View at Publisher · View at Google Scholar · View at Scopus
  135. K. Utispan, P. Thuwajit, Y. Abiko et al., “Gene expression profiling of cholangiocarcinoma-derived fibroblast reveals alterations related to tumor progression and indicates periostin as a poor prognostic marker,” Molecular Cancer, vol. 9, article 13, 2010. View at Publisher · View at Google Scholar · View at Scopus
  136. H. Kawase, K. Fujii, M. Miyamoto et al., “Differential LC-MS-based proteomics of surgical human cholangiocarcinoma tissues,” Journal of Proteome Research, vol. 8, no. 8, pp. 4092–4103, 2009. View at Publisher · View at Google Scholar · View at Scopus
  137. D. A. Lauffenburger and A. F. Horwitz, “Cell migration: a physically integrated molecular process,” Cell, vol. 84, no. 3, pp. 359–369, 1996. View at Publisher · View at Google Scholar · View at Scopus
  138. K. Honda, T. Yamada, R. Endo et al., “Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion,” The Journal of Cell Biology, vol. 140, no. 6, pp. 1383–1393, 1998. View at Publisher · View at Google Scholar · View at Scopus
  139. R. H. Kim, M. Peters, Y. Jang et al., “DJ-1, a novel regulator of the tumor suppressor PTEN,” Cancer Cell, vol. 7, no. 3, pp. 263–273, 2005. View at Publisher · View at Google Scholar · View at Scopus
  140. D. Nagakubo, T. Taira, H. Kitaura et al., “DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras,” Biochemical and Biophysical Research Communications, vol. 231, no. 2, pp. 509–513, 1997. View at Publisher · View at Google Scholar · View at Scopus
  141. L. Cao, R. T. Taggart, I. M. Berquin, K. Moin, D. Fong, and B. F. Sloane, “Human gastric adenocarcinoma cathepsin B: isolation and sequencing of full-length cDNAs and polymorphisms of the gene,” Gene, vol. 139, no. 2, pp. 163–169, 1994. View at Publisher · View at Google Scholar · View at Scopus
  142. J. S. Mort and D. J. Buttle, “Cathepsin B,” The International Journal of Biochemistry & Cell Biology, vol. 29, no. 5, pp. 715–720, 1997. View at Publisher · View at Google Scholar · View at Scopus
  143. Z. Li and P. Srivastava, “Appendix 1T Heat-shock proteins,” in Current Protocols in Immunology, appendix 1, John Wiley & Sons, 2004. View at Publisher · View at Google Scholar
  144. A. Silsirivanit, K. Sawanyawisuth, G. J. Riggins, and C. Wongkham, “Cancer biomarker discovery for cholangiocarcinoma: the high-throughput approaches,” Journal of Hepato-Biliary-Pancreatic Sciences, vol. 21, no. 6, pp. 388–396, 2014. View at Publisher · View at Google Scholar · View at Scopus
  145. R. Thanan, S. Oikawa, P. Yongvanit et al., “Inflammation-induced protein carbonylation contributes to poor prognosis for cholangiocarcinoma,” Free Radical Biology and Medicine, vol. 52, no. 8, pp. 1465–1472, 2012. View at Publisher · View at Google Scholar · View at Scopus
  146. S. Boonjaraspinyo, T. Boonmars, S. Kaewkes et al., “Down-regulated expression of HSP70 in correlation with clinicopathology of cholangiocarcinoma,” Pathology and Oncology Research, vol. 18, no. 2, pp. 227–237, 2012. View at Publisher · View at Google Scholar · View at Scopus
  147. T. Shirota, H. Ojima, N. Hiraoka et al., “Heat shock protein 90 is a potential therapeutic target in cholangiocarcinoma,” Molecular Cancer Therapeutics, 2015. View at Publisher · View at Google Scholar
  148. C. Srisomsap, P. Sawangareetrakul, P. Subhasitanont et al., “Proteomic analysis of cholangiocarcinoma cell line,” Proteomics, vol. 4, no. 4, pp. 1135–1144, 2004. View at Publisher · View at Google Scholar · View at Scopus
  149. R. Lotan, H. Ito, W. Yasui, H. Yokozaki, D. Lotan, and E. Tahara, “Expression of a 31-kDa lactoside-binding lectin in normal human gastric mucosa and in primary and metastatic gastric carcinomas,” International Journal of Cancer, vol. 56, no. 4, pp. 474–480, 1994. View at Publisher · View at Google Scholar · View at Scopus
  150. X. Sanjuan, P. L. Fernandez, A. Castells et al., “Differential expression of galectin 3 and galectin 1 in colorectal cancer progression,” Gastroenterology, vol. 113, no. 6, pp. 1906–1915, 1997. View at Publisher · View at Google Scholar · View at Scopus
  151. D. M. Skrincosky, H. J. Allen, and R. J. Bernacki, “Galaptin-mediated adhesion of human ovarian carcinoma A121 cells and detection of cellular galaptin-binding glycoproteins,” Cancer Research, vol. 53, no. 11, pp. 2667–2675, 1993. View at Google Scholar · View at Scopus
  152. X.-C. Xu, A. K. El-Naggar, and R. Lotan, “Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications,” The American Journal of Pathology, vol. 147, no. 3, pp. 815–822, 1995. View at Google Scholar · View at Scopus
  153. P. Yonglitthipagon, C. Pairojkul, V. Bhudhisawasdi, J. Mulvenna, A. Loukas, and B. Sripa, “Proteomics-based identification of α-enolase as a potential prognostic marker in cholangiocarcinoma,” Clinical Biochemistry, vol. 45, no. 10-11, pp. 827–834, 2012. View at Publisher · View at Google Scholar · View at Scopus
  154. A. M. Gomes, M. P. Stelling, and M. S. G. Pavão, “Heparan sulfate and heparanase as modulators of breast cancer progression,” BioMed Research International, vol. 2013, Article ID 852093, 11 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  155. J. O. Nyalwidhe, L. R. Betesh, T. W. Powers et al., “Increased bisecting N-acetylglucosamine and decreased branched chain glycans of N-linked glycoproteins in expressed prostatic secretions associated with prostate cancer progression,” Proteomics—Clinical Applications, vol. 7, no. 9-10, pp. 677–689, 2013. View at Publisher · View at Google Scholar · View at Scopus
  156. A. Silsirivanit, N. Araki, C. Wongkham et al., “CA-S27: a novel Lewis a associated carbohydrate epitope is diagnostic and prognostic for cholangiocarcinoma,” Cancer Science, vol. 104, no. 10, pp. 1278–1284, 2013. View at Publisher · View at Google Scholar · View at Scopus
  157. S. Wongkham and A. Silsirivanit, “State of serum markers for detection of cholangiocarcinoma,” Asian Pacific Journal of Cancer Prevention, vol. 13, supplement, pp. 17–27, 2012. View at Publisher · View at Google Scholar · View at Scopus
  158. D. W. Kufe, “Mucins in cancer: function, prognosis and therapy,” Nature Reviews Cancer, vol. 9, no. 12, pp. 874–885, 2009. View at Publisher · View at Google Scholar · View at Scopus
  159. F. Levitin, O. Stern, M. Weiss et al., “The MUC1 SEA module is a self-cleaving domain,” The Journal of Biological Chemistry, vol. 280, no. 39, pp. 33374–33386, 2005. View at Publisher · View at Google Scholar · View at Scopus
  160. M. J. L. Ligtenberg, L. Kruijshaar, F. Buijs, M. Van Meijer, S. V. Litvinov, and J. Hilkens, “Cell-associated episialin is a complex containing two proteins derived from a common precursor,” The Journal of Biological Chemistry, vol. 267, no. 9, pp. 6171–6177, 1992. View at Google Scholar · View at Scopus
  161. B. Macao, D. G. A. Johansson, G. C. Hansson, and T. Härd, “Autoproteolysis coupled to protein folding in the SEA domain of the membrane-bound MUC1 mucin,” Nature Structural and Molecular Biology, vol. 13, no. 1, pp. 71–76, 2006. View at Publisher · View at Google Scholar · View at Scopus
  162. M. Yamamoto, A. Bharti, Y. Li, and D. Kufe, “Interaction of the DF3/MUC1 breast carcinoma-associated antigen and β-catenin in cell adhesion,” The Journal of Biological Chemistry, vol. 272, no. 19, pp. 12492–12494, 1997. View at Publisher · View at Google Scholar · View at Scopus
  163. N. Matsumura, M. Yamamoto, A. Aruga, K. Takasaki, and M. Nakano, “Correlation between expression of MUC1 core protein and outcome after surgery in mass-forming intrahepatic cholangiocarcinoma,” Cancer, vol. 94, no. 6, pp. 1770–1776, 2002. View at Publisher · View at Google Scholar · View at Scopus
  164. C. Boonla, B. Sripa, P. Thuwajit et al., “MUC1 and MUC5AC mucin expression in liver fluke-associated intrahepatic cholangiocarcinoma,” World Journal of Gastroenterology, vol. 11, no. 32, pp. 4939–4946, 2005. View at Google Scholar · View at Scopus
  165. H. Shibahara, S. Tamada, M. Higashi et al., “MUC4 is a novel prognostic factor of intrahepatic cholangiocarcinoma-mass forming type,” Hepatology, vol. 39, no. 1, pp. 220–229, 2004. View at Publisher · View at Google Scholar · View at Scopus
  166. T. Lang, G. C. Hansson, and T. Samuelsson, “Gel-forming mucins appeared early in metazoan evolution,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 41, pp. 16209–16214, 2007. View at Publisher · View at Google Scholar · View at Scopus
  167. S.-M. Hong, H. Cho, C. A. Moskaluk, H. F. Frierson Jr., E. Yu, and J. Y. Ro, “CDX2 and MUC2 protein expression in extrahepatic bile duct carcinoma,” American Journal of Clinical Pathology, vol. 124, no. 3, pp. 361–370, 2005. View at Publisher · View at Google Scholar · View at Scopus
  168. K.-S. Suh, S.-H. Chang, H.-J. Lee, H. R. Roh, S. H. Kim, and K. U. Lee, “Clinical outcomes and apomucin expression of intrahepatic cholangiocarcinoma according to gross morphology,” Journal of the American College of Surgeons, vol. 195, no. 6, pp. 782–789, 2002. View at Publisher · View at Google Scholar · View at Scopus
  169. S. Tamada, M. Goto, M. Nomoto et al., “Expression of MUC1 and MUC2 mucins in extrahepatic bile duct carcinomas: its relationship with tumor progression and prognosis,” Pathology International, vol. 52, no. 11, pp. 713–723, 2002. View at Publisher · View at Google Scholar · View at Scopus
  170. M. Higashi, S. Yonezawa, J. J. L. Ho et al., “Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its relationship with a new morphological classification of cholangiocarcinoma,” Hepatology, vol. 30, no. 6, pp. 1347–1355, 1999. View at Publisher · View at Google Scholar · View at Scopus
  171. A. W. Sharif, H. R. T. Williams, T. Lampejo et al., “Metabolic profiling of bile in cholangiocarcinoma using in vitro magnetic resonance spectroscopy,” HPB, vol. 12, no. 6, pp. 396–402, 2010. View at Publisher · View at Google Scholar · View at Scopus
  172. S. A. Khan, H. C. Thomas, B. R. Davidson, and S. D. Taylor-Robinson, “Cholangiocarcinoma,” The Lancet, vol. 366, no. 9493, pp. 1303–1314, 2005. View at Publisher · View at Google Scholar · View at Scopus
  173. D. Komichi, S. Tazuma, T. Nishioka, H. Hyogo, and K. Chayama, “Glycochenodeoxycholate plays a carcinogenic role in immortalized mouse cholangiocytes via oxidative DNA damage,” Free Radical Biology and Medicine, vol. 39, no. 11, pp. 1418–1427, 2005. View at Publisher · View at Google Scholar · View at Scopus
  174. F. Hirschhaeuser, U. G. A. Sattler, and W. Mueller-Klieser, “Lactate: a metabolic key player in cancer,” Cancer Research, vol. 71, no. 22, pp. 6921–6925, 2011. View at Publisher · View at Google Scholar · View at Scopus
  175. P. P. Hsu and D. M. Sabatini, “Cancer cell metabolism: warburg and beyond,” Cell, vol. 134, no. 5, pp. 703–707, 2008. View at Publisher · View at Google Scholar · View at Scopus
  176. M. G. V. Heiden, L. C. Cantley, and C. B. Thompson, “Understanding the Warburg effect: the metabolic requirements of cell proliferation,” Science, vol. 324, no. 5930, pp. 1029–1033, 2009. View at Publisher · View at Google Scholar · View at Scopus
  177. A.-G. Wang, S. Y. Yoon, J.-H. Oh et al., “Identification of intrahepatic cholangiocarcinoma related genes by comparison with normal liver tissues using expressed sequence tags,” Biochemical and Biophysical Research Communications, vol. 345, no. 3, pp. 1022–1032, 2006. View at Publisher · View at Google Scholar · View at Scopus
  178. M.-C. Lai, D.-R. Yang, and M.-J. Chuang, “Regulatory factors associated with synthesis of the osmolyte glycine betaine in the halophilic methanoarchaeon Methanohalophilus portucalensis,” Applied and Environmental Microbiology, vol. 65, no. 2, pp. 828–833, 1999. View at Google Scholar · View at Scopus
  179. Y.-C. Huang, M. Chen, Y.-M. Shyr et al., “Glycine N-methyltransferase is a favorable prognostic marker for human cholangiocarcinoma,” Journal of Gastroenterology and Hepatology, vol. 23, no. 9, pp. 1384–1389, 2008. View at Publisher · View at Google Scholar · View at Scopus
  180. F. Yang, J. B. Lum, J. R. McGill et al., “Human transferrin: cDNA characterization and chromosomal localization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 81, no. 9, pp. 2752–2756, 1984. View at Publisher · View at Google Scholar · View at Scopus
  181. J.-Y. Lee, Y.-N. Park, K.-O. Uhm, S.-Y. Park, and S.-H. Park, “Genetic alterations in intrahepatic cholangiocarcinoma as revealed by degenerate oligonucleotide primed PCR-comparative genomic hybridization,” Journal of Korean Medical Science, vol. 19, no. 5, pp. 682–687, 2004. View at Publisher · View at Google Scholar · View at Scopus
  182. K.-O. Uhm, Y.-N. Park, J.-Y. Lee, D.-S. Yoon, and S.-H. Park, “Chromosomal imbalances in Korean intrahepatic cholangiocarcinoma by comparative genomic hybridization,” Cancer Genetics and Cytogenetics, vol. 157, no. 1, pp. 37–41, 2005. View at Publisher · View at Google Scholar · View at Scopus
  183. K. Shiraishi, K. Okita, T. Harada et al., “Comparative genomic hybridization analysis of genetic aberrations associated with development and progression of biliary tract carcinomas,” Cancer, vol. 91, no. 3, pp. 570–577, 2001. View at Google Scholar · View at Scopus
  184. M. J. Borad, M. D. Champion, J. B. Egan et al., “Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma,” PLoS Genetics, vol. 10, no. 2, Article ID e1004135, 2014. View at Publisher · View at Google Scholar · View at Scopus
  185. S. Zou, J. Li, H. Zhou et al., “Mutational landscape of intrahepatic cholangiocarcinoma,” Nature Communications, vol. 5, article 5696, 2014. View at Google Scholar
  186. J. Harder, O. Waiz, F. Otto et al., “EGFR and HER2 expression in advanced biliary tract cancer,” World Journal of Gastroenterology, vol. 15, no. 36, pp. 4511–4517, 2009. View at Publisher · View at Google Scholar · View at Scopus
  187. S. Jang, S.-M. Chun, S.-M. Hong et al., “High throughput molecular profiling reveals differential mutation patterns in intrahepatic cholangiocarcinomas arising in chronic advanced liver diseases,” Modern Pathology, vol. 27, no. 5, pp. 731–739, 2014. View at Publisher · View at Google Scholar · View at Scopus
  188. M. Simbolo, M. Fassan, A. Ruzzenente et al., “Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups,” Oncotarget, vol. 5, no. 9, pp. 2839–2852, 2014. View at Google Scholar · View at Scopus
  189. G.-Y. Gwak, J.-H. Yoon, C. M. Shin et al., “Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinomas,” Journal of Cancer Research and Clinical Oncology, vol. 131, no. 10, pp. 649–652, 2005. View at Publisher · View at Google Scholar · View at Scopus
  190. J. B. Andersen, B. Spee, B. R. Blechacz et al., “Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors,” Gastroenterology, vol. 142, no. 4, pp. 1021.e15–1031.e15, 2012. View at Publisher · View at Google Scholar · View at Scopus
  191. S. Yabuuchi, Y. U. Katayose, O. D. A. Akira et al., “ZD1839 (IRESSA) stabilizes p27kip1 and enhances radiosensitivity in cholangiocarcinoma cell lines,” Anticancer Research, vol. 29, no. 4, pp. 1169–1180, 2009. View at Google Scholar · View at Scopus
  192. G. S. Papaetis and K. N. Syrigos, “Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies,” BioDrugs, vol. 23, no. 6, pp. 377–389, 2009. View at Publisher · View at Google Scholar · View at Scopus
  193. G. Aparicio-Gallego, M. Blanco, A. Figueroa et al., “New insights into molecular mechanisms of sunitinib-associated side effects,” Molecular Cancer Therapeutics, vol. 10, no. 12, pp. 2215–2223, 2011. View at Publisher · View at Google Scholar · View at Scopus
  194. R. Schmieder, J. Hoffmann, M. Becker et al., “Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer,” International Journal of Cancer, vol. 135, no. 6, pp. 1487–1496, 2014. View at Publisher · View at Google Scholar · View at Scopus
  195. M. A. Fabian, W. H. Biggs III, D. K. Treiber et al., “A small molecule-kinase interaction map for clinical kinase inhibitors,” Nature Biotechnology, vol. 23, no. 3, pp. 329–336, 2005. View at Publisher · View at Google Scholar
  196. S. M. Wilhelm, J. Dumas, L. Adnane et al., “Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity,” International Journal of Cancer, vol. 129, no. 1, pp. 245–255, 2011. View at Publisher · View at Google Scholar · View at Scopus
  197. S. Wilhelm, C. Carter, M. Lynch et al., “Discovery and development of sorafenib: a multikinase inhibitor for treating cancer,” Nature Reviews Drug Discovery, vol. 5, no. 10, pp. 835–844, 2006. View at Publisher · View at Google Scholar · View at Scopus
  198. T. Waddell and D. Cunningham, “Evaluation of regorafenib in colorectal cancer and GIST,” The Lancet, vol. 381, no. 9863, pp. 273–275, 2013. View at Publisher · View at Google Scholar · View at Scopus
  199. D. R. Borger, K. K. Tanabe, K. C. Fan et al., “Frequent Mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping,” Oncologist, vol. 17, no. 1, pp. 72–79, 2012. View at Publisher · View at Google Scholar · View at Scopus
  200. Y. Jiao, T. M. Pawlik, R. A. Anders et al., “Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas,” Nature Genetics, vol. 45, no. 12, pp. 1470–1473, 2013. View at Publisher · View at Google Scholar · View at Scopus
  201. M. B. Pappalardi, D. E. McNulty, J. D. Martin et al., “Biochemical characterization of human HIF hydroxylases using HIF protein substrates that contain all three hydroxylation sites,” Biochemical Journal, vol. 436, no. 2, pp. 363–369, 2011. View at Publisher · View at Google Scholar · View at Scopus
  202. D. Rohle, J. Popovici-Muller, N. Palaskas et al., “An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells,” Science, vol. 340, no. 6132, pp. 626–630, 2013. View at Publisher · View at Google Scholar · View at Scopus
  203. F. Wang, J. Travins, B. DeLaBarre et al., “Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation,” Science, vol. 340, no. 6132, pp. 622–626, 2013. View at Publisher · View at Google Scholar · View at Scopus
  204. J. Lamb, E. D. Crawford, D. Peck et al., “The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease,” Science, vol. 313, no. 5795, pp. 1929–1935, 2006. View at Publisher · View at Google Scholar · View at Scopus
  205. M.-H. Chen, K.-J. Lin, W.-L. R. Yang et al., “Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma,” Cancer, vol. 119, no. 2, pp. 293–303, 2013. View at Publisher · View at Google Scholar · View at Scopus
  206. K. Kosriwong, T. R. Menheniott, A. S. Giraud, P. Jearanaikoon, B. Sripa, and T. Limpaiboon, “Trefoil factors: tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma,” World Journal of Gastroenterology, vol. 17, no. 12, pp. 1631–1641, 2011. View at Publisher · View at Google Scholar · View at Scopus
  207. N. S. Sandanayake, J. Sinclair, F. Andreola et al., “A combination of serum leucine-rich alpha-2-glycoprotein 1, CA19-9 and interleukin-6 differentiate biliary tract cancer from benign biliary strictures,” British Journal of Cancer, vol. 105, no. 9, pp. 1370–1378, 2011. View at Publisher · View at Google Scholar · View at Scopus
  208. H. Isomoto, S. Kobayashi, N. W. Werneburg et al., “Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells,” Hepatology, vol. 42, no. 6, pp. 1329–1338, 2005. View at Publisher · View at Google Scholar · View at Scopus
  209. G. W. Kim, N. R. Lee, R. H. Pi et al., “IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future,” Archives of Pharmacal Research, vol. 38, no. 5, pp. 575–584, 2015. View at Publisher · View at Google Scholar
  210. H. S. Abou-Auda and W. Sakr, “Tocilizumab: a new anti-rheumatic drug,” Saudi Pharmaceutical Journal, vol. 18, no. 4, pp. 257–259, 2010. View at Publisher · View at Google Scholar · View at Scopus
  211. F. Hayakawa, K. Sugimoto, Y. Harada et al., “A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases,” Blood Cancer Journal, vol. 3, no. 11, article e166, 2013. View at Publisher · View at Google Scholar · View at Scopus
  212. Y. Kim, J. Hsu, T. Zhou et al., “Abstract LB-317: potent in vivo pharmacology of AZD9150, a next-generation, constrained ethyl-modified antisense oligonucleotide targeting STAT3 in multiple preclinical cancer models,” Cancer Research, vol. 73, no. 8, supplement, p. LB-317, 2013. View at Publisher · View at Google Scholar
  213. A. W. Sharif, H. R. Williams, T. Lampejo et al., “Metabolic profiling of bile in cholangiocarcinoma using in vitro magnetic resonance spectroscopy,” HPB, vol. 12, no. 6, pp. 396–402, 2010. View at Google Scholar
  214. A. van Helvoort, A. J. Smith, H. Sprong et al., “MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine,” Cell, vol. 87, no. 3, pp. 507–517, 1996. View at Publisher · View at Google Scholar · View at Scopus
  215. T. H. Mauad, C. M. J. Van Nieuwkerk, K. P. Dingemans et al., “Mice with homozygous disruption of the mdr2 P-glycoprotein gene a novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis,” The American Journal of Pathology, vol. 145, no. 5, pp. 1237–1245, 1994. View at Google Scholar · View at Scopus
  216. E. Zigmond, A. Ben Ya'acov, H. Lee et al., “Suppression of hepatocellular carcinoma by inhibition of overexpressed ornithine aminotransferase,” ACS Medicinal Chemistry Letters, vol. 6, no. 8, pp. 840–844, 2015. View at Publisher · View at Google Scholar