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Hepatocellular carcinoma and liver transplantation: clinical perspective on molecular targeted strategies

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Abstract

Hepatocellular carcinoma (HCC) has an aggressive clinical course with frequent recurrence and metastasis. Orthotopic liver transplantation has been the only curative tool for unresectable HCC; therefore, recent advances in molecular targeted therapy may improve the prognosis of HCC. The multiple kinase inhibitor sorafenib and the macrolide antibiotic rapamycin are currently the most promising agents for treating unresectable HCC. A large population-based clinical trial revealed that sorafenib significantly prolonged the overall survival of HCC patients. However, subsequent clinical studies showed that sorafenib rarely reduced tumor volume and inadequately prolonged survival of patients with severe liver damage. To improve its therapeutic effect, the development of a predictive biomarker and a sorafenib-based combination is awaited. Another molecular targeting agent, rapamycin, has now been considered as a putative agent for preventing tumor recurrence in post-liver transplantation HCC patients, because it not only has immunosuppressive activity but also exerts an anti-tumor effect. In the near future, a combination of molecular targeting agents, such as sorafenib and rapamycin, may become a standard protocol for treating unresectable HCC. For specifying cases with more effective and less harmful modalities, further investigation in clinical and basic research to identify unexpected effects are needed.

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References

  1. Hochhaus A, Rosée PL, Müller MC, Ernst T, Cross NC (2011) Impact of BCR-ABL mutations on patients with chronic myeloid leukemia. Cell Cycle 10:250–260

    Article  PubMed  CAS  Google Scholar 

  2. Jubb AM, Harris AL (2010) Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol 11:1172–1183

    Article  PubMed  CAS  Google Scholar 

  3. Pérez-Galán P, Mora-Jensen H, Weniger MA, Shaffer AL 3rd, Rizzatti EG, Chapman CM, Mo CC, Stennett LS, Rader C, Liu P, Raghavachari N, Stetler-Stevenson M, Yuan C, Pittaluga S, Maric I, Dunleavy KM, Wilson WH, Staudt LM, Wiestner A (2010) Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation. Blood 117:542–552

    Article  PubMed  Google Scholar 

  4. El Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132: 2557–2576

    Article  PubMed  Google Scholar 

  5. Ishikawa Y, Wada I, Fukumoto M (2001) Alpha-particle carcinogenesis in Thorotrast patients: epidemiology, dosimetry, pathology, and molecular analysis. J Environ Pathol Toxicol Oncol 20: 311–315

    PubMed  CAS  Google Scholar 

  6. Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51:1820–1832

    Article  PubMed  Google Scholar 

  7. Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362:1907–1917

    Article  PubMed  Google Scholar 

  8. Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42:1208–1236

    Article  PubMed  Google Scholar 

  9. Takayasu K, Arii S, Ikai I, Omata M, Okita K, Ichida T, Matsuyama Y, Nakanuma Y, Kojiro M, Makuuchi M, Yamaoka Y (2006) Liver Cancer Study Group of Japan. Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients. Gastroenterology 131(2):461–469

    Article  PubMed  CAS  Google Scholar 

  10. Arii S, Yamaoka Y, Futagawa S, Inoue K, Kobayashi K, Kojiro M, Makuuchi M, Nakamura Y, Okita K, Yamada R (2000) Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology 32:1224–1229

    CAS  Google Scholar 

  11. Kuwahara Y, Li L, Baba T, Nakagawa H, Shimura T, Yamamoto Y, Ohkubo Y, Fukumoto M (2009) Clinically relevant radioresistant cells efficiently repair DNA double-strand breaks induced by X-rays. Cancer Sci 100:747–752

    Article  PubMed  CAS  Google Scholar 

  12. Adler M, De Pauw F, Vereerstraeten P, Fancello A, Lerut J, Starkel P, Van Vlierberghe H, Troisi R, Donckier V, Detry O, Delwaide J, Michielsen P, Chapelle T, Pirenne J, Nevens F (2008) Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the Eurotransplant allocation system. Liver Transpl 14:526–533

    Article  PubMed  Google Scholar 

  13. Llovet JM, Bruix J (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37:429–442

    Article  PubMed  CAS  Google Scholar 

  14. Avruch J, Zhang XF, Kyriakis JM (1994) Raf meets Ras: completing the framework of a signal transduction pathway. Trends Biochem Sci 19:279–283

    Article  PubMed  CAS  Google Scholar 

  15. Chen J, Siddiqui A (2007) Hepatitis B virus X protein stimulates the mitochondrial translocation of Raf-1 via oxidative stress. J Virol 81:6757–6760

    Article  PubMed  CAS  Google Scholar 

  16. Aoki H, Hayashi J, Moriyama M, Arakawa Y, Hino O (2000) Hepatitis C virus core protein interacts with 14-3-3 protein and activates the kinase Raf-1. J Virol 74:1736–1741

    Article  PubMed  CAS  Google Scholar 

  17. Bürckstümmer T, Kriegs M, Lupberger J, Pauli EK, Schmittel S, Hildt E (2006) Raf-1 kinase associates with hepatitis C virus NS5A and regulates viral replication. FEBS Lett 580:575–580

    Article  PubMed  Google Scholar 

  18. Hwang YH, Choi JY, Kim S, Chung ES, Kim T, Koh SS, Lee B, Bae SH, Kim J, Park YM (2004) Over-expression of c-raf-1 protooncogene in liver cirrhosis and hepatocellular carcinoma. Hepatol Res 29:113–121

    Article  PubMed  CAS  Google Scholar 

  19. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109

    Article  PubMed  CAS  Google Scholar 

  20. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    Article  PubMed  CAS  Google Scholar 

  21. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10:25–34

    Article  PubMed  CAS  Google Scholar 

  22. Pinter M, Sieghart W, Graziadei I, Vogel W, Maieron A, Königsberg R, Weissmann A, Kornek G, Plank C, Peck-Radosavljevic M (2009) Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist 14:70–76

    Article  PubMed  Google Scholar 

  23. Schütte K, Zimmermann L, Bornschein J, Csepregi A, Rühl R, Ricke J, Malfertheiner P (2011) Sorafenib therapy in patients with advanced hepatocellular carcinoma in advanced liver cirrhosis. Digestion 83:275–282

    Article  PubMed  Google Scholar 

  24. So BJ, Bekaii-Saab T, Bloomston MA, Patel T (2008) Complete clinical response of metastatic hepatocellular carcinoma to sorafenib in a patient with hemochromatosis: a case report. J Hematol Oncol 1:18

    Article  PubMed  Google Scholar 

  25. Yeganeh M, Finn RS, Saab S (2009) Apparent remission of a solitary metastatic pulmonary lesion in a liver transplant recipient treated with sorafenib. Am J Transpl 9:2851–2854

    Article  CAS  Google Scholar 

  26. Wang SX, Byrnes A, Verma S, Pancoast JR, Rixe O (2010) Complete remission of unresectable hepatocellular carcinoma treated with reduced dose of sorafenib: a case report. Target Oncol 5:59–63

    Article  PubMed  Google Scholar 

  27. Sacco R, Bargellini I, Giannelli G, Bertini M, Bozzi E, Altomare E, Battaglia V, Romano A, Bertoni M, Capria A, Bresci G, Bartolozzi C (2011) Complete response for advanced liver cancer during sorafenib therapy: case report. BMC Gastroenterol 11:4

    Article  PubMed  CAS  Google Scholar 

  28. Curtit E, Thiery-Vuillemin A, Nguyen T, Heyd B, Pivot X, Di Martino V, Borg C (2011) Complete histologic response induced by sorafenib in advanced hepatocellular carcinoma: a case report. J Clin Oncol 29:e330–332

    Article  PubMed  Google Scholar 

  29. Kudo M, Ueshima K (2010) Positioning of a molecular-targeted agent, sorafenib, in the treatment algorithm for hepatocellular carcinoma and implication of many complete remission cases in Japan. Oncology 78(suppl 1):154–166

    Article  PubMed  CAS  Google Scholar 

  30. Chaudhury PK, Hassanain M, Bouteaud JM, Alcindor T, Nudo CG, Valenti D, Cabrera T, Kavan P, Feteih I, Metrakos P (2010) Complete response of hepatocellular carcinoma with sorafenib and Y radioembolization. Curr Oncol 17:67–69

    PubMed  CAS  Google Scholar 

  31. Chelis L, Ntinos N, Souftas V, Deftereos S, Xenidis N, Chamalidou E, Maltezos E, Kakolyris S (2010) Complete response after sorafenib therapy for hepatocellular carcinoma in an HIV-HBV co-infected patient: possible synergy with HAART? A case report. Med Oncol doi:10.1007/s12032-010-9669-y

  32. Prete SD, Montella L, Caraglia M, Maiorino L, Cennamo G, Montesarchio V, Piai G, Febbraro A, Tarantino L, Capasso E, Palmieri G, Guarrasi R, Bianco M, Mamone R, Savastano C, Pisano A, Vincenzi B, Sabia A, D’Agostino A, Faiola V, Addeo R (2010) Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study. Cancer Chemother Pharmacol 66:837–844

    Article  PubMed  Google Scholar 

  33. Becker G, Allgaier HP, Olschewski M, Zähringer A, Blum HE; HECTOR Study Group. (2007) Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind study. Hepatology 45:9–15

    Article  PubMed  CAS  Google Scholar 

  34. Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB (2010) Doxorubicin plus sorafenib vs. doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 304: 2154–2160

    Article  PubMed  CAS  Google Scholar 

  35. Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4:335–348

    Article  PubMed  CAS  Google Scholar 

  36. Easton JB, Houghton PJ (2006) mTOR and cancer therapy. Oncogene 25:6436–6446

    Article  PubMed  CAS  Google Scholar 

  37. Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5:671–688

    Article  PubMed  CAS  Google Scholar 

  38. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22

    Article  PubMed  CAS  Google Scholar 

  39. Fingar DC, Blenis J (2004) Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23:3151–3171

    Article  PubMed  CAS  Google Scholar 

  40. Aoki M, Blazek E, Vogt PK (2001) A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc Natl Acad Sci U S A 98:136–141

    Article  PubMed  CAS  Google Scholar 

  41. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101

    Article  PubMed  CAS  Google Scholar 

  42. Sieghart W, Fuereder T, Schmid K, Cejka D, Werzowa J, Wrba F, Wang X, Gruber D, Rasoul-Rockenschaub S, Peck-Radosavljevic M, Wacheck V (2007) Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation 83:425–432

    Article  PubMed  CAS  Google Scholar 

  43. Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M (2004) mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 10:8421–8425

    Article  PubMed  CAS  Google Scholar 

  44. Baba HA, Wohlschlaeger J, Cicinnati VR, Hilgard P, Lang H, Sotiropoulos GC, Takeda A, Beckebaum S, Schmitz KJ (2009) Phosphorylation of p70S6 kinase predicts overall survival in patients with clear margin-resected hepatocellular carcinoma. Liver Int 29:399–405

    Article  PubMed  CAS  Google Scholar 

  45. Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, Tovar V, Roayaie S, Minguez B, Sole M, Battiston C, Van Laarhoven S, Fiel MI, Di Feo A, Hoshida Y, Yea S, Toffanin S, Ramos A, Martignetti JA, Mazzaferro V, Bruix J, Waxman S, Schwartz M, Meyerson M, Friedman SL, Llovet JM (2008) Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 135: 1972–1983

    Article  PubMed  CAS  Google Scholar 

  46. Zhou L, Huang Y, Li J, Wang Z (2010) The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Med Oncol 27:255–261

    Article  PubMed  CAS  Google Scholar 

  47. Llovet JM, Schwartz M, Mazzaferro V (2005) Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 25:181–200

    Article  PubMed  Google Scholar 

  48. Freise CE, Ferrell L, Liu T, Ascher NL, Roberts JP (1999) Effect of systemic cyclosporine on tumor recurrence after liver transplantation in a model of hepatocellular carcinoma. Transplantation 67:510–513

    Article  PubMed  CAS  Google Scholar 

  49. Herman M, Weinstein T, Korzets A, Chagnac A, Ori Y, Zevin D, Malachi T, Gafter U (2001) Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients. J Lab Clin Med 137:14–20

    Article  PubMed  CAS  Google Scholar 

  50. Schumacher G, Oidtmann M, Rosewicz S, Langrehr J, Jonas S, Mueller AR, Rueggeberg A, Neuhaus R, Bahra M, Jacob D, Gerlach H, Neuhaus P (2002) Sirolimus inhibits growth of human hepatoma cells in contrast to tacrolimus which promotes cell growth. Transpl Proc 34:1392–1393

    Article  CAS  Google Scholar 

  51. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128–135

    Article  PubMed  CAS  Google Scholar 

  52. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR (2004) mTOR inhibition reverses Aktdependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10:594–601

    Article  PubMed  CAS  Google Scholar 

  53. Treiber G (2009) mTOR inhibitors for hepatocellular cancer: a forward-moving target. Expert Rev Anticancer Ther 9:247–261

    Article  PubMed  CAS  Google Scholar 

  54. Terada N, Patel HR, Takase K, Kohno K, Nairn AC, Gelfand EW (1994) Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. Proc Natl Acad Sci U SA 91:11477–11481

    Article  CAS  Google Scholar 

  55. Jefferies HB, Fumagalli S, Dennis BP, Reinhard C, Pearson RB, Thomas G (1997) Rapamycin suppresses 5 -TOP mRNA translation through inhibition of p70s6k. EMBO J 16:3693–3704

    Article  PubMed  CAS  Google Scholar 

  56. Watson CJ, Friend PJ, Jamieson NV, Frick TW, Alexander G, Gimson AE, Calne R (1999) Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 67:505–509

    Article  PubMed  CAS  Google Scholar 

  57. Guba M, Graeb C, Jauch KW, Geissler EK (2004) Pro- and anticancer effects of immunosuppressive agents used in organ transplantation. Transplantation 77:1777–1782

    Article  PubMed  CAS  Google Scholar 

  58. Kneteman NM, Oberholzer J, Al Saghier M, Meeberg GA, Blitz M, Ma MM, Wong WW, Gutfreund K, Mason AL, Jewell LD, Shapiro AM, Bain VG, Bigam DL (2004) Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 10:1301–1311

    Article  PubMed  Google Scholar 

  59. Elsharkawi M, Staib L, Henne-Bruns D, Mayer J (2005) Complete remission of posttransplant lung metastases from hepatocellular carcinoma under therapy with sirolimus and mycophenolate mofetil. Transplantation 79:855–857

    Article  PubMed  Google Scholar 

  60. Zhou J, Fan J, Wang Z, Wu ZQ, Qiu SJ, Huang XW, Yu Y, Sun J, Xiao YS, He YF, Wang YQ, Tang ZY (2006) Conversion to sirolimus immunosuppression in liver transplantation recipients with hepatocellular carcinoma: report of an initial experience. World J Gastroenterol 12:3114–3118

    PubMed  CAS  Google Scholar 

  61. Morard I, Dumortier J, Spahr L, Hadengue A, Majno P, Morel P, Mentha G, Giostra E (2007) Conversion to sirolimus-based immunosuppression in maintenance liver transplantation patients. Liver Transpl 13:658–664

    Article  PubMed  Google Scholar 

  62. Zhou J, Wang Z, Wu ZQ, Qiu SJ, Yu Y, Huang XW, Tang ZY, Fan J (2008) Sirolimus-based immunosuppression therapy in liver transplantation for patients with hepatocellular carcinoma exceeding the Milan criteria. Transpl Proc 40:3548–3553

    Article  CAS  Google Scholar 

  63. Toso C, Merani S, Bigam DL, Shapiro AM, Kneteman NM (2010) Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology 51:1237–1243

    Article  PubMed  CAS  Google Scholar 

  64. Schnitzbauer AA, Zuelke C, Graeb C, Rochon J, Bilbao I, Burra P, de Jong KP, Duvoux C, Kneteman NM, Adam R, Bechstein WO, Becker T, Beckebaum S, Chazouillères O, Cillo U, Colledan M, Fändrich F, Gugenheim J, Hauss JP, Heise M, Hidalgo E, Jamieson N, Königsrainer A, Lamby PE, Lerut JP, Mäkisalo H, Margreiter R, Mazzaferro V, Mutzbauer I, Otto G, Pageaux GP, Pinna AD, Pirenne J, Rizell M, Rossi G, Rostaing L, Roy A, Turrion VS, Schmidt J, Troisi RI, van Hoek B, Valente U, Wolf P, Wolters H, Mirza DF, Scholz T, Steininger R, Soderdahl G, Strasser SI, Jauch KW, Neuhaus P, Schlitt HJ, Geissler EK (2010) A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 10:190

    Article  PubMed  Google Scholar 

  65. Wang Z, Zhou J, Fan J, Qiu SJ, Yu Y, Huang XW, Tang ZY (2008) Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res 14:5124–5130

    Article  PubMed  CAS  Google Scholar 

  66. Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Thng CH, Chow P, Ong HS, Chung A, Soo KC (2009) Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Cell Mol Med 13:2673–2683

    Article  PubMed  Google Scholar 

  67. Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, Savic R, Hoshida Y, Lim KH, Melgar-Lesmes P, Yea S, Peix J, Deniz K, Fiel MI, Thung S, Alsinet C, Tovar V, Mazzaferro V, Bruix J, Roayaie S, Schwartz M, Friedman SL, Llovet JM (2009) Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol 51:725–733

    Article  PubMed  CAS  Google Scholar 

  68. Wang Y, Speeg KV, Washburn WK, Halff G (2010) Sirolimus plus sorafenib in treating HCC recurrence after liver transplantation: a case report. World J Gastroenterol 16:5518–5522

    Article  PubMed  CAS  Google Scholar 

  69. Kim R, Aucejo F (2010) Radiologic complete response with sirolimus and sorafenib in a hepatocellular carcinoma patient who relapsed after orthotopic liver transplantation. J Gastrointest Cancer doi:10.1007/s12029-010-9196-2

  70. Kelley RK, Nimeiri HS, Vergo MT, Bergsland EK, Ko AH, Munster PN, Reinert A, Mulcahy MF, Benson AB, Venook AP (2010) A phase I trial of the combination of temsirolimus (TEM) and sorafenib (SOR) in advanced hepatocellular carcinoma (HCC). J Clin Oncol 28(suppl):TPS213

    Google Scholar 

  71. Matsuda Y, Yamagiwa S, Takamura M, Honda Y, Ishimoto Y, Ichida T, Aoyagi Y (2005) Overexpressed Id-1 is associated with a high risk of hepatocellular carcinoma development in patients with cirrhosis without transcriptional repression of p16. Cancer (Phila) 104:1037–1044

    Article  CAS  Google Scholar 

  72. Honma N, Genda T, Matsuda Y, Yamagiwa S, Takamura M, Ichida T, Aoyagi Y (2006) MEK/ERK signaling is a critical mediator for integrin-induced cell scattering in highly metastatic hepatocellular carcinoma cells. Lab Invest 86:687–696

    Article  PubMed  CAS  Google Scholar 

  73. Matsuda Y, Ichida T (2006) p16 and p27 are functionally correlated during the progress of hepatocarcinogenesis. Med Mol Morphol 39:169–175

    Article  PubMed  Google Scholar 

  74. Moustafa MA, Ogino D, Nishimura M, Ueda N, Naito S, Furukawa M, Uchida T, Ikai I, Sawada H, Fukumoto M (2004) Comparative analysis of ATP-binding cassette (ABC) transporter gene expression levels in peripheral blood leukocytes and in liver with hepatocellular carcinoma. Cancer Sci 95:530–536

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Niigata, 951-8518, Japan

    Yasunobu Matsuda

  2. Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan

    Takafumi Ichida

  3. Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

    Manabu Fukumoto

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  3. Manabu Fukumoto
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Correspondence to Yasunobu Matsuda.

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Matsuda, Y., Ichida, T. & Fukumoto, M. Hepatocellular carcinoma and liver transplantation: clinical perspective on molecular targeted strategies. Med Mol Morphol 44, 117–124 (2011). https://doi.org/10.1007/s00795-011-0547-2

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