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Frequent activation of mitogen-activated protein kinase relative to Akt in extrahepatic biliary tract cancer

  • Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Lack of effective adjuvant therapy against advanced extrahepatic biliary tract carcinoma (BTC) requires that new therapeutic methods, such as molecular targeted therapy, be developed. The mitogen-activated protein kinase (MAPK) and Akt signaling pathways, which activate cell proliferation and suppress apoptosis, respectively, may function as important targets for such therapies. The aim of this study was to examine the expression patterns of phosphorylated MAPK (p-MAPK) and phosphorylated Akt (p-Akt) proteins in BTC cell lines and clinical specimens.

Methods

Expression of p-MAPK and p-Akt proteins in four human BTC cell lines and in frozen sections of 20 advanced extrahepatic BTC specimens was analyzed by Western blotting. Thirty formalin-fixed BTC specimens were immunohistochemically stained for p-MAPK and p-Akt using labeled streptavidin–biotin conjugates.

Results

Expression of p-MAPK was observed in three of four (75%) BTC cell lines, whereas no expression of p-Akt was observed. Twenty-three of 30 formalin-fixed specimens stained positive for p-MAPK (77%), whereas only 47% stained positively for p-Akt. Expression of p-MAPK relative to that of p-Akt was also seen more frequently in the frozen specimens.

Conclusions

The results of this study suggest that MAPK is activated more frequently than Akt in extrahepatic biliary tract carcinoma.

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References

  1. Japan VSo. Tokyo (Japan): Japanese Ministry of Health and Welfare: Statistics Assoc.; 1998

  2. M Miyazaki H Itoh S Ambiru H Shimizu A Togawa E Gohchi et al. (1996) ArticleTitleRadical surgery for advanced gallbladder carcinoma Br J Surg 83 478–81 Occurrence Handle8665234 Occurrence Handle10.1002/bjs.1800830413 Occurrence Handle1:STN:280:BymB28zhtlc%3D

    Article  PubMed  CAS  Google Scholar 

  3. Y Nimura J Kamiya S Kondo M Nagino K Uesaka K Oda et al. (2000) ArticleTitleAggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience J Hepatobiliary Pancreat Surg 7 155–62 Occurrence Handle10982608 Occurrence Handle10.1007/s005340050170 Occurrence Handle1:STN:280:DC%2BD3cvotFyqsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  4. H Onoyama M Yamamoto A Tseng T Ajiki Y Saitoh (1995) ArticleTitleExtended cholecystectomy for carcinoma of the gallbladder World J Surg 19 758–63 Occurrence Handle7571677 Occurrence Handle10.1007/BF00295925 Occurrence Handle1:STN:280:BymD2MnjsFQ%3D

    Article  PubMed  CAS  Google Scholar 

  5. S Kondo Y Nimura J Kamiya M Nagino M Kanai K Uesaka et al. (2002) ArticleTitleMode of tumor spread and surgical strategy in gallbladder carcinoma Langenbecks Arch Surg 387 222–8 Occurrence Handle12410358 Occurrence Handle10.1007/s00423-002-0318-6

    Article  PubMed  Google Scholar 

  6. N Kokudo M Makuuchi T Natori Y Sakamoto J Yamamoto M Seki et al. (2003) ArticleTitleStrategies for surgical treatment of gallbladder carcinoma based on information available before resection Arch Surg 138 741–50 Occurrence Handle12860755 Occurrence Handle10.1001/archsurg.138.7.741

    Article  PubMed  Google Scholar 

  7. WR Jarnagin L Ruo SA Little D Klimstra M D'Angelica RP DeMatteo et al. (2003) ArticleTitlePatterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies Cancer 98 1689–700 Occurrence Handle14534886 Occurrence Handle10.1002/cncr.11699

    Article  PubMed  Google Scholar 

  8. K Nakano K Chijiiwa T Toyonaga J Ueda Y Takamatsu M Kimura et al. (2003) ArticleTitleCombination therapy of resection and intraoperative radiation for patients with carcinomas of extrahepatic bile duct and ampulla of Vater: prognostic advantage over resection alone? Hepatogastroenterology 50 928–33 Occurrence Handle12845952

    PubMed  Google Scholar 

  9. T Todoroki T Kawamoto M Otsuka N Koike S Yoshida Y Takada et al. (1999) ArticleTitleBenefits of combining radiotherapy with aggressive resection for stage IV gallbladder cancer Hepatogastroenterology 46 1585–91 Occurrence Handle10430299 Occurrence Handle1:STN:280:DyaK1Mzlslelug%3D%3D

    PubMed  CAS  Google Scholar 

  10. T Okusaka H Ishii A Funakoshi K Yamao S Ohkawa S Saito et al. (2006) ArticleTitlePhase II study of single-agent gemcitabine in patients with advanced biliary tract cancer Cancer Chemother Pharmacol 57 647–53 Occurrence Handle16142487 Occurrence Handle10.1007/s00280-005-0095-3 Occurrence Handle1:CAS:528:DC%2BD28XhsVartLY%3D

    Article  PubMed  CAS  Google Scholar 

  11. JS Park SY Oh SH Kim HC Kwon JS Kim H Jin-Kim et al. (2005) ArticleTitleSingle-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study Jpn J Clin Oncol 35 68–73 Occurrence Handle15709089 Occurrence Handle10.1093/jjco/hyi021

    Article  PubMed  Google Scholar 

  12. SM Thomas M DeMarco G D'Arcangelo S Halegoua JS Brugge (1992) ArticleTitleRas is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases Cell 68 1031–40 Occurrence Handle1312392 Occurrence Handle10.1016/0092-8674(92)90075-N Occurrence Handle1:CAS:528:DyaK38XisV2gt7s%3D

    Article  PubMed  CAS  Google Scholar 

  13. SJ Leevers CJ Marshall (1992) ArticleTitleActivation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein EMBO J 11 569–74 Occurrence Handle1371463 Occurrence Handle1:CAS:528:DyaK38Xks1Omurs%3D

    PubMed  CAS  Google Scholar 

  14. I Rubio P Rodriguez-Viciana J Downward R Wetzker (1997) ArticleTitleInteraction of Ras with phosphoinositide 3-kinase gamma Biochem J 326 891–5 Occurrence Handle9307042 Occurrence Handle1:CAS:528:DyaK2sXmsVKju70%3D

    PubMed  CAS  Google Scholar 

  15. T Ajiki T Fujimori H Onoyama M Yamamoto S Kitazawa S Maeda et al. (1996) ArticleTitleK-ras gene mutation in gall bladder carcinomas and dysplasia Gut 38 426–9 Occurrence Handle8675098 Occurrence Handle1:CAS:528:DyaK28XitlOjt7s%3D

    PubMed  CAS  Google Scholar 

  16. E Hidaka A Yanagisawa M Seki K Takano T Setoguchi Y Kato (2000) ArticleTitleHigh frequency of K-ras mutations in biliary duct carcinomas of cases with a long common channel in the papilla of Vater Cancer Res 60 522–4 Occurrence Handle10676628 Occurrence Handle1:CAS:528:DC%2BD3cXht1GmtrY%3D

    PubMed  CAS  Google Scholar 

  17. M Watanabe M Asaka J Tanaka M Kurosawa M Kasai T Miyazaki (1994) ArticleTitlePoint mutation of K-ras gene codon 12 in biliary tract tumors Gastroenterology 107 1147–53 Occurrence Handle7926462 Occurrence Handle1:CAS:528:DyaK2MXitVWqtrc%3D

    PubMed  CAS  Google Scholar 

  18. S Tanno N Yanagawa A Habiro K Koizumi Y Nakano M Osanai et al. (2004) ArticleTitleSerine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance Cancer Res 64 3486–90 Occurrence Handle15150102 Occurrence Handle10.1158/0008-5472.CAN-03-1788 Occurrence Handle1:CAS:528:DC%2BD2cXktVWhsLg%3D

    Article  PubMed  CAS  Google Scholar 

  19. MM Javle J Yu T Khoury KC Chadha RV Iyer J Foster et al. (2006) ArticleTitleAkt expression may predict favorable prognosis in cholangiocarcinoma J Gastroenterol Hepatol 21 1744–51 Occurrence Handle16984600 Occurrence Handle10.1111/j.1440-1746.2006.04373.x Occurrence Handle1:CAS:528:DC%2BD28Xht1eru77I

    Article  PubMed  CAS  Google Scholar 

  20. Y Moon WK Dahlberg Y Yu T Ohno T Todoroki JB Little (1997) ArticleTitleRadiosensitivity of human biliary tract cancer cell lines in vitro Int J Oncol 10 545–51 Occurrence Handle1:CAS:528:DyaK2sXitVeisb0%3D

    CAS  Google Scholar 

  21. S Homma S Hasumura S Nagamori H Kameda (1988) ArticleTitleEstablishment and characterization of a human gallbladder carcinoma cell line NOZ Hum Cell 1 95–7 Occurrence Handle3154020 Occurrence Handle1:STN:280:By6C3cvlvV0%3D

    PubMed  CAS  Google Scholar 

  22. I Kobayashi S Semba Y Matsuda Y Kuroda H Yokozaki (2006) ArticleTitleSignificance of Akt phosphorylation on tumor growth and vascular endothelial growth factor expression in human gastric carcinoma Pathobiology 73 8–17 Occurrence Handle16785763 Occurrence Handle10.1159/000093087 Occurrence Handle1:CAS:528:DC%2BD28XmtVarsrw%3D

    Article  PubMed  CAS  Google Scholar 

  23. T Ajiki H Onoyama M Yamamoto T Fujimori S Maeda Y Saitoh (1995) ArticleTitleDetection of point mutations in K-ras gene at codon 12 in bile from percutaneous transhepatic choledochal drainage tubes for diagnosis of biliary strictures Int J Pancreatol 18 215–20 Occurrence Handle8708392 Occurrence Handle1:CAS:528:DyaK28Xpt1ylug%3D%3D

    PubMed  CAS  Google Scholar 

  24. S Yoshida T Todoroki Y Ichikawa S Hanai H Suzuki M Hori et al. (1995) ArticleTitleMutations of p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in biliary tract cancers Cancer Res 55 2756–60 Occurrence Handle7796400 Occurrence Handle1:CAS:528:DyaK2MXmsFyksrk%3D

    PubMed  CAS  Google Scholar 

  25. M Ghosh N Koike G Yanagimoto S Tsunoda S Kaul T Hirano et al. (2004) ArticleTitleEstablishment and characterization of unique human gallbladder cancer cell lines Int J Oncol 24 1189–96 Occurrence Handle15067341

    PubMed  Google Scholar 

  26. H Horiuchi H Kawamata T Fujimori Y Kuroda (2003) ArticleTitleA MEK inhibitor (U0126) prolongs survival in nude mice bearing human gallbladder cancer cells with K-ras mutation: analysis in a novel orthotopic inoculation model Int J Oncol 23 957–63 Occurrence Handle12963974 Occurrence Handle1:CAS:528:DC%2BD3sXovV2gtbY%3D

    PubMed  CAS  Google Scholar 

  27. A Tannapfel F Sommerer M Benicke A Katalinic D Uhlmann H Witzigmann et al. (2003) ArticleTitleMutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma Gut 52 706–12 Occurrence Handle12692057 Occurrence Handle10.1136/gut.52.5.706 Occurrence Handle1:CAS:528:DC%2BD3sXjvVeiu7g%3D

    Article  PubMed  CAS  Google Scholar 

  28. Y Yamagiwa C Marienfeld L Tadlock T Patel (2003) ArticleTitleTranslational regulation by p38 mitogen-activated protein kinase signaling during human cholangiocarcinoma growth Hepatology 38 158–66 Occurrence Handle12829998 Occurrence Handle10.1053/jhep.2003.50257 Occurrence Handle1:CAS:528:DC%2BD3sXlvFaju7g%3D

    Article  PubMed  CAS  Google Scholar 

  29. N Kanno G Lesage JL Phinizy S Glaser H Francis G Alpini (2002) ArticleTitleStimulation of alpha2-adrenergic receptor inhibits cholangiocarcinoma growth through modulation of Raf-1 and B-Raf activities Hepatology 35 1329–40 Occurrence Handle12029618 Occurrence Handle10.1053/jhep.2002.33330 Occurrence Handle1:CAS:528:DC%2BD38XkvFSnsLs%3D

    Article  PubMed  CAS  Google Scholar 

  30. K Hanada M Itoh K Fujii A Tsuchida H Ooishi G Kajiyama (1996) ArticleTitleK-ras and p53 mutations in stage I gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct Cancer 77 452–8 Occurrence Handle8630951 Occurrence Handle10.1002/(SICI)1097-0142(19960201)77:3<452::AID-CNCR5>3.0.CO;2-M Occurrence Handle1:CAS:528:DyaK28Xht12jsL4%3D

    Article  PubMed  CAS  Google Scholar 

  31. H Horiuchi H Kawamata T Furihata F Omotehara H Hori Y Shinagawa et al. (2004) ArticleTitleA MEK inhibitor (U0126) markedly inhibits direct liver invasion of orthotopically inoculated human gallbladder cancer cells in nude mice J Exp Clin Cancer Res 23 599–606 Occurrence Handle15743030 Occurrence Handle1:CAS:528:DC%2BD2MXhsVGrtrk%3D

    PubMed  CAS  Google Scholar 

  32. TF Franke DR Kaplan LC Cantley (1997) ArticleTitlePI3K: downstream AKTion blocks apoptosis Cell 88 435–7 Occurrence Handle9038334 Occurrence Handle10.1016/S0092-8674(00)81883-8 Occurrence Handle1:CAS:528:DyaK2sXhtlKqs70%3D

    Article  PubMed  CAS  Google Scholar 

  33. Z Songyang D Baltimore LC Cantley DR Kaplan TF Franke (1997) ArticleTitleInterleukin 3-dependent survival by the Akt protein kinase Proc Natl Acad Sci U S A 94 11345–50 Occurrence Handle9326612 Occurrence Handle10.1073/pnas.94.21.11345 Occurrence Handle1:CAS:528:DyaK2sXmslejsLs%3D

    Article  PubMed  CAS  Google Scholar 

  34. A Bellacosa D de Feo AK Godwin DW Bell JQ Cheng DA Altomare et al. (1995) ArticleTitleMolecular alterations of the AKT2 oncogene in ovarian and breast carcinomas Int J Cancer 64 280–5 Occurrence Handle7657393 Occurrence Handle10.1002/ijc.2910640412 Occurrence Handle1:CAS:528:DyaK2MXos1Gqsbw%3D

    Article  PubMed  CAS  Google Scholar 

  35. JQ Cheng B Ruggeri WM Klein G Sonoda DA Altomare DK Watson et al. (1996) ArticleTitleAmplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA Proc Natl Acad Sci USA 93 3636–41 Occurrence Handle8622988 Occurrence Handle10.1073/pnas.93.8.3636 Occurrence Handle1:CAS:528:DyaK28XisVWiurs%3D

    Article  PubMed  CAS  Google Scholar 

  36. MD Ringel N Hayre J Saito B Saunier F Schuppert H Burch et al. (2001) ArticleTitleOverexpression and overactivation of Akt in thyroid carcinoma Cancer Res 61 6105–11 Occurrence Handle11507060 Occurrence Handle1:CAS:528:DC%2BD3MXmt12ktLo%3D

    PubMed  CAS  Google Scholar 

  37. K Nakatani DA Thompson A Barthel H Sakaue W Liu RJ Weigel et al. (1999) ArticleTitleUp-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines J Biol Chem 274 21528–32 Occurrence Handle10419456 Occurrence Handle10.1074/jbc.274.31.21528 Occurrence Handle1:CAS:528:DyaK1MXltVymsr0%3D

    Article  PubMed  CAS  Google Scholar 

  38. M Sun G Wang JE Paciga RI Feldman ZQ Yuan XL Ma et al. (2001) ArticleTitleAKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells Am J Pathol 159 431–7 Occurrence Handle11485901 Occurrence Handle1:CAS:528:DC%2BD3MXms1Wisb8%3D

    PubMed  CAS  Google Scholar 

  39. J Hsu Y Shi S Krajewski S Renner M Fisher JC Reed et al. (2001) ArticleTitleThe AKT kinase is activated in multiple myeloma tumor cells Blood 98 2853–5 Occurrence Handle11675360 Occurrence Handle10.1182/blood.V98.9.2853 Occurrence Handle1:CAS:528:DC%2BD3MXotVegtrg%3D

    Article  PubMed  CAS  Google Scholar 

  40. K Kiguchi S Carbajal K Chan L Beltran L Ruffino J Shen et al. (2001) ArticleTitleConstitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma Cancer Res 61 6971–6 Occurrence Handle11585718 Occurrence Handle1:CAS:528:DC%2BD3MXnsVeiu7o%3D

    PubMed  CAS  Google Scholar 

  41. DL Dai M Martinka G Li (2005) ArticleTitlePrognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases J Clin Oncol 23 1473–82 Occurrence Handle15735123 Occurrence Handle10.1200/JCO.2005.07.168 Occurrence Handle1:CAS:528:DC%2BD2MXis1Gmsr8%3D

    Article  PubMed  CAS  Google Scholar 

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Hori, H., Ajiki, T., Mita, Y. et al. Frequent activation of mitogen-activated protein kinase relative to Akt in extrahepatic biliary tract cancer. J Gastroenterol 42, 567–572 (2007). https://doi.org/10.1007/s00535-007-2055-7

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  • DOI: https://doi.org/10.1007/s00535-007-2055-7

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