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Published in: Journal of Cancer Research and Clinical Oncology 12/2006

01-12-2006 | Original Paper

Expression of phosphorylated ERK1/2 and homeodomain protein CDX2 in cholangiocarcinoma

Authors: Artit Jinawath, Yoshimitsu Akiyama, Yasuhito Yuasa, Chawalit Pairojkul

Published in: Journal of Cancer Research and Clinical Oncology | Issue 12/2006

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Abstract

Purpose

The extracellular signal-regulated kinase (ERK) 1/2 pathway plays important roles in the regulation of cell proliferation, differentiation and cell survival. The caudal-related homeobox protein CDX2 is essential for the development of the intestine, and is related to gastric and gallbladder cancers with the intestinal phenotype. However, the roles of ERK1/2 phosphorylation (pERK1/2) and CDX2 in cholangiocarcinogenesis remain unknown.

Methods

We investigated the expression of pERK1/2, CDX2 and MUC2 in Thai cholangiocarcinoma (CCA) specimens by means of immunohistochemical staining, and compared the expression of these proteins with clinicopathological factors.

Results

The pERK1/2 protein was expressed in 29 of 59 (49.2%) CCA cases. Interestingly, in tubular-type CCA, the frequency of pERK1/2 expression was associated with a higher grade of differentiation (P = 0.001). CDX2 expression was observed in 22 of the 59 (37.3%) CCA cases, showed a relationship with MUC2 expression (P = 0.001), and was much higher in papillary-type than tubular-type CCA (P = 0.002).

Conclusion

These results imply that pERK1/2 may be important for the differentiation of tubular-type CCA, while CDX2 is related to the intestinal phenotype of papillary-type CCA.
Literature
go back to reference Bai YQ, Yamamoto H, Akiyama Y, Tanaka H, Takizawa T, Koike M, Kenji Yagi O, Saitoh K, Takeshita K, Iwai T, Yuasa Y (2002) Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach. Cancer Lett 176:47–55PubMedCrossRef Bai YQ, Yamamoto H, Akiyama Y, Tanaka H, Takizawa T, Koike M, Kenji Yagi O, Saitoh K, Takeshita K, Iwai T, Yuasa Y (2002) Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach. Cancer Lett 176:47–55PubMedCrossRef
go back to reference Beck F, Tata F, Chawengsaksophak K (2000) Homeobox genes and gut development. Bioessays 22:431–441PubMedCrossRef Beck F, Tata F, Chawengsaksophak K (2000) Homeobox genes and gut development. Bioessays 22:431–441PubMedCrossRef
go back to reference Blackhall FH, Pintilie M, Michael M, Leighl N, Feld R, Tsao MS, Shepherd FA (2003) Expression and prognostic significance of kit, protein kinase B, and mitogen-activated protein kinase in patients with small cell lung cancer. Clin Cancer Res 6:2241–2247 Blackhall FH, Pintilie M, Michael M, Leighl N, Feld R, Tsao MS, Shepherd FA (2003) Expression and prognostic significance of kit, protein kinase B, and mitogen-activated protein kinase in patients with small cell lung cancer. Clin Cancer Res 6:2241–2247
go back to reference Chang F, Steelman LS, Lee JT, Shelton JG, Navolanic PM, Blalock WL, Franklin RA, McCubrey JA (2003) Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 17:1263–1293PubMedCrossRef Chang F, Steelman LS, Lee JT, Shelton JG, Navolanic PM, Blalock WL, Franklin RA, McCubrey JA (2003) Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 17:1263–1293PubMedCrossRef
go back to reference Chun KS, Surh YJ (2004) Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. Biochem Pharmacol 68:1089–1100PubMedCrossRef Chun KS, Surh YJ (2004) Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. Biochem Pharmacol 68:1089–1100PubMedCrossRef
go back to reference Eda A, Osawa H, Satoh K, Yanaka I, Kihira K, Ishino Y, Mutoh H, Sugano K (2003) Aberrant expression of CDX2 in Barrett’s epithelium and inflammatory esophageal mucosa. J Gastroenterol 38:14–22PubMedCrossRef Eda A, Osawa H, Satoh K, Yanaka I, Kihira K, Ishino Y, Mutoh H, Sugano K (2003) Aberrant expression of CDX2 in Barrett’s epithelium and inflammatory esophageal mucosa. J Gastroenterol 38:14–22PubMedCrossRef
go back to reference Endo K, Yoon BI, Pairojkul C, Demetris AJ, Sirica AE (2002) ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. Hepatology 36:439–450PubMedCrossRef Endo K, Yoon BI, Pairojkul C, Demetris AJ, Sirica AE (2002) ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. Hepatology 36:439–450PubMedCrossRef
go back to reference Hansel DE, Maitra A, Lin JW, Goggins M, Argani P, Yeo CJ, Piantadosi S, Leach SD, Biankin AV (2005) Expression of the caudal-type homeodomain transcription factors CDX 1/2 and outcome in carcinomas of the ampulla of Vater. J Clin Oncol 23:1811–1818PubMedCrossRef Hansel DE, Maitra A, Lin JW, Goggins M, Argani P, Yeo CJ, Piantadosi S, Leach SD, Biankin AV (2005) Expression of the caudal-type homeodomain transcription factors CDX 1/2 and outcome in carcinomas of the ampulla of Vater. J Clin Oncol 23:1811–1818PubMedCrossRef
go back to reference Ishikawa A, Sasaki M, Ohira S, Ohta T, Oda K, Nimura Y, Chen MF, Jan YY, Yeh TS, Nakanuma Y (2004) Aberrant expression of CDX2 is closely related to the intestinal metaplasia and MUC2 expression in intraductal papillary neoplasm of the liver in hepatolithiasis. Lab Invest 84:629–638PubMedCrossRef Ishikawa A, Sasaki M, Ohira S, Ohta T, Oda K, Nimura Y, Chen MF, Jan YY, Yeh TS, Nakanuma Y (2004) Aberrant expression of CDX2 is closely related to the intestinal metaplasia and MUC2 expression in intraductal papillary neoplasm of the liver in hepatolithiasis. Lab Invest 84:629–638PubMedCrossRef
go back to reference Kiba T, Tsuda H, Pairojkul C, Inoue S, Sugimura T, Hirohashi S (1993) Mutations of the p53 tumor suppressor gene and the ras gene family in intrahepatic cholangiocellular carcinomas in Japan and Thailand. Mol Carcinog 8:312–318PubMed Kiba T, Tsuda H, Pairojkul C, Inoue S, Sugimura T, Hirohashi S (1993) Mutations of the p53 tumor suppressor gene and the ras gene family in intrahepatic cholangiocellular carcinomas in Japan and Thailand. Mol Carcinog 8:312–318PubMed
go back to reference Makuuchi M, Belghiti J, Belli G, Fan ST, Lau JW, Ringe B, Strasberg SM, Vauthey JN, Yamaoka Y, Yamasaki S, Working Group of the International Scientific Committee of the International Hepato-Pancreato-Biliary Association (2003) IHPBA concordant classification of primary liver cancer: working group report. J Hepatobiliary Pancreat Surg 10:26–30PubMed Makuuchi M, Belghiti J, Belli G, Fan ST, Lau JW, Ringe B, Strasberg SM, Vauthey JN, Yamaoka Y, Yamasaki S, Working Group of the International Scientific Committee of the International Hepato-Pancreato-Biliary Association (2003) IHPBA concordant classification of primary liver cancer: working group report. J Hepatobiliary Pancreat Surg 10:26–30PubMed
go back to reference Mizoshita T, Tsukamoto T, Nakanishi H, Inada K, Ogasawara N, Joh T, Itoh M, Yamamura Y, Tatematsu M (2003) Expression of Cdx2 and the phenotype of advanced gastric cancers: relationship with prognosis. J Cancer Res Clin Oncol 129:727–734PubMedCrossRef Mizoshita T, Tsukamoto T, Nakanishi H, Inada K, Ogasawara N, Joh T, Itoh M, Yamamura Y, Tatematsu M (2003) Expression of Cdx2 and the phenotype of advanced gastric cancers: relationship with prognosis. J Cancer Res Clin Oncol 129:727–734PubMedCrossRef
go back to reference Nakanuma Y, Harada K, Ishikawa A, Zen Y, Sasaki M (2003) Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 10:265–281PubMedCrossRef Nakanuma Y, Harada K, Ishikawa A, Zen Y, Sasaki M (2003) Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 10:265–281PubMedCrossRef
go back to reference Rescan C, Le Bras S, Lefebvre VH, Frandsen U, Klein T, Foschi M, Pipeleers DG, Scharfmann R, Madsen OD, Heimberg H (2005) EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade. Lab Invest 85:65–74PubMed Rescan C, Le Bras S, Lefebvre VH, Frandsen U, Klein T, Foschi M, Pipeleers DG, Scharfmann R, Madsen OD, Heimberg H (2005) EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade. Lab Invest 85:65–74PubMed
go back to reference Sebolt-Leopold JS, Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4:937–947PubMedCrossRef Sebolt-Leopold JS, Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4:937–947PubMedCrossRef
go back to reference Silberg DG, Swain GP, Suh ER, Traber PG (2000) Cdx1 and cdx2 expression during intestinal development. Gastroenterology 119:961–971PubMedCrossRef Silberg DG, Swain GP, Suh ER, Traber PG (2000) Cdx1 and cdx2 expression during intestinal development. Gastroenterology 119:961–971PubMedCrossRef
go back to reference Sobin LH, Wittekind Ch (1997) In: Sobin LH, Wittekind Ch (eds) International Union Against Cancer (UICC): the TNM classification of malignant tumors, 5th edn. Wiley-Liss, New York Sobin LH, Wittekind Ch (1997) In: Sobin LH, Wittekind Ch (eds) International Union Against Cancer (UICC): the TNM classification of malignant tumors, 5th edn. Wiley-Liss, New York
go back to reference Suzuki H, Isaji S, Pairojkul C, Uttaravichien T (2000) Comparative clinicopathological study of resected intrahepatic cholangiocarcinoma in northeast Thailand and Japan. J Hepatobiliary Pancreat Surg 7:206–211PubMedCrossRef Suzuki H, Isaji S, Pairojkul C, Uttaravichien T (2000) Comparative clinicopathological study of resected intrahepatic cholangiocarcinoma in northeast Thailand and Japan. J Hepatobiliary Pancreat Surg 7:206–211PubMedCrossRef
go back to reference Tajima Y, Kuroki T, Fukuda K, Tsuneoka N, Furui J, Kanematsu T (2004) An intraductal papillary component is associated with prolonged survival after hepatic resection for intrahepatic cholangiocarcinoma. Br J Surg 91:99–104PubMedCrossRef Tajima Y, Kuroki T, Fukuda K, Tsuneoka N, Furui J, Kanematsu T (2004) An intraductal papillary component is associated with prolonged survival after hepatic resection for intrahepatic cholangiocarcinoma. Br J Surg 91:99–104PubMedCrossRef
go back to reference Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, Hauss J, Wittekind C (2003) Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52:706–712PubMedCrossRef Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, Hauss J, Wittekind C (2003) Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52:706–712PubMedCrossRef
go back to reference Vatanasapt V, Sripa B (2000) Liver cancer in Thailand: epidemiology, diagnosis and control. Siriphan Press, Khon Kaen, pp 1–28 Vatanasapt V, Sripa B (2000) Liver cancer in Thailand: epidemiology, diagnosis and control. Siriphan Press, Khon Kaen, pp 1–28
go back to reference Vicent S, Lopez-Picazo JM, Toledo G, Lozano MD, Torre W, Garcia-Corchon C, Quero C, Soria JC, Martin-Algarra S, Manzano RG, Montuenga LM (2004) ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours. Br J Cancer 90:1047–1052PubMedCrossRef Vicent S, Lopez-Picazo JM, Toledo G, Lozano MD, Torre W, Garcia-Corchon C, Quero C, Soria JC, Martin-Algarra S, Manzano RG, Montuenga LM (2004) ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours. Br J Cancer 90:1047–1052PubMedCrossRef
go back to reference Webb CP, van Aelst L, Wigler MH, van de Woude GF (1998) Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc Natl Acad Sci USA 95:8773–8778PubMedCrossRef Webb CP, van Aelst L, Wigler MH, van de Woude GF (1998) Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc Natl Acad Sci USA 95:8773–8778PubMedCrossRef
go back to reference Wu XS, Akiyama Y, Igari T, Kawamura T, Hiranuma S, Shibata T, Tsuruta K, Koike M, Arii S, Yuasa Y (2005) Expression of homeodomain protein CDX2 in gallbladder carcinomas. J Cancer Res Clin Oncol 131:271–278PubMedCrossRef Wu XS, Akiyama Y, Igari T, Kawamura T, Hiranuma S, Shibata T, Tsuruta K, Koike M, Arii S, Yuasa Y (2005) Expression of homeodomain protein CDX2 in gallbladder carcinomas. J Cancer Res Clin Oncol 131:271–278PubMedCrossRef
go back to reference Yagi OK, Akiyama Y, Ohkura Y, Ban S, Endo M, Saitoh K, Yuasa Y (1997) Analyses of the APC and TGF-beta type II receptor genes, and microsatellite instability in mucosal colorectal carcinomas. Jpn J Cancer Res 88:718–724PubMed Yagi OK, Akiyama Y, Ohkura Y, Ban S, Endo M, Saitoh K, Yuasa Y (1997) Analyses of the APC and TGF-beta type II receptor genes, and microsatellite instability in mucosal colorectal carcinomas. Jpn J Cancer Res 88:718–724PubMed
go back to reference Yamamoto H, Bai YQ, Yuasa Y (2003) Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression. Biochem Biophys Res Commun 300:813–818PubMedCrossRef Yamamoto H, Bai YQ, Yuasa Y (2003) Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression. Biochem Biophys Res Commun 300:813–818PubMedCrossRef
go back to reference Yuasa Y (2003) Control of gut differentiation and intestinal-type gastric carcinogenesis. Nat Rev Cancer 3:592–600PubMedCrossRef Yuasa Y (2003) Control of gut differentiation and intestinal-type gastric carcinogenesis. Nat Rev Cancer 3:592–600PubMedCrossRef
Metadata
Title
Expression of phosphorylated ERK1/2 and homeodomain protein CDX2 in cholangiocarcinoma
Authors
Artit Jinawath
Yoshimitsu Akiyama
Yasuhito Yuasa
Chawalit Pairojkul
Publication date
01-12-2006
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 12/2006
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-006-0129-1

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