Kosriwong K, Menheniott TR, Giraud AS, Jearanaikoon P, Sripa B, Limpaiboon T. Trefoil factors: Tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma. World J Gastroenterol 2011; 17(12): 1631-1641 [PMID: 21472131 DOI: 10.3748/wjg.v17.i12.1631]
Corresponding Author of This Article
Dr. Temduang Limpaiboon, Department of Clinical Chemistry, Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand. temduang@kku.ac.th
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World J Gastroenterol. Mar 28, 2011; 17(12): 1631-1641 Published online Mar 28, 2011. doi: 10.3748/wjg.v17.i12.1631
Trefoil factors: Tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma
Kanuengnuch Kosriwong, Trevelyan R Menheniott, Andrew S Giraud, Patcharee Jearanaikoon, Banchob Sripa, Temduang Limpaiboon
Kanuengnuch Kosriwong, Graduate School, Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
Trevelyan R Menheniott, Andrew S Giraud, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia
Patcharee Jearanaikoon, Temduang Limpaiboon, Department of Clinical Chemistry, Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
Banchob Sripa, Department of Pathology, Faculty of Medicine, Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
Author contributions: Kosriwong K, Menheniott TR, Giraud AS and Limpaiboon T designed the research, analyzed the data and wrote the paper; Kosriwong K and Menheniott TR performed the research; Sripa B and Kosriwong K performed IHC; Sripa B performed anti O. viverrini antibody; Jearanaikoon P analyzed and interpreted the data; Limpaiboon T, Kosriwong K, Menheniott TR and Giraud AS revised and approved the article.
Supported by The Thailand Research Fund through the Royal Golden Jubilee PhD program (grant PHD/0121/2547 code 5LKK/47/B1 to Kosriwong K and Limpaiboon T); Khon Kaen University Research Affairs (grant 48-03-1-01-03); and the Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences (No. 06-01), Thailand
Correspondence to: Dr. Temduang Limpaiboon, Department of Clinical Chemistry, Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand. temduang@kku.ac.th
Telephone: +66-43-362028 Fax: +66-43-202088
Received: October 13, 2010 Revised: November 23, 2010 Accepted: November 30, 2010 Published online: March 28, 2011
Abstract
AIM: To investigate trefoil factor (TFF) gene copy number, mRNA and protein expression as potential biomarkers in cholangiocarcinoma (CCA).
METHODS: TFF mRNA levels, gene copy number and protein expression were determined respectively by quantitative reverse transcription polymerase chain reaction (PCR), quantitative PCR and immunohistochemistry in bile duct epithelium biopsies collected from individuals with CCA, precancerous bile duct dysplasia and from disease-free controls. The functional impact of recombinant human (rh)TFF2 peptide treatment on proliferation and epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling was assessed in the CCA cell line, KMBC, by viable cell counting and immunoblotting, respectively.
RESULTS: TFF1, TFF2 and TFF3 mRNA expression was significantly increased in CCA tissue compared to disease-free controls, and was unrelated to gene copy number. TFF1 immunoreactivity was strongly increased in both dysplasia and CCA, whereas TFF2 immunoreactivity was increased only in CCA compared to disease-free controls. By contrast, TFF3 immunoreactivity was moderately decreased in dysplasia and further decreased in CCA. Kaplan-Meier analysis found no association of TFF mRNA, protein and copy number with age, gender, histological subtype, and patient survival time. Treatment of KMBC cells with rhTFF2 stimulated proliferation, triggered phosphorylation of EGFR and downstream extracellular signal related kinase (ERK), whereas co-incubation with the EGFR tyrosine kinase inhibitor, PD153035, blocked rhTFF2-dependent proliferation and EGFR/ERK responses.
CONCLUSION: TFF mRNA/protein expression is indicative of CCA tumor progression, but not predictive for histological sub-type or survival time. TFF2 is mitogenic in CCA via EGFR/MAPK activation.
