title: EpCAM nuclear localization identifies aggressive thyroid cancer and is a marker for poor prognosis.
abstract: BACKGROUND
  Proteolytic cleavage of the extracellular domain (EpEx) of Epithelial cell adhesion molecule (EpCAM) and nuclear signaling by its intracellular oncogenic domain Ep-ICD has recently been implicated in increased proliferation of cancer cells. The clinical significance of Ep-ICD in human tumors remains an enigma.
  
  
  METHODS
  EpEx, Ep-ICD and beta-catenin immunohistochemistry using specific antibodies was conducted on 58 archived thyroid cancer (TC) tissue blocks from 34 patients and correlated with survival analysis of these patients for up to 17 years.
  
  
  RESULTS
  The anaplastic (ATC) and aggressive thyroid cancers showed loss of EpEx and increased nuclear and cytoplasmic accumulation of Ep-ICD. In contrast, the low grade papillary thyroid cancers (PTC) showed membranous EpEx and no detectable nuclear Ep-ICD. The ATC also showed concomitant nuclear expression of Ep-ICD and beta-catenin. Kaplan-Meier Survival analysis revealed reduced overall survival (OS) for TC patients showing nuclear Ep-ICD expression or loss of membranous EpEx (p < 0.0004), median OS = 5 months as compared to 198 months for patients who did not show nuclear Ep-ICD or demonstrated only membranous EpE.
  
  
  CONCLUSIONS
  We report reciprocal loss of membrane EpEx but increased nuclear and cytoplasmic accumulation of Ep-ICD in aggressive TC; nuclear Ep-ICD correlated with poor OS of TC patients. Thus nuclear Ep-ICD localization may serve as a useful biomarker for aggressive TC and may represent a novel diagnostic, prognostic and therapeutic target for aggressive TC.
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery Program, Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, 600 University Avenue, Toronto, ON M5G1X5, Canada. rralhan@mtsinai.on.ca
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.forename: Terence
authors.initials: T
authors.lastname: Lim
authors.forename: Christina
authors.initials: C
authors.lastname: Macmillan
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Freeman
authors.forename: Paul G
authors.initials: PG
authors.lastname: Walfish
mesh_terms: D000231:Adenocarcinoma, Papillary / Q000378:metabolism* / Q000473:pathology; D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D007124:Immunoenzyme Techniques; D011379:Prognosis; D015996:Survival Rate; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D051176:beta Catenin