Abstract
BackgroundNuclear accumulation of the intracellular domain of epithelial cell adhesion molecule (Ep-ICD) in tumor cells was demonstrated to predict poor prognosis in thyroid carcinoma patients in our earlier study. Here, we investigated the clinical significance of Ep-ICD subcellular localization index (ESLI) in distinguishing aggressive papillary thyroid carcinoma (PTC) from non-aggressive cases.MethodsUsing domain specific antibodies against the intracellular (Ep-ICD) and extracellular (EpEx) domains of epithelial cell adhesion molecule, 200 archived tissues from a new cohort of patients with benign thyroid disease as well as malignant aggressive and non aggressive PTC were analyzed by immunohistochemistry (IHC). ESLI was defined as sum of the IHC scores for accumulation of nuclear and cytoplasmic Ep-ICD and loss of membranous EpEx; ESLI = [Ep-ICDnuc + Ep-ICDcyt + loss of membranous EpEx].ResultsFor the benign thyroid tissues, non-aggressive PTC and aggressive PTC, the mean ESLI scores were 4.5, 6.7 and 11 respectively. Immunofluorescence double staining confirmed increased nuclear Ep-ICD accumulation and decreased membrane EpEx expression in aggressive PTC. Receiver-operating characteristic (ROC) curve analysis showed an area under the curve (AUC) of 0.841, 70.2% sensitivity and 83.9% specificity for nuclear Ep-ICD for differentiating aggressive PTC from non-aggressive PTC. ESLI distinguished aggressive PTC from non-aggressive cases with improved AUC of 0.924, 88.4% sensitivity and 85.5% specificity. Our study confirms nuclear accumulation of Ep-ICD and loss of membranous EpEx occurs in aggressive PTC underscoring the potential of Ep-ICD and ESLI to serve as diagnostic markers for aggressive PTC. Kaplan Meier survival analysis revealed significantly reduced disease free survival (DFS) for ESLI positive (cutoff >10) PTC (p<0.05), mean DFS = 133 months as compared to 210 months for patients who did not show positive ESLI.ConclusionESLI scoring improves the identification of aggressive PTC and thereby may serve as a useful index for defining aggressiveness and poor prognosis among PTC patients.
Highlights
Epithelial cell adhesion molecule (EpCAM) is a transmembrane protein involved in cell adhesion and mitogenic signalling and is frequently overexpressed in embryonic stem cells, cancer initiating cells and human cancers [1,2,3,4,5,6,7,8,9,10]
Recent studies demonstrated that homophilic aggregation of EpCAM on opposing cells activates mitogenic signalling by regulated intramembrane proteolysis in vitro and in vivo [11]
We demonstrated that increased nuclear and cytoplasmic accumulation of epithelial cell adhesion molecule (Ep-ICD) predicts poor prognosis in thyroid carcinoma patients and that loss of membrane EpEx is associated with reduced overall survival [14]
Summary
Epithelial cell adhesion molecule (EpCAM) is a transmembrane protein involved in cell adhesion and mitogenic signalling and is frequently overexpressed in embryonic stem cells, cancer initiating cells and human cancers [1,2,3,4,5,6,7,8,9,10]. The extracellular domain termed EpEx is shed as an ectodomain which can bind to the intact EpCAM protein to foster regulated intramembrane proteolysis This ectodomain shedding is a prerequisite for intramembrane cleavage of the remaining C-terminal fragment by tumor necrosis factoralpha convertase (TACE) enzyme and a c-secretase complex containing presenilin as a catalytic subunit which releases its intracellular domain termed Ep-ICD, a small 5-kDa protein. EpICD complexed with an adaptor protein FHL2 (four-and-a-half LIM domains protein 2) and b-catenin before it translocates into the nucleus This multiprotein complex interacts with the transcription factor Lef-1 to regulate gene transcription and cell proliferation. Nuclear accumulation of the intracellular domain of epithelial cell adhesion molecule (Ep-ICD) in tumor cells was demonstrated to predict poor prognosis in thyroid carcinoma patients in our earlier study. We investigated the clinical significance of Ep-ICD subcellular localization index (ESLI) in distinguishing aggressive papillary thyroid carcinoma (PTC) from non-aggressive cases
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