Abstract
BackgroundSlug, a regulator of epithelial mesenchymal transition, was identified to be differentially expressed in esophageal squamous cell carcinoma (ESCC) using cDNA microarrays by our laboratory. This study aimed to determine the clinical significance of Slug overexpression in ESCC and determine its correlation with clinicopathological parameters and disease prognosis for ESCC patients. MethodsImmunohistochemical analysis of Slug expression was carried out in archived tissue sections from 91 ESCCs, 61 dysplastic and 47 histologically normal esophageal tissues. Slug immunopositivity in epithelial cells was correlated with clinicopathological parameters and disease prognosis over up to 7.5 years for ESCC patients. ResultsIncreased expression of Slug was observed in esophageal dysplasia [cytoplasmic, 24/61 (39.3%) cases, p = 0.001, odd’s ratio (OR) = 4.7; nuclear, 11/61 (18%) cases, p < 0.001, OR = 1.36] in comparison with normal esophageal tissues. The Slug expression was further increased in ESCCs [cytoplasmic, 64/91 (70.3%) p < 0.001, OR = 10.0; nuclear, 27/91 (29.7%) p < 0.001, OR = 1.42]. Kaplan Meier survival analysis showed significant association of nuclear Slug accumulation with reduced disease free survival of ESCC patients (median disease free survival (DFS) = 6 months, as compared to those that did not show overexpression, DFS = 18 months; p = 0.006). In multivariate Cox regression analysis nuclear Slug expression [p= 0.005, Hazard’s ratio (HR) = 2.269, 95% CI = 1.289 - 3.996] emerged as the most significant independent predictor of poor prognosis for ESCC patients. ConclusionsAlterations in Slug expression occur in early stages of development of ESCC and are sustained during disease progression. Slug may serve as a diagnostic biomarker and as a predictor of poor disease prognosis to identify ESCC patients that are likely to show recurrence of the disease.
Highlights
Epithelial to mesenchymal transition (EMT) is a dynamic cellular process by which cells lose cell-cell junctions and basoapical polarity acquiring mesenchymal characteristics with increased motility and invasive potential, stemlike characteristics and resistance to apoptosis that are essential for the development of metastatic disease
To determine the clinical significance of Slug protein in esophageal cancer, its expression was analysed in clinical specimens from histologically normal esophageal tissues, dysplasia, and esophageal squamous cell carcinoma (ESCC) using a specific anti-Slug antibody by immunohistochemistry
Chi square trend analysis showed significant increase in Slug expression in tissues obtained from different stages of esophageal tumorigenesis
Summary
Epithelial to mesenchymal transition (EMT) is a dynamic cellular process by which cells lose cell-cell junctions and basoapical polarity acquiring mesenchymal characteristics with increased motility and invasive potential, stemlike characteristics and resistance to apoptosis that are essential for the development of metastatic disease. Major signaling pathways involved in EMT include Ras, transforming growth factor-β (TGF-β), Wnt, epidermal growth factor (EGF), Notch and Hedgehog These signalling pathways activated by extrinsic or intrinsic stimuli will converge on any of the transcription factors, including nuclear factor kappa B (NFκB) and zinc finger proteins Snail and Slug, Twist, ZEB 1/2, and Smads that will likely culminate in transcriptional repression of E-cadherin. EGF and TGF-β promote EMT by regulating Snail, Twist, and Slug through direct regulation of genes involved in cellular adhesion, migration, and invasion [1,2,3]. These EMT regulators may play an important role in cancer progression. Slug may serve as a diagnostic biomarker and as a predictor of poor disease prognosis to identify ESCC patients that are likely to show recurrence of the disease
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