Title: Expression of β-catenin, CDX1 and CDX2 in esophageal adenocarcinoma: association with survival after esophageal resection
Abstract: A25 Background: The Wnt/β-catenin signaling pathway is a key regulator of cellular growth and differentiation, and its dysregulation has recently been implicated in the molecular pathogenesis of human esophageal adenocarcinoma (EADC). Similarly, the caudal-related homologues (CDX1 and CDX2) are integral to gastrointestinal proliferation and differentiation, and are transcriptional targets of the Wnt/ β-catenin pathway. The aim of this study was to characterize β-catenin, CDX 1 , and CDX 2 mRNA and protein expression in human EADC and to correlate expression profiles with histo-pathologic and clinical parameters including patient survival.Methods: Total RNA was extracted from human esophageal tissues (tumor and matched normal) obtained with informed consent from 28 patients who underwent esophageal resection for primary EADC between 2002 and 2003. Semi-quantitative RT-PCR using primers to amplify target sequences of β-catenin, CDX 1 and CDX 2 was performed and normalized to β-actin as an internal control. Levels of mRNA expression in EADC were determined relative to histologically normal esophageal squamous epithelia from the same patient. Immunohistochemistry (IHC) was used to study protein distribution in corresponding formalin-fixed, paraffin-embedded tissue sections. Statistical analyses were performed to determine associations between expression levels of β-catenin, CDX 1 , CDX 2 , and selected clinico-pathologic parameters (including tumor grade and stage) and postoperative survival (median survival below or greater than 14 months).Results: Overexpression of β-catenin mRNA was found in 10/28 EADCs, and was associated with survival over 14 months (9/10 vs. 9/18, p=0.034). Overexpression of CDX 1 and CDX 2 mRNA was seen in 13/28 and 15/28 EADCs, respectively, but no association with clinico-pathologic parameters or outcome was seen. Although not statistically significant, CDX 1 mRNA overexpression was associated with increased β-catenin mRNA expression (7/10 vs. 6/18, p=0.062). IHC revealed heterogenous patterns of immunoreactivity, with cell nuclear positivity for β-catenin in 12 tumors, and cytoplasmic staining for CDX2 in 21 EADCs.Conclusions: The significant association between β-catenin mRNA expression and survival after esophagectomy suggests that β-catenin may be a useful molecular prognostic marker in patients with EADC. Furthermore, these exploratory studies implicate CDX1 in the molecular pathogenesis of EADC, perhaps through modulation of the Wnt/ β-catenin pathway.
Publication Year: 2006
Publication Date: 2006-10-01
Language: en
Type: article
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