Abstract
BackgroundMost colorectal carcinomas are driven by an activation of the canonical Wnt signalling pathway, which promotes the expression of multiple target genes mediating proliferation inavasion and invasion. Upon activation of the Wnt signalling pathway its key player β-catenin translocates from the cytoplasm to the nucleus and binds to members of the T-cell factor (TCF)/lymphoid enhancer factor (LEF-1) family namely LEF-1 and TCF4 which are central mediators of transcription. In this study we investigated the expression of β-Catenin, LEF1 and TCF4 in colorectal carcinomas and their prognostic significance.MethodsImmunohistochemical analyses of LEF-1, TCF4 and nuclear β-Catenin were done using a tissue microarray with 214 colorectal cancer specimens. The expression patterns were compared with each other and the results were correlated with clinicopathologic variables and overall survival in univariate and multivariate analysis.ResultsLEF-1 expression was found in 56 (26%) and TCF4 expression in 99 (46%) of colorectal carcinomas and both were heterogenously distributed throughout the tumours. Comparing LEF-1, TCF4 and β-catenin expression patterns we found no correlation. In univariate analysis, TCF4 expression turned out to be a negative prognostic factor being associated with shorter overall survival (p = 0.020), whereas LEF-1 expression as well as a LEF-1/TCF4 ratio were positive prognostic factors and correlated with longer overall survival (p = 0.015 respectively p = 0.001). In multivariate analysis, LEF-1 and TCF4 expression were confirmed to be independent predictors of longer respectively shorter overall survival, when considered together with tumour stage, gender and age (risk ratio for LEF-1: 2.66; p = 0.027 risk ratio for TCF4: 2.18; p = 0.014).ConclusionsThis study demonstrates different prognostic values of LEF-1 and TCF4 expression in colorectal cancer patients indicating different regulation of these transcription mediators during tumour progression. Moreover both factors may serve as new potential predictive markers in low stage colon cancer cases in advance.
Highlights
Most colorectal carcinomas are driven by an activation of the canonical Wnt signalling pathway, which promotes the expression of multiple target genes mediating proliferation inavasion and invasion
As LEF-1 is not expressed in the normal colon mucosa [13], but is found in human colorectal cancer [14], a shift of b-catenin binding partners from TCF4 to LEF-1 might occur during carcinogenesis which might enable enhanced epithelial-mesenchymal transition (EMT) and malignant progression
LEF-1 and TCF4 expression in colorectal cancer To investigate the localisation of LEF-1 and TCF4 in human colorectal cancer, we evaluated the expression of these proteins by immunostaining on tissue microarrays
Summary
Most colorectal carcinomas are driven by an activation of the canonical Wnt signalling pathway, which promotes the expression of multiple target genes mediating proliferation inavasion and invasion. Upon activation of the Wnt signalling pathway its key player b-catenin translocates from the cytoplasm to the nucleus and binds to members of the T-cell factor (TCF)/lymphoid enhancer factor (LEF-1) family namely LEF-1 and TCF4 which are central mediators of transcription. Effects of signalling activity of b-catenin are mediated by members of the T-cell factor (TCF)/lymphoid enhancer factor (LEF-1) family These DNA binding proteins interact with b-catenin in the nucleus and stimulate a. LEF-1 on the other hand is a cell type specific transcription factor which was initially discovered in pre-T and B lymphocytes [5,6,7] It belongs to the family of high mobility group (HMG) proteins which induce structural alterations in the DNA-Helix [8,9]. As LEF-1 is not expressed in the normal colon mucosa [13], but is found in human colorectal cancer [14], a shift of b-catenin binding partners from TCF4 to LEF-1 might occur during carcinogenesis which might enable enhanced epithelial-mesenchymal transition (EMT) and malignant progression
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