ZEB1 in Colorectal Cancer

Colorectal cancer (CRC) is one of the commonest malignancies in the United Kingdom and tumour cell invasion and metastasis is the main cause of death. The transcriptional repressor ZEB1 has been shown to be expressed in several epithelial malignancies and embryonic epithelial-mesenchymal transitions (EMT). The understanding of cellular signalling cascades should allow the discovery of novel targets for potential future therapeutic manipulation in the treatment of colorectal cancer and other malignancies. Here, in order to further investigate the role of ZEB1 in CRC, in vitro investigations and immunohistochemical analysis of 101 colorectal cancers and their matched lymph node and liver metastases are performed. The Wnt-Inducible Signalling Proteins and Plakophilin-3 are also investigated for their relationship with ZEB1 signalling. ZEB1 is expressed in tumour cell lines with mesenchymal characteristics and over-expression in an epithelial-phenotype cancer cell line causes down-regulation of epithelial markers such as E-cadherin and Plakophilin-3. Knockdown of ZEB1 in mesenchymal cell lines caused up-regulation of PKP-3 expression. In vitro attempts at manipulation of WISP expression were unsuccessful. In CRC tumours ZEB1 was noted to be up-regulated at the tumour invasive front, with concomitant loss of Plakophilin-3 expression. However expression of these markers did not correlate with disease stage or survival on multivariable analysis. Increased WISP-1 nuclear and cytoplasmic expression were noted at the tumour invasive front and correlated with disease stage and several pathological factors on univariable analysis. Increased nuclear WISP-1 expression at the invasive front correlated with survival on uni- and multivariable analysis. This study demonstrates that ZEB1, Plakophilin-3 and WISP-1 are expressed in CRC and may be involved in tumour cell invasion and dissemination at the invasive front. Expression of nuclear WISP-1 is an independent predictor of poor survival and is worthy of further investigation as a target of future therapeutic intervention.