An investigation into the relevance of dual-specificity phosphatase 6 in colorectal cancer

Abstract

A negative regulator of ERK; dual-specificity phosphatase 6 (DUSP6), has been implicated in the pathogenesis of a variety of cancers including lung, pancreatic and oesophageal. Additionally DUSP6 expression has been associated with treatment response in breast, lung and ovarian cancer. Despite this range of investigations little is known about its involvement in colorectal cancer. The main aims of this study were firstly to explore the landscape of DUSP6 protein expression across formalin fixed paraffin embedded (FFPE) samples representing the main stages of progression from normal mucosa to adenocarcinoma. Secondly, to assess the relationship between DUSP6 protein expression and RAS genotype in colorectal adenocarcinoma and finally to explore the impact of DUSP6 manipulation in vitro on response to the anti-EGFR monoclonal antibody Cetuximab. Immunohistochemical analysis of DUSP6 in FFPE samples demonstrated a significant increased expression in adenoma, specifically those with high grade dysplasia in comparison to normal mucosa and adenocarcinoma. No significant association between RAS genotype and DUSP6 protein expression was observed based upon immunofluorescence assessment of an FFPE colorectal adenocarcinoma cohort. Expression of DUSP6 in both RG/C2/80 adenoma and C99 adenocarcinoma cell lines provides evidence for a functional relationship between DUSP6 and regulation of activated ERK. In preliminary studies using C99 cells, over-expression of DUSP6 increased sensitivity to Cetuximab treatment.

In conclusion, this series of investigations has highlighted a potential tumour suppressive role for DUSP6 in colorectal adenoma. It is hypothesised that up-regulation of DUSP6 in response to increased MAPK pathway activation attempts to reduce overall proliferation and survival of dysregulated cells which have the potential for malignant transformation. Further work is warranted to confirm the role of specific DUSP6 isoforms in colorectal pathogenesis.