Da Costa Antas, Pedro Rafael; (2017) Identification and characterisation of novel Wnt regulators in colorectal cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Colorectal cancer (CRC) is a multistep mutagenic process that provides tumour cells with a growth advantage for clonal expansion. The Wnt signalling pathway is crucial for regulating ISC maintenance and differentiation, whilst aberrant Wnt activation is a hallmark of human CRC. Recent advances in genome-scale analysis of large cohorts of CRCs have uncovered a large number of novel mutations that had not been previously characterised. Interestingly, hierarchical clustering analyses of the related expression data reveals a cluster of differentially expressed genes that is enriched in the previously reported ISC markers, Wnt targets and/or Wnt inhibitors. We hypothesised that some of the genes within the cluster are expressed at the intestinal crypt bottoms to antagonise Wnt signalling to form part of a negative feedback mechanism for ISC homeostasis. The aim of my project was to screen for novel Wnt regulators within this gene cluster. Comprehensive analysis of the cluster identified two potential Wnt regulators: the SH3 domain-binding protein 4 (SH3BP4) and the serine/threonine kinase ZAK/MAP3K20. Here we show that both Sh3bp4 and Zak are expressed at the ISC compartment and are enriched in Apc-mutated tumours. Deletion of Zak enhances radiation-induced intestinal regeneration, suggesting a growth inhibitory role of ZAK in the intestine. Loss of SH3BP4 in vivo exacerbates the Apcmin tumour phenotype by promoting the total number of adenomas and high-grade dysplasia. Mechanistically, ZAK and SH3BP4 suppresses Wnt signalling downstream of -catenin phosporylation. The data revealed novel roles for both ZAK and SH3BP4 in intestinal homeostasis and tumourigenesis via Wnt/-catenin signalling regulation. Taken together, the findings highlight the crucial role that these newly identified genes play in Wnt negative feedback mechanisms in intestinal regeneration and tumourigenesis, which may provide new insights into targeted therapeutic intervention.

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