PO-127 Role of the NEDD4 family of E3 ubiquitin ligases in colorectal cancer pathogenesis and their potential as biomarkers

IntroductionColorectal cancer (CRC) is a global health challenge. There is limited response to standard oncological treatment and few stratified treatment options based on prognostic and/or predictive factors. The four biologically distinct and gene expression-based consensus molecular subtypes (CMS...

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Published in:	ESMO open Vol. 3; no. Suppl 2; p. A70
Main Authors:	Knudsen, LM, Sveen, A, Bergsland, CH, Five, MB, Rasmussen, NL, Totland, MZ, Eide, PW, Bruun, J, Lothe, RA, Leithe, E
Format:	Journal Article
Language:	English
Published:	Elsevier Ltd 01-07-2018
Online Access:	Get full text
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Summary:	IntroductionColorectal cancer (CRC) is a global health challenge. There is limited response to standard oncological treatment and few stratified treatment options based on prognostic and/or predictive factors. The four biologically distinct and gene expression-based consensus molecular subtypes (CMS) provide prognostic stratification independent of cancer stage, and represent a new potential paradigm for stratified treatment. In this project, we are analysing the biomarker and drug target potential of members of the HECT (homologous to E6AP C-terminus) family of E3 ubiquitin ligases in CRC.Material and methodsA total of 412 primary CRCs and 51 normal colonic mucosa samples were subjected to genome wide expression analysis at exon level resolution using either the Affymetrix Human Exon Array or the Affymetrix Human Transcriptome Array. The CRISPR/Cas9 system was applied to generate NEDD4 knock-out Caco2 cell lines.Results and discussionsWe identified NEDD4 (neural precursor cell-expressed developmentally down-regulated 4) as significantly overexpressed in CRC, while the NEDD4 homolog NEDD4L was significantly down regulated. Furthermore, we found that NEDD4 is differentially expressed between the different CMS classes, with high expression particularly in the epithelial and canonical CMS2 group. CRISPR/Cas9-mediated knock-out of NEDD4 in the CRC cell line Caco2 was found to result in altered growth characteristics.ConclusionThe data indicate that NEDD4 and NEDD4L are differently expressed in CRC samples compared to normal colonic mucosa, and that knock-out of NEDD4 in Caco2 cells affects their growth characteristics.
ISSN:	2059-7029 2059-7029
DOI:	10.1136/esmoopen-2018-EACR25.168