LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity

Morgan, Rhys G; Mortensson, Eleanor; Legge, Danny N; Gupta, B.; Collard, Tracey J; Greenhough, Alexander; Williams, Ann C

Abstract

© The Author(s) named above 2018. Background:LGR5 serves as a co-receptor for Wnt/β-catenin signalling and marks normal intestinal stem cells; however, its role in colorectal cancer (CRC) remains controversial. LGR5 + cells are known to exist outside the stem cell niche during CRC progression, and the requirement for epidermal growth factor (EGF) signalling within early adenomas remains to be fully elucidated.Methods:Epidermal growth factor and gefitinib treatments were performed in EGF-responsive LGR5 + early adenoma RG/C2 cells. 2D growth assays were measured using an IncuCyte. LGR5 or MEK1/2 silencing studies were executed using siRNA and LGR5 expression was assessed by qRT-PCR and immunoblotting. Ki67 level and cell cycle status were analysed by flow cytometry.Results:Epidermal growth factor suppresses expression of LGR5 at both the transcript and protein level in colorectal adenoma and carcinoma cells. Suppression of LGR5 reduces the survival of EGF-treated adenoma cells by increasing detached cell yield but also inducing a proliferative state, as evidenced by elevated Ki67 level and enhanced cell cycle progression. Repression of LGR5 further increases the sensitivity of adenoma cells to EGFR inhibition.Conclusions:LGR5 has an important role in the EGF-mediated survival and proliferation of early adenoma cells and could have clinical utility in predicting response of CRC patients to EGFR therapy.

• Journal Article Type: Article
• Acceptance Date: Oct 19, 2017
• Online Publication Date: Nov 16, 2017
• Publication Date: Feb 20, 2018
• Deposit Date: Feb 12, 2019
• Publicly Available Date: Feb 14, 2019
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Springer Nature [academic journals on nature.com]
• Peer Reviewed: Peer Reviewed
• Volume: 118
• Issue: 4
• Pages: 558-565
• DOI: https://doi.org/10.1038/bjc.2017.412
• Public URL: https://uwe-repository.worktribe.com/output/871357
• Publisher URL: https://doi.org/10.1038/bjc.2017.412
• Contract Date: Feb 12, 2019