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.

Citation

Morgan, R. G., Mortensson, E., Legge, D. N., Gupta, B., Collard, T. J., Greenhough, A., & Williams, A. C. (2018). LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity. British Journal of Cancer, 118(4), 558-565. https://doi.org/10.1038/bjc.2017.412

• 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