bjc2017412.pdf (1.61 MB)
LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity.
journal contribution
posted on 2023-06-09, 13:12 authored by Rhys MorganRhys Morgan, E Mortensson, D N Legge, B Gupta, T J Collard, A Greenhough, A C WilliamsBACKGROUND LGR5 serves as a co-receptor for Wnt/ß-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.
History
Publication status
- Published
File Version
- Published version
Journal
British Journal of CancerISSN
1532-1827Publisher
Nature Publishing GroupExternal DOI
Issue
4Volume
118Page range
558-565Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-05-10First Open Access (FOA) Date
2018-05-10First Compliant Deposit (FCD) Date
2018-05-09Usage metrics
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