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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)558-565
Number of pages8
JournalBritish Journal of Cancer
Volume118
Issue number4
Early online date16 Nov 2017
DOIs
DateAccepted/In press - 19 Oct 2017
DateE-pub ahead of print - 16 Nov 2017
DatePublished (current) - 20 Feb 2018

Abstract

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.British Journal of Cancer advance online publication, 16 November 2017; doi:10.1038/bjc.2017.412 www.bjcancer.com.

    Research areas

  • LGR5, EGF, colorectal, adenoma, proliferation, survival, EGFRi, gefitinib

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Nature at https://www.nature.com/articles/bjc2017412 . Please refer to any applicable terms of use of the publisher.

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