LGR5 promotes survival in human colorectal adenoma cells and is upregulated by PGE 2 : implications for targeting adenoma stem cells with NSAIDs

Author： Al-Kharusi Manal R.A. Smartt Helena J.M. Greenhough Alexander Collard Tracey J. Emery Elizabeth D. Williams Ann C. Paraskeva Chris

Publisher： Oxford University Press

ISSN： 1460-2180

Source： Carcinogenesis, Vol.34, Iss.5, 2013-05, pp. : 1150-1157

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

Cyclooxygenase-2 is overexpressed in the majority of colorectal tumours leading to elevated levels of prostaglandin E₂ (PGE₂), promoting many hallmarks of cancer. Importantly, PGE₂ is reported to enhance Wnt/β-catenin signalling in colorectal carcinoma cells and in normal haematopoietic stem cells where it promotes stem cell function. Although Wnt signalling plays a crucial role in intestinal stem cells, the relationship between PGE₂ and intestinal stem cells is unclear. Given that the key intestinal cancer stem cell marker LGR5 (leucine-rich G-protein coupled receptor 5) is a Wnt target and PGE₂ enhances Wnt signalling, the focus of this study was to investigate whether PGE₂ regulated LGR5 expression in colorectal adenoma cells and whether LGR5 was important for tumour cell survival. PGE₂ upregulated LGR5 protein in adenoma (RG/C2) and carcinoma (DLD-1) cell lines. LGR5 knockdown induced cell death in RG/C2 and AA/C1 adenoma cells, suggesting that LGR5 has an important survival-promoting role in adenoma cells. Indeed, we detected LGR5 protein expression in 4 of 4 human adenoma cell lines. Furthermore, LGR5 small interfering RNA inhibited the survival-promoting effects of PGE₂ in RG/C2, suggesting that PGE₂ promotes adenoma cell survival, at least in part, by increasing LGR5 expression. These studies, therefore, show the first link between PGE₂ and LGR5 in human colorectal adenoma and carcinoma cells and demonstrate a survival-promoting role of LGR5. As non-steroidal anti-inflammatory drugs (NSAIDs) cause adenomas to regress in FAP patients, these studies could have important implications for the mechanism by which NSAIDs are chemopreventive, as lowering PGE₂ levels could reduce LGR5 expression and survival of LGR5⁺ adenoma stem cells.