Full-length LGR5-positive cells have chemoresistant characteristics in colorectal cancer

Abstract

Background:Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a target of Wnt signalling and considered both a cancer stem cell marker and intestinal stem cell marker. We found first some splice variants of LGR5 in human intestine and elucidated the functional feature of full-length LGR5 (LGR5FL).Methods:Reverse transcript PCR using mRNA extracted from intestine revealed the existence of LGR5 splice variants. We designed an antibody that recognises only LGR5FL and assessed immunohistochemically the distribution of LGR5FL-positive cells and Ki-67-positive cells in clinical samples.Results:Two LGR5 splice variants were expressed in the human intestine crypt cells; one lacked exon 5 and the other lacked exons 5–8. Only LGR5FL appeared during cell cycle arrest, whereas the transcript variants appeared when the cell cycle was proceeding. Immunohistochemistry and in situ hybridisation showed that LGR5FL-positive cells were negative for Ki-67. Comparing prechemotherapy and post-chemotherapy specimens, the population of LGR5FL-positive cells significantly increased with therapy (P<0.01).Conclusions:The function of LGR5FL-positive cells had low cell proliferative ability compared with the cells, which expressed splice variants of LGR5 and remained after chemotherapy. Designing therapeutic strategies that target LGR5FL-positive cells seems to be important in colorectal cancer.