In Pursuit of Leucine-Rich Repeat-Containing G Protein-Coupled Receptor-5 Regulation and Function in the Uterus

Abstract

Leucine-rich repeat-containing G protein-coupled receptor (LGR)-5 is a recently identified marker of stem cells in adult intestinal epithelium and hair follicles. Because of this characteristic, we studied the status of Lgr5 expression in the mouse uterus under various conditions. Lgr5 is highly expressed in the uterine epithelium of immature mice and is dramatically down-regulated after the mice resume estrous cycles. Surprisingly, whereas its expression is up-regulated in uteri of ovariectomized mice, the expression is down-regulated by estrogen and progesterone via their cognate nuclear receptors, estrogen receptor-alpha and progesterone receptor, respectively. Using a mouse endometrial cancer model, we also found that Lgr5 is highly expressed in the epithelium during the initial stages of tumorigenesis but is remarkably down-regulated in fully developed tumors. Lgr5 is a downstream target of Wnt signaling in the intestine. Genetic evidence shows that either excessive or absence of Wnt signaling dampens Lgr5 expression in the uterus. Collectively, our results show that Lgr5 expression in the mouse uterine epithelium is unique and dynamically regulated under various physiological and pathological states of the uterus, suggesting that this orphan receptor has important functions in uterine biology. However, identifying definitive uterine function of LGR5 will require further investigation using conditional deletion of uterine Lgr5 because systemic deletion of this gene is neonatally lethal.

LgR5 expression and cancer stem cell hypothesis: clue to define the true origin of esophageal adenocarcinomas with and without Barrett's Esophagus?

“…In the endometrium, high expression of LgR5 is observed during the initial stages of tumorigenesis, but down-regulation of LgR5 is described for fully developed tumors [30]. This is well in line with our findings in EAC.…”

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“…4C). Moreover, Lgr5 was downregulated upon hormonal treatment, in agreement with a previous report (Sun et al, 2009), whereas Lgr4 expression showed no change (Fig. 4C).…”

“…Lgr5 expression was found to be downregulated in the mouse EMOs after E2 and Prog treatment. By analogy, Lgr5 mRNA is highly expressed in pre-pubertal mouse uterus and is strongly downregulated in ovariectomized mice upon hormone injection (Sun et al, 2009). In the human EMOs, LGR4 and LGR5 gene expression did not change under hormone treatment, in agreement with a previous report (Krusche et al, 2007).…”

LGRs receptors as peculiar GPCRs involved in cancer

“…LGR5 function: As compared to its paralogues that are not direct Wnt target genes, Lgr5 expression is induced by Wnt signaling in a suggested bi-modal manner [56][57][58]. Expression of the receptor would occur under a narrow range of "not too low, not too high" Wnt stimulation, which may explain in part why the Lgr5 function is still subject to discussion.…”

“…In mammary glands, oncogenic mutation in the Lgr6 +ve cells induces expansion of luminal cells generating tumor development [72]. In a mouse endometrial cancer model, Lgr5 is highly expressed in the initial stages of tumorigenesis but is downregulated in fully developed tumors [57]. In a skin carcinogenesis model involving UV or chemical treatments, Lgr5 +ve or Lgr6 +ve cells did not appear as tumor-initiating cells [83,84].…”