Expression Profile of LGR5 and Its Prognostic Significance in Colorectal Cancer Progression

Abstract

We investigated the expression profile of leucine-rich, repeat-containing, G-protein-coupled receptor 5 (LGR5) during colorectal cancer (CRC) progression and determined the prognostic impact of LGR5 in a large cohort of CRC samples. LGR5 expression was higher in CRCs than in normal mucosa, and was not associated with other cancer stem cell markers. LGR5 positivity was observed in 68% of 788 CRCs and was positively correlated with older age, moderately to well-differentiated cells, and nuclear β-catenin expression. Enhanced LGR5 expression remained persistent during the adenoma-carcinoma transition, but markedly declined in the budding cancer cells at the invasive fronts, which was not due to altered wingless-type mouse mammary tumor virus integration site family (Wnt) or epithelial-mesenchymal transition signaling. LGR5 showed negative correlations with microsatellite instability and CpG island methylator phenotype, and was not associated with KRAS or BRAF mutation. Notably, LGR5 positivity was an independent prognostic marker for better clinical outcomes in CRC patients. LGR5 overexpression attenuated tumor growth by decreasing ERK phosphorylation along with decreased colony formation and migration abilities in DLD1 cells. Likewise, knockdown of LGR5 expression resulted in a decline in the colony-forming and migration capacities in LoVo cells. Taken together, our data suggest a suppressive role of LGR5 in CRC progression.

Characterization of LGR5 expression in poorly differentiated colorectal carcinoma with mismatch repair protein deficiency

“…It may be because many prognostic evaluations are performed by immunohistostaining. In a report using the RNA in situ hybridization method, high expression of LGR5 was observed in well differentiated CRC and showed better prognosis [4]. PD-CRC can arise through the adenomacarcinoma sequence or the serrated neoplasia pathway.…”

“…A recent report described differences in the presence of LGR5-positive carcinoma stem cells based on differences in MMR protein expression [4]. However, no studies have previously analyzed LGR5 expression in detail in PD-CRC cases alone.…”

“…LGR5 is also a candidate marker for colorectal cancer (CRC) stem cells [2] and may be closely involved in the progression and prognosis of CRC [3]. However, Jang et al suggested a suppressive role for LGR5 in CRC progression [4].…”

Cancer stem cells, stemness markers and selected drug targeting: metastatic colorectal cancer and cyclooxygenase-2/prostaglandin E2 connection to WNT as a model system

“…Thus, LGR5 is a marker for early CSCs and relates to their WNT promoted self-renewing capacity. Enhanced LGR5 expression remains persistent during adenoma to carcinoma transition in human CRC samples, but markedly declines in the budding cancer cells at the invasive tumor fronts, and was not associated with either WNT-or EMT-signalling pathways [98] . In the latter study, LGR5 overexpression attenuated proliferation, migration, and colony-forming capacities in colon cancer cells.…”

“…Most colorectal cancer cell lines and sporadic colonic adenomas exhibit significant LGR5 expression [98] , although this is linked with stemness and renewal but not tumor progression because overexpressing LGR5 caused greater cell-cell adhesion, reduced tumor growth, invasiveness, migration and metastasis [98,99] . Recently, LGR5 was established as a definitive surface marker for colorectal CSCs (reviewed in [90,100] ), particularly when co-expressed with CD44 and EPCAM [101] .…”