Abstract
BackgroundTumor recurrence, the chief reason for poor prognosis of glioma, is largely attributed to glioma stem cells (GSCs) and epithelial-mesenchymal transition (EMT). However, the mechanisms among them remain unknown. Here, we determined whether leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), known as a stem cell marker for colon cancer and gastric cancer, can serve as a novel GSC marker involved in EMT and a therapeutic target in glioma.MethodsStemness properties were examined in FACS-isolated LGR5+/LGR5− cells. Reported stem cell markers, EMT and the Wnt/β-catenin pathway were examined in stable LGR5 knockdown or overexpressed GSCs by Western Blot. The treatment experiment was performed in an intracranial orthotopic xenograft model by knockdown of LGR5 or by using the Wnt/β-catenin pathway inhibitor Wnt-C59. LGR5 expression was determined in 268 glioma specimens by immunohistochemistry.ResultsLGR5+ cells possessed stronger stemness properties compared to LGR5− cells. The expression of SOX2, Nanog, CD133, CD44, CD24 and EpCAM was modulated by LGR5. Both LGR5 knockdown and Wnt-C59 reduced tumor invasion and migration and blocked EMT by inhibiting the Wnt/β-catenin pathway in vitro and suppressed the intracranial orthotopic xenograft growth and prolonged the survival of xenograft mice in vivo. Moreover, LGR5 was positively correlated with Ki67, N-cadherin and WHO grade and negatively correlated with IDH1. Glioma patients with high expression of LGR5 showed significantly poorer prognosis.ConclusionsLGR5 is a new functional GSC marker and prognostic indicator that can promote EMT by activating the Wnt/β-catenin pathway and would thus be a novel therapeutic target for glioma.
Highlights
Tumor recurrence, the chief reason for poor prognosis of glioma, is largely attributed to glioma stem cells (GSCs) and epithelial-mesenchymal transition (EMT)
Recent developments in stem cell research have revealed the existence of glioma stem cells (GSCs) which are analogous to cancer stem cells (CSCs) and determined that GSCs represent a subpopulation of cells with strong tumorigenesis, invasiveness, chemoradiotherapy resistance and EMT properties [7, 8]
Percentage of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)+ cells is higher in enriched cells than that in parent cells To determine the expression and localization of LGR5 in glioma cells, LGR5 staining was performed in 3 types of glioma cell lines (U251, U87 and A172) and 3 types of human primary glioma cells (8591, LHH and 7112), demonstrating that LGR5 was expressed in the cell membrane and cytoplasm (Fig. 1a)
Summary
The chief reason for poor prognosis of glioma, is largely attributed to glioma stem cells (GSCs) and epithelial-mesenchymal transition (EMT). Recent developments in stem cell research have revealed the existence of glioma stem cells (GSCs) which are analogous to cancer stem cells (CSCs) and determined that GSCs represent a subpopulation of cells with strong tumorigenesis, invasiveness, chemoradiotherapy resistance and EMT properties [7, 8]. Because of these characteristics, GSCs are considered as responsible for failure of treatment and tumor recurrence [8,9,10,11,12]. GSCs are regarded as a relevant target for glioma therapy
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