LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/β-catenin signalling in neuroblastoma

摘要: LGR5 is a marker of normal and cancer stem cells in various tissues where it functions as receptor for R-spondins increases canonical Wnt signalling amplitude. Here we report that also highly expressed subset high grade neuroblastomas. Neuroblastoma clinically heterogenous paediatric comprising proportion poor prognosis cases (~40%) which are frequently lethal. Unlike many cancers, pathway mutations not apparent neuroblastoma, although previous microarray analyses have implicated deregulated high-risk neuroblastoma. We demonstrate facilitates neuroblastoma cell lines treated with Wnt3a R-spondins, SK-N-BE(2)-C, SK-N-NAS SH-SY5Y cell-lines all displaying strong induction. These represent MYCN-amplified, NRAS ALK mutant subtypes respectively. Wnt3a/R-Spondin treatment promoted nuclear translocation β-catenin, increased proliferation activation target genes. Strikingly, short-interfering RNA mediated knockdown induces dramatic Wnt-independent apoptosis three cell-lines, accompanied by greatly diminished phosphorylation mitogen/extracellular signal-regulated kinases (MEK1/2) extracellular (ERK1/2), an increase BimEL, facilitator downstream ERK. Akt decreased Rictor dependent, PDK1-independent mechanism. expression cycle regulated depletion triggers G1 cell-cycle arrest, p27 phosphorylated retinoblastoma protein. Our study therefore characterises new cancer-associated pathways LGR5, suggest targeting may be therapeutic benefit neuroblastomas diverse etiologies, well other cancers expressing LGR5.