LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/β-catenin signalling in neuroblastoma
Chockalingam, S.; Vieira, Gabriella Cunha; Melegh, Zsombor; Kaidi, Abderrahmane; Bates, David O.; Gabb, Peter David; Sankarakuttalam, Chockalingam; Melegh, Zsombor B; Greenhough, Alexander; Malik, Sally; Szemes, Marianna; Park, Ji Hyun; Zhou, Li; Catchpoole, Daniel; Morgan, Rhys
Gabriella Cunha Vieira
David O. Bates
Peter David Gabb
Zsombor B Melegh
Alexander Greenhough Alexander.Greenhough@uwe.ac.uk
Senior Lecturer Biomedical Science
Ji Hyun Park
LGR5 is a marker of normal and cancer stem cells in various tissues where it functions as a receptor for R-spondins and increases canonical Wnt signalling amplitude. Here we report that LGR5 is also highly expressed in a subset of high grade neuroblastomas. Neuroblastoma is a clinically heterogenous paediatric cancer comprising a high proportion of poor prognosis cases (~40%) which are frequently lethal. Unlike many cancers, Wnt pathway mutations are not apparent in neuroblastoma, although previous microarray analyses have implicated deregulated Wnt signalling in high-risk neuroblastoma. We demonstrate that LGR5 facilitates high Wnt signalling in neuroblastoma cell lines treated with Wnt3a and R-spondins, with SK-N-BE(2)-C, SK-N-NAS and SH-SY5Y cell-lines all displaying strong Wnt induction. These lines represent MYCN-amplified, NRAS and ALK mutant neuroblastoma subtypes respectively. Wnt3a/R-Spondin treatment also promoted nuclear translocation of β-catenin, increased proliferation and activation of Wnt target genes. Strikingly, short-interfering RNA mediated knockdown of LGR5 induces dramatic Wntindependent apoptosis in all three cell-lines, accompanied by greatly diminished phosphorylation of mitogen/extracellular signal-regulated kinases (MEK1/2) and extracellular signal-regulated kinases (ERK1/2), and an increase of BimEL, an apoptosis facilitator downstream of ERK. Akt signalling is also decreased by a Rictor dependent, PDK1-independent mechanism. LGR5 expression is cell cycle regulated and LGR5 depletion triggers G1 cell-cycle arrest, increased p27 and decreased phosphorylated retinoblastoma protein. Our study therefore characterises new cancer-associated pathways regulated by LGR5, and suggest that targeting of LGR5 may be of therapeutic benefit for neuroblastomas with diverse etiologies, as well as other cancers expressing high LGR5.
|Journal Article Type||Article|
|Publication Date||Jan 1, 2015|
|Peer Reviewed||Peer Reviewed|
|APA6 Citation||Gabb, P. D., Bates, D. O., Kaidi, A., Melegh, Z., Chockalingam, S., Vieira, G. C., …Malik, K. (2015). LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/β-catenin signalling in neuroblastoma. Oncotarget, 6(37), 40053-40067. https://doi.org/10.18632/oncotarget.5548|
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