title: Maintenance of stem cell self-renewal in head and neck cancers requires actions of GSK3β influenced by CD44 and RHAMM.
abstract: Cells sorted from head and neck cancers on the basis of their high expression of CD44 have high potency for tumor initiation. These cells are also involved in epithelial to mesenchymal transition (EMT) and we have previously reported that cancer stem cells (CSCs) exist as two biologically distinct phenotypes. Both phenotypes are CD44(high) but one is also ESA(high) and maintains epithelial characteristics, the other is ESA(low) , has mesenchymal characteristics and is migratory. Examining CD44-regulated signal pathways in these cells we show that CD44, and also RHAMM, act to inhibit phosphorylation of glycogen synthase kinase 3β (GSK3β). We show that inhibitory phosphorylation reduces the formation of both "tumor spheres" and "holoclone" colonies, functional indicators of stemness. GSK3β inhibition also reduces the expression of stem cell markers such as Oct4, Sox2, and Nanog and upregulates expression of the differentiation markers Calgranulin B and Involucrin in the CD44(high) /ESA(high) cell fraction. Transition of CSCs out of EMT and back to the epithelial CSC phenotype is induced by GSK3β knockdown. These results indicate that GSK3β plays a central role in determining and maintaining the phenotypes and behavior of CSCs in vitro and are likely to be involved in controlling the growth and spread of tumors in vivo.
authors: Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London United Kingdom; Department of Oral and Maxillofacial Surgery, Division of Cervico-Gnathostomatology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors: Hideo
authors: H
authors: Shigeishi
authors: Adrian
authors: A
authors: Biddle
authors: Luke
authors: L
authors: Gammon
authors: Helena
authors: H
authors: Emich
authors: Camila O
authors: CO
authors: Rodini
authors: Emilios
authors: E
authors: Gemenetzidis
authors: Bilal
authors: B
authors: Fazil
authors: Masaru
authors: M
authors: Sugiyama
authors: Nobuyuki
authors: N
authors: Kamata
authors: Ian C
authors: IC
authors: Mackenzie
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational
chemical_list: C497483:CD44 protein, human; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: CD44; Cancer stem cells; Glycogen synthase kinase 3β; Head and neck squamous cell carcinoma; Receptor for hyaluronan-mediated motility