Roles of GSK-3 and microRNAs on epithelial mesenchymal transition and cancer stem cells

// James A. McCubrey 1 , Timothy L. Fitzgerald 2 , Li V. Yang 3 , Kvin Lertpiriyapong 4 , Linda S. Steelman 1 , Stephen L. Abrams 1 , Giuseppe Montalto 5,6 , Melchiorre Cervello 6 , Luca M. Neri 7 , Lucio Cocco 8 , Alberto M. Martelli 8 , Piotr Laidler 9 , Joanna Dulińska-Litewka 9 , Dariusz Rakus 10 , Agnieszka Gizak 10 , Ferdinando Nicoletti 11 , Luca Falzone 11 , Saverio Candido 11 and Massimo Libra 11 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA 2 Department of Surgery, Brody School of Medicine at East Carolina University, Greenville, NC, USA 3 Department of Internal Medicine, Hematology/Oncology Section, Brody School of Medicine at East Carolina University, Greenville, NC, USA 4 Department of Comparative Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, USA 5 Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 6 Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy 7 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy 8 Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy 9 Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland 10 Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland 11 Department of Biomedical and Biotechnological Sciences – Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy Correspondence to: James A. McCubrey, email: // Massimo Libra, email: // Keywords : GSK-3, cancer stem cells, Wnt/beta-catenin, PI3K, Akt Received : October 28, 2016 Accepted : December 13, 2016 Published : December 16, 2016 Abstract Various signaling pathways exert critical roles in the epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). The Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, hedgehog (Hh), Notch and TP53 pathways elicit essential regulatory influences on cancer initiation, EMT and progression. A common kinase involved in all these pathways is moon-lighting kinase glycogen synthase kinase-3 (GSK-3). These pathways are also regulated by micro-RNAs (miRs). TP53 and components of these pathways can regulate the expression of miRs. Targeting members of these pathways may improve cancer therapy in those malignancies that display their abnormal regulation. This review will discuss the interactions of the multi-functional GSK-3 enzyme in the Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, Hh, Notch and TP53 pathways. The regulation of these pathways by miRs and their effects on CSC generation, EMT, invasion and metastasis will be discussed.