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

James A. McCubrey _, Timothy L. Fitzgerald, Li V. Yang, Kvin Lertpiriyapong, Linda S. Steelman, Stephen L. Abrams, Giuseppe Montalto, Melchiorre Cervello, Luca M. Neri, Lucio Cocco, Alberto M. Martelli, Piotr Laidler, Joanna Dulińska-Litewka, Dariusz Rakus, Agnieszka Gizak, Ferdinando Nicoletti, Luca Falzone, Saverio Candido and Massimo Libra

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Oncotarget. 2017; 8:14221-14250. https://doi.org/10.18632/oncotarget.13991

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James A. McCubrey1, Timothy L. Fitzgerald2, Li V. Yang3, Kvin Lertpiriyapong4, Linda S. Steelman1, Stephen L. Abrams1, Giuseppe Montalto5,6, Melchiorre Cervello6, Luca M. Neri7, Lucio Cocco8, Alberto M. Martelli8, Piotr Laidler9, Joanna Dulińska-Litewka9, Dariusz Rakus10, Agnieszka Gizak10, Ferdinando Nicoletti11, Luca Falzone11, Saverio Candido11 and Massimo Libra11

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


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.

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