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; Massimo Libra

doi:10.18632/oncotarget.13991

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

Oncotarget. 2017 Feb 21;8(8):14221-14250. doi: 10.18632/oncotarget.13991.

Authors

James A McCubrey¹, Timothy L Fitzgerald², Li V Yang³, Kvin Lertpiriyapong⁴, Linda S Steelman¹, Stephen L Abrams¹, Giuseppe Montalto^{5

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, Massimo Libra¹¹

Affiliations

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.

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.

Keywords: Akt; GSK-3; PI3K; Wnt/beta-catenin; cancer stem cells.

Publication types

Review

MeSH terms

Animals
Epithelial-Mesenchymal Transition / physiology*
Glycogen Synthase Kinase 3 / metabolism*
Humans
MicroRNAs / metabolism*
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology*
Signal Transduction / physiology*

Substances

MicroRNAs
Glycogen Synthase Kinase 3