Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial-Mesenchymal Transition.

Wook Jin

doi:10.3390/cells9010217

Abstract

The JAK/STAT3 signaling pathway plays an essential role in various types of cancers. Activation of this pathway leads to increased tumorigenic and metastatic ability, the transition of cancer stem cells (CSCs), and chemoresistance in cancer via enhancing the epithelial–mesenchymal transition (EMT). EMT acts as a critical regulator in the progression of cancer and is involved in regulating invasion, spread, and survival. Furthermore, accumulating evidence indicates the failure of conventional therapies due to the acquisition of CSC properties. In this review, we summarize the effects of JAK/STAT3 activation on EMT and the generation of CSCs. Moreover, we discuss cutting-edge data on the link between EMT and CSCs in the tumor microenvironment that involves a previously unknown function of miRNAs, and also discuss new regulators of the JAK/STAT3 signaling pathway.

Highlights

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway played a crucial role in many biological functions during the multistep development of human tumors, including proliferation, inflammation, and survival
Recent studies have demonstrated that induced MK is significantly associated with chemoresistance in pancreatic cancer via the activation of NF-κB signaling and Hes1-induced JAK2/STAT3 signaling through cleavage and activation of MK-mediated Notch signaling [54,55]
Along with its essential role in the progression of cancer, the interleukin 6 (IL-6)/JAK/STAT3 signaling axis incorporates various unexpected components and miRNAs that contribute to JAK/STAT3 activation in cancer

Summary

Introduction

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway played a crucial role in many biological functions during the multistep development of human tumors, including proliferation, inflammation, and survival. CXCL12-induced CXCR7 receptor results in increased IL-8 and VEGF levels, and subsequently, EMT by induction of Snail through the activation of AKT, ERK, and STAT3 in bladder cancer and BC [49,50]. Aberrant EGF/EGFR signaling enhances EMT and cisplatin-resistance through the activation of JAK2/STAT3 via the following: increasing IL-6 and LIF production [65], src-induced Zeb and Zeb upregulation [66], and increasing Twist-1 expression via binding of STAT3 to the promoter of. Neurotrophin receptors, TrkB and TrkC, are regulators of JAK/STAT3 signaling Both TrkB and TrkC increase JAK2 stability through inhibition of SOCS-3-mediated JAK2 degradation via direct interaction with JAK2, thereby resulting in the induction of EMT and metastasis of BC [78,79]. IL-6/JAK/STAT3 activation induces c-Myc expression through the upregulation of PIM-1 to enhance EMT and stemness [91]

Other Proteins as Orchestrators

MicroRNAs as Positive Regulators

Findings

Conclusions