Abstract
The neoplastic transformation of normal to metastatic cancer cells is a complex multistep process involving the progressive accumulation of interacting genetic and epigenetic changes that alter gene function and affect cell physiology and homeostasis. Epigenetic changes including DNA methylation, histone modifications and changes in noncoding RNA expression, and deregulation of epigenetic processes can alter gene expression during the multistep process of carcinogenesis. Cancer progression and metastasis through an ‘invasion–metastasis cascade’ involving an epithelial-to-mesenchymal cell transition (EMT), the generation of cancer stem cells (CSCs), invasion of adjacent tissues, and dissemination are fueled by inflammation, which is considered a hallmark of cancer. Chronic inflammation is generated by inflammatory cytokines secreted by the tumor and the tumor-associated cells within the tumor microenvironment. Inflammatory cytokine signaling initiates signaling pathways leading to the activation of master transcription factors (TFs) such as Smads, STAT3, and NF-κB. Moreover, the same inflammatory responses also activate EMT-inducing TF (EMT-TF) families such as Snail, Twist, and Zeb, and epigenetic regulators including DNA and histone modifying enzymes and micoRNAs, through complex interconnected positive and negative feedback loops to regulate EMT and CSC generation. Here, we review the molecular regulatory feedback loops and networks involved in inflammatory cytokine-induced EMT and CSC generation.
Highlights
The hallmarks of cancer refer to several biological capabilities acquired during the multistep process of tumor initiation and development, which contribute to cancer cell growth, progression, and metastasis
The link between epithelial-to-mesenchymal cell transition (EMT) and cancer stem cells (CSCs) generation is regulated by the balance of complex interacting transcription factors (TFs)-miRNA regulatory loops, such as that of the p53-miRNA and the NF-κB–miRNA molecular circuits, which play a crucial role in the control of EMT and cancer cell metastasis [9,39,58,135]
Inflammatory cytokine-driven EMT mediated by Smad, STAT3, and NF-κB TFs leads to the activation of oncogenic EMT-inducing TF (EMT-TF), which recruit epigenetic regulators in the CDH1 gene promoter resulting in the silencing of E-cadherin expression
Summary
The hallmarks of cancer refer to several biological capabilities acquired during the multistep process of tumor initiation and development, which contribute to cancer cell growth, progression, and metastasis. EMT-inducing signals activate a small set of pleiotropic transcription factors (TFs) that can lead to dynamic and reversible reprogramming of epithelial-to-mesenchymal cell states These oncogenic EMT-inducing transcription factors (EMT-TFs) recruit and interact with epigenetic regulators creating feedback molecular loops that regulate cellular plasticity, and link inflammation with EMT and CSC generation during cancer progression and metastasis [16,22,27,28,29,36,37,41,42,44,45,46,47,48,56,57,65,66,67,68,69,70,71,72,73]. The link between EMT and CSC generation is regulated by the balance of complex interacting TF-miRNA regulatory loops, such as that of the p53-miRNA and the NF-κB–miRNA molecular circuits, which play a crucial role in the control of EMT and cancer cell metastasis [9,39,58,135]
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