Abstract
CXCL1 is one of the most important chemokines, part of a group of chemotactic cytokines involved in the development of many inflammatory diseases. It activates CXCR2 and, at high levels, CXCR1. The expression of CXCL1 is elevated in inflammatory reactions and also has important functions in physiology, including the induction of angiogenesis and recruitment of neutrophils. Due to a lack of reviews that precisely describe the regulation of CXCL1 expression and function, in this paper, we present the mechanisms of CXCL1 expression regulation with a special focus on cancer. We concentrate on the regulation of CXCL1 expression through the regulation of CXCL1 transcription and mRNA stability, including the involvement of NF-κB, p53, the effect of miRNAs and cytokines such as IFN-γ, IL-1β, IL-17, TGF-β and TNF-α. We also describe the mechanisms regulating CXCL1 activity in the extracellular space, including proteolytic processing, CXCL1 dimerization and the influence of the ACKR1/DARC receptor on CXCL1 localization. Finally, we explain the role of CXCL1 in cancer and possible therapeutic approaches directed against this chemokine.
Highlights
Academic Editors: Michihiro Mutoh, Intercellular signaling is an essential part of the functioning of a multicellular organism, involving the flow of information between different cells through either direct contact or via factors secreted outside the cell: simple compounds such as lactate [1], or large structures such as extracellular vesicles [2]
SMAD family member 4 (SMAD4) expression is reduced in colorectal cancer cells, as it interferes with the action of transforming growth factor β (TGF-β), and leads to an increase in CXC motif chemokine ligand 1 (CXCL1) expression in the cancer cell [61]
The precise regulation of CXCL1 expression by SET-domain-containing 2 (SETD2) is not known. As this enzyme modifies a fragment very far from the CXCL1 gene, it is possible that it alters the ability to bind some proteins that are important for the regulation of gene expression (Table 1)
Summary
Academic Editors: Michihiro Mutoh, Intercellular signaling is an essential part of the functioning of a multicellular organism, involving the flow of information between different cells through either direct contact or via factors secreted outside the cell: simple compounds such as lactate [1], or large structures such as extracellular vesicles [2]. One group of factors responsible for intercellular signaling is chemokines, a group of about 50 chemotactic cytokines grouped according to the conserved N-terminal cysteine motif: CXC chemokines (α-chemokines), CC chemokines (β-chemokines), C chemokines (γ-chemokines) and CX3 C chemokines (δ-chemokines) [3]. Considering the number of available scientific papers, CXCL1 is one of the four most studied CXC chemokines, with more than 5000 experimental papers available on PubMed (https://pubmed.ncbi.nlm.nih.gov; accessed date: 15 November 2021), with more than 1000 of these on the role of CXCL1 in cancer. Each year more than 400 new papers are published about this chemokine, there are no available review papers summarizing the current knowledge in this area. This paper is part of a greater project that aims to provide a comprehensive series of reviews on CXCL1; our focus is on the regulation of expression and activity of this chemokine in the intercellular space.
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