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The Role of CXCL16 in the Pathogenesis of Cancer and Other Diseases

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The Role of CXCL16 in the Pathogenesis of Cancer and Other Diseases International Journal of Molecular Sciences Review The Role of CXCL16 in the Pathogenesis of Cancer and Other Diseases Jan Korbecki 1 , Karolina Bajdak-Rusinek 2 , Patrycja Kupnicka 1 , Patrycja Kapczuk 1, Donata Simi ´nska 1 , Dariusz Chlubek 1 and Irena Baranowska-Bosiacka 1,* 1 Department of Biochemistry and Medical Chemistry, Powsta´nców Wielkopolskich 72 Av., Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; [email protected] (J.K.); [email protected] (P.K.); [email protected] (P.K.); [email protected] (D.S.); [email protected] (D.C.) 2 Department of Medical Genetics, School of Medicine in Katowice, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-(91)-466-1515 Abstract: CXCL16 is a chemotactic cytokine belonging to the α-chemokine subfamily. It plays a significant role in the progression of cancer, as well as the course of atherosclerosis, renal fibrosis, and non-alcoholic fatty liver disease (NAFLD). Since there has been no review paper discussing the importance of this chemokine in various diseases, we have collected all available knowledge about CXCL16 in this review. In the first part of the paper, we discuss background information about CXCL16 and its receptor, CXCR6. Next, we focus on the importance of CXCL16 in a variety of diseases, with an emphasis on cancer. We discuss the role of CXCL16 in tumor cell proliferation, migration, invasion, and metastasis. Next, we describe the role of CXCL16 in the tumor microenviron- ment, including involvement in angiogenesis, and its significance in tumor-associated cells (cancer Citation: Korbecki, J.; associated fibroblasts (CAF), microglia, tumor-associated macrophages (TAM), tumor-associated Bajdak-Rusinek, K.; Kupnicka, P.; neutrophils (TAN), mesenchymal stem cells (MSC), myeloid suppressor cells (MDSC), and regulatory Kapczuk, P.; Simi´nska,D.; Chlubek, T cells (Treg)). Finally, we focus on the antitumor properties of CXCL16, which are mainly caused by D.; Baranowska-Bosiacka, I. The Role natural killer T (NKT) cells. At the end of the article, we summarize the importance of CXCL16 in of CXCL16 in the Pathogenesis of cancer therapy. Cancer and Other Diseases. Int. J. Mol. Sci. 2021, 22, 3490. https:// Keywords: CXCL16; CXCR6; cancer; tumor; NKT cells; SR-PSOX; ADAM10; tumor microenviron- doi.org/10.3390/ijms22073490 ment; inflammation Academic Editor: Sherine F. Elsawa Received: 2 February 2021 1. Introduction Accepted: 26 March 2021 Published: 28 March 2021 A tumor mass comprises not just cancer cells but also tumor growth supporting cells and tumor-suppressing immune cells [1]. All these cells forming the tumor microenviron- ment secrete various factors into the intercellular space. To date, many of these factors have Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in been characterized. The most significant of these are chemokines, a group of approximately published maps and institutional affil- 50 chemotactic cytokines [2]. Earlier studies have characterized chemokines as a signifi- iations. cant factor in immune system cell function [3,4]. However, over time, more studies have emerged showing the significance of a variety of chemokines in cancer development and growth [5]. One such chemokine is CXC motif chemokine ligand 16 (CXCL16), belonging to the sub-family of α-chemokines. To date, there has not been a review summarizing current knowledge on CXCL16 and its receptor CXC motif chemokine receptor 6 (CXCR6) Copyright: © 2021 by the authors. in a tumor. Therefore, the aim of this review is to collect and summarize all available Licensee MDPI, Basel, Switzerland. This article is an open access article knowledge about CXCL16 to make it more accessible to scientists studying the role of distributed under the terms and chemokines in cancer. conditions of the Creative Commons 2. CXC Motif Chemokine Ligand 16 (CXCL16): Background Information Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ CXCL16 is a chemokine distinct from other CXC chemokines. The CXCL16 gene 4.0/). is located on chromosome 17p13 [6], separate from other chemokine genes, and it has Int. J. Mol. Sci. 2021, 22, 3490. https://doi.org/10.3390/ijms22073490 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 27 2. CXC Motif Chemokine Ligand 16 (CXCL16): Background Information CXCL16 is a chemokine distinct from other CXC chemokines. The CXCL16 gene is located on chromosome 17p13 [6], separate from other chemokine genes, and it has poor homology with the other chemokines [7]. There are two CXCL16 transcripts, 1.8 kb and Int. J. Mol. Sci. 2021, 22, 3490 2.5 kb in length, formed by alternative splicing [8]. Both transcripts2 of 27 differ in the 3′-noncoding regions and the location of their expression. The 1.8 kb transcript is found mostly in the spleen, thymus, and testis. In contrast, the 2.5 kb transcript is found in the poorheart, homology kidney, with liver, the otherlung, chemokines peripheral [7 ].blood There leukocytes, are two CXCL16 pancreas, transcripts, and1.8 prostate kb [8]. Alter- andnative 2.5 kbRNA in length, splicing formed produces by alternative two splicingother transcripts [8]. Both transcripts having differ70 (CXCL16v1) in the and 121 0 3(CXCL16v2)-noncoding regions extra and nucleotides, the location as of theirdemonstrated expression. Thein dendritic 1.8 kb transcript cells is[9]. found In these additional mostlysequences, in the spleen,a STOP thymus, codon and is testis.present. In contrast,This results the 2.5 in kb a transcript shorter isprotein found in having only the the heart, kidney, liver, lung, peripheral blood leukocytes, pancreas, and prostate [8]. Alternativechemokine RNA domain. splicing The produces other two domains other transcripts typically having found 70 in (CXCL16v1) CXCL16 andare 121not present. (CXCL16v2)After extra translation, nucleotides, a hydrophobic as demonstrated signal in dendritic peptide cells is [9 ].cleaved In these at additional the N-terminus of the sequences,CXCL16 apolypeptide STOP codon is[7]. present. The human This results CXCL16 in a shorter protein protein is 254 having aa long only [6,7], the while the mu- chemokinerine CXCL16 domain. is The246 other aa long domains and typically is 44% found similar in CXCL16 to the are human not present. CXCL16 [8]. The newly After translation, a hydrophobic signal peptide is cleaved at the N-terminus of the CXCL16synthesized polypeptide CXCL16 [7]. The for human both CXCL16species protein is the is so-called 254 aa long membrane-bound [6,7], while the murine form of CXCL16 CXCL16(mCXCL16) is 246 aa [6]. long The and structure is 44% similar of tothis the humanprotein CXCL16 is very [8]. similar The newly to synthesizedtransmembrane CX3CL1 CXCL16[10] because for both it species consists is the of so-called a small membrane-bound (24-27aa long) form cytoplasmic of CXCL16 (mCXCL16) tail with [a6 ].YXPV motif [6]. TheThis structure motif can of this be protein phosphorylated is very similar on to tyrosi transmembranene to provide CX3CL1 an SH2-binding [10] because it site. mCXCL16 consists of a small (24–27 aa long) cytoplasmic tail with a YXPV motif [6]. This motif can also consists of a CXC chemokine domain and a transmembrane domain (Figure 1) [6]. be phosphorylated on tyrosine to provide an SH2-binding site. mCXCL16 also consists ofBoth a CXC of chemokinethese domains domain are and separated a transmembrane from domaineach other (Figure by1 )[a 6spacer]. Both ofregion, these approximately domains100 aa arelong, separated rich in from serine, each other threonine, by a spacer and region, proline. approximately It is a site 100 aaof long,heavy rich O-glycosylation inwhich serine, results threonine, in and the proline. formation It is a siteof ofa heavymucin-like O-glycosylation stalk [6,7], which essential results in for the chemokine do- formationmain presentation of a mucin-like and, stalk therefore, [6,7], essential significant for chemokine for mCXCL16 domain presentation properties and, [11,12]. mCXCL16 therefore, significant for mCXCL16 properties [11,12]. mCXCL16 has a molecular weight of 60has kDa. a molecular weight of 60 kDa. FigureFigure 1. mCXCL161. mCXCL16 structure. structure. CXC motifCXC chemokine motif chemokine ligand 16 (CXCL16)ligand 16 is (CXCL16) a membrane is proteina membrane protein consistingconsisting of aof chemokine a chemokine domain, domain, highly glycosylatedhighly glycosylated mucin-like mucin-like stalk, transmembrane stalk, transmembrane domain domain andand cytoplasmic cytoplasmic tail. tail. After CXCL16 cleavage, the 35 kDa chemokine domain is released and becomes a solubleAfter form ofCXCL16 CXCL16 cleavage, (sCXCL16). the This 35 process kDa chemokine is regulated bydomain disintegrin is released and met- and becomes a alloproteinasesoluble form 10 of (ADAM10) CXCL16 [13(sCXCL16).–15]. However, This disintegrin process is and regulated metalloproteinase by disintegrin 17 and metal- (ADAM17)loproteinase may also10 be(ADAM10) responsible for[13–15]. sCXCL16 Howeve sheddingr, in thedisintegrin absence of ADAM10and metalloproteinase [16] 17 or(ADAM17) by using phorbol may 12-myristate also be responsible 13-acetate (PMA) for sCXC as an inflammatoryL16 shedding inducer in the [13 ].absence Stud- of ADAM10 ies on mesangial cells have shown that pro-inflammatory cytokines increase sCXCL16 [16] or by using phorbol 12-myristate 13-acetate (PMA) as an inflammatory inducer [13]. shedding via ADAM10 and ADAM17 [17]. Although sCXCL16 is released from mCXCL16, theStudies remainder on of mesangial the mCXCL16 cells (mucin-like have stalk, shown transmembrane that pro-inflammatory domain, and cytoplasmic cytokines increase sCXCL16 shedding via ADAM10 and ADAM17 [17]. Although sCXCL16 is released from mCXCL16, the remainder of the mCXCL16 (mucin-like stalk, transmembrane domain, Int. J. Mol. Sci. 2021, 22, 3490 3 of 27 tail) is still present in the cell membrane. These domains are firstly proteolytically cleaved by γ-secretases and then proteolytically degraded [15]. Importantly, many papers do not distinguish between two forms of CXCL16.
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