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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review CXCL5 (chemokine (C-X-C motif) ligand 5) Anna A Bulysheva, W Andrew Yeudall VCU Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA (AAB, WAY) Published in Atlas Database: May 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/CXCL5ID40223ch4q13.html DOI: 10.4267/2042/51814 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology acids. The N-terminal 36 amino acids are removed to generate the mature molecule 78 amino acids in length. An E-L-R (Glu-Leu-Arg) motif, important for receptor binding, is found immediately N-terminal to the C-X-C motif (Cys-Val-Cys). The E-L-R motif is found in pro-angiogenic chemokines (Belperio et al., 2000), while the presence of the C-X-C motif places this protein into the CXCchemokine family. CXCL5 has homology to CXCL8 (Walz et al., 1991). Identity Other names: ENA-78, SCYB5 HGNC (Hugo): CXCL5 Location: 4q13.3 Local order: On the reverse strand. DNA/RNA Description Expression The CXCL5 gene is located on human chromosome 4 at 4q13.3, starting at position 74861359 and ending at position 74864496 on the reverse strand. It consists of 4 exons. Ubiquitous in adult. Localisation Secreted. Transcription Function The transcript consists of 2538bp. The coding sequence begins at residue 119 and ends at residue 463. The mRNA is polyadenylated and is translated to produce a 114 residue polypeptide. Chemotaxis, neutrophil activation, angiogenesis. Human CXCL5 is a substrate for several proteases (Van den Steen et al., 2003; Dean et al., 2008; Starr et al., 2012). These include matrix metalloprotease MMP-1, MMP-9, MMP-12, and MMP-25 (MT6-MMP), which cleave the N-terminal region of the mature (78aa) polypeptide. Protein Description The full length polypeptide consists of 114 amino Solid blue boxes - coding regions; patterned boxes - non-coding regions; single lines - intervening (intronic) sequences; start / stop codons and direction of transcription are indicated. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 749 SGOL1 (shugoshin-like 1 (S. pombe)) Kahyo T, Sugimura H Schematic representation of human CXCL5. C-X-C motif is indicated in red, together with predicted intrachain disulphide bridges; E-LR motif is indicated in blue. MMP-12 has been reported to inactivate CXCL5, as it results in cleavage within the ELR motif, as well as between residues 5 and 6. MMP-25 is also thought to activate CXCL5 by removing the N-terminal 7 amino acids from the mature polypeptide, resulting in a 71 amino acid product (8-78). MMP-9 digests CXCL5 at multiple sites: early proteolysis involves the N-terminal region and is thought to potentiate CXCL5 activity, whereas later proteolysis (upon extended incubation with the protease) results in CXCL5 inactivation. CXCL5 relative to primary tumor cells, as measured by microarray and confirmed by quantitative real-time PCR and analysis of conditioned medium (Miyazaki et al., 2006). Biological consequences of CXCL5 overexpression have been investigated in terms of tumor cell proliferation and motility, both of which are reduced if CXCL5 expression is inhibited. In vivo growth of xenografted tumor cells was abrogated when CXCL5 expression was repressed by small hairpin RNA. Homology Gastric cancer IL-8. Conservation of this gene is observed in chimpanzee, dog and cow. Oncogenesis Overexpression of CXCL5 has been found to correlate with late stage gastric cancer and high N stage, suggesting a role for CXCL5 in progression of gastric cancer and nodal metastasis (Park et al., 2007). This was revealed by immunostaining of gastric tumors for CXCL5, as well as enzyme-linked immunosorbent assay (ELISA) measurement of serum CXCL5 levels. Implicated in Cancer, pulmonary fibrosis, inflammatory diseases and endometriosis Note CXCL5 is reportedly overexpressed in a number of human tumors such as head and neck squamous cell carcinoma, gastric, pancreatic, colorectal, prostate and lung cancer as well as in lung tissue of patients with pulmonary fibrosis. CXCL5 was found to be upregulated in many types of inflammatory conditions. It plays a significant role in inflammation that occurs in diseases such as acute coronary syndrome, allergy, rheumatoid arthritis, inflammatory bowel disease, pulmonary sarcoidosis, pancreatitis and endometriosis. Oncogenesis Abnormal expression of CXCL5 has been correlated with increased tumor cell motility and proliferation in vitro and increased tumorigenicity in vivo. It is also associated with worse clinical prognosis in several cancer types. Colorectal cancer Oncogenesis Low expression of CXCL5 in a rat model of colorectal cancer has been reported to increase the tumorigenic potential of cells that would otherwise form a less aggressive type of colon cancer (Speetjens et al., 2008). It has also been observed that human patients with low CXCL5 levels in their colorectal tumors had a poorer prognosis than those with higher expression of CXCL5. Pancreatic cancer Oncogenesis CXCL5 is secreted by pancreatic cancer cell lines, and antibody-mediated blockade of the CXCR2 receptor inhibits neovascularization in corneal angiogenesis assays (Wente et al., 2006). CXCL5 is also overexpressed in pancreatic cancer specimens, and is linked to poor patient survival (Frick et al., 2008). Blocking CXCR2 with an antibody, or inhibiting CXCL5 expression with siRNA, inhibits tumor xenograft formation. CXCL5 activates signaling through AKT-, ERK- and STAT-dependent pathways in pancreatic cancer cells (Li et al., 2011). Head and neck squamous cell carcinoma Oncogenesis It has been reported that metastatic head and neck cancer cells express comparatively high levels of Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 750 CXCL5 (chemokine (C-X-C motif) ligand 5) Bulysheva AA, Yeudall WA compared to patients with other forms of arthritis (Koch et al., 1994). Studies of rat adjuvant-induced arthritis (AIA), as a model for RA, showed elevated CXCL5 levels in serum with progressive development of arthritis compared to control animals. Joint homogenates also had increased levels of CXCL5 and this correlated with disease progression. Anti-CXCL5 antibody treatments prior to the onset of AIA decreased the severity of the disease (Halloran et al., 1999). The results indicate that CXCL5 plays an important role in the onset and progression of RA. Prostate cancer Oncogenesis Androgen-independent prostate cancers tend to overexpress CXCL5. It has been reported that CXCL5 overexpression leads to increased cell migration and epithelial-to-mesenchymal transition (Kuo et al., 2011). Non-small cell lung cancer Oncogenesis CXCL5 was found to play a role in development of non-small cell lung cancer by enhancing tumor angiogenesis (Arenberg et al., 1998). High expression of CXCL5 was correlated with vascularity of tumors. Passive immunity against CXCL5 resulted in a reduction of tumor growth, vascularity and metastases in vivo, although there was no effect of passive immunity on tumor cell proliferation. Inflammatory bowel disease Note Immunohistochemical studies of colonic epithelial cells in normal subjects and patients with inflammatory bowel disease showed that CXCL5 is expressed predominantly by crypt epithelial cells (Keates et al., 1997). CXCL5 production is significantly higher in patients with ulcerative colitis, with less intense expression in Crohn's disease patients. Pulmonary fibrosis Note Analysis of bronchoalveolar lavage (BAL) fluid and lung tissue from patients with idiopathic pulmonary fibrosis revealed elevated levels of the angiogenic chemokines CXCL5 and CXCL8, together with a relative decrease of angiostatic factors, correlating with increased fibrosis of lung tissue (Streiter et al., 2007). Pulmonary sarcoidosis Note Increased levels of CXCL5 were found in the serum and BAL fluid of patients with pulmonary sarcoidosis compared to normal subjects, as judged by ELISA. BAL levels of CXCL5 were elevated in stage III sarcoidosis (Sujiyama et al., 2006). Acute coronary syndrome (ACS) Note Examination of CXCL5 in inflammation associated with acute coronary syndrome indicated that a polymorphism in CXCL5 (156G>C; rs352046) was linked to a 2.7-fold rise in 3-year mortality (all causes; C/C genotype only). Mortality was reduced in G/G genotype individuals by the use of statins. Treatment of human umbilical vein endothelial cells (HUVECs) with atorvastatin in vitro reduced the levels of IL-1βinduced CXCL5 in a dose-dependent manner (Zineh et al., 2008). Pancreatitis Note Patients with severe acute pancreatitis had significantly higher serum levels of CXCL5 compared to individuals with mild acute pancreatitis (Shokuhi et al., 2002). Samples from patients with chronic pancreatitis also showed higher expression of CXCL5 than normal pancreatic tissues, predominantly in centroacinar ducts of pancreatic lobuli (Saurer et al., 2000). These findings suggest a role for CXCL5 in development and maintenance of both acute and chronic pancreatitis. Allergy Note Activated mast cells have been shown to increase CXCL5 production significantly compared to the level of CXCL5 in resting cells. Supernatants from sonicated MC-9 mast cells elicited a significant influx of neutrophils when injected intratracheally in mice. When the same supernatants were preincubated with CXCL5-specific antibodies, neutrophil influx was dramatically reduced, implicating CXCL5 produced by activated mast cells as a critical chemoattractant for neutrophils (Lukacs et al., 1998). Endometriosis Note CXCL5 has also been implicated in the pathogenesis of endometriosis, with elevated levels of CXCL5 found in peritoneal fluid of patients with endometriosis compared to control subjects (Mueller et al., 2003). Further studies showed that glandular cells, stromal fibroblasts and peritoneal macrophages were primarily responsible for CXCL5 production in patients with endometriosis. Elevated levels of CXCL5 have also been found in the follicular fluid of patients with endometriosis compared to controls (Wunder et al., 2006). Together, these studies implicate CXCL5 in the pathogenesis of endometriosis. Rheumatoid arthritis (RA) Note CXCL5 is reported to be significantly elevated in synovial fluid of patients with rheumatoid arthritis Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 751 SGOL1 (shugoshin-like 1 (S. pombe)) Kahyo T, Sugimura H References and epithelial neutrophil-activating peptide-78 in patients with pulmonary sarcoidosis. Respirology. 2006 Nov;11(6):708-14 Walz A, Burgener R, Car B, Baggiolini M, Kunkel SL, Strieter RM. Structure and neutrophil-activating properties of a novel inflammatory peptide (ENA-78) with homology to interleukin 8. J Exp Med. 1991 Dec 1;174(6):1355-62 Wente MN, Keane MP, Burdick MD, Friess H, Büchler MW, Ceyhan GO, Reber HA, Strieter RM, Hines OJ. Blockade of the chemokine receptor CXCR2 inhibits pancreatic cancer cellinduced angiogenesis. Cancer Lett. 2006 Sep 28;241(2):221-7 Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, Pope RM, Walz A, Strieter RM. Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis. J Clin Invest. 1994 Sep;94(3):1012-8 Wunder DM, Mueller MD, Birkhäuser MH, Bersinger NA. Increased ENA-78 in the follicular fluid of patients with endometriosis. Acta Obstet Gynecol Scand. 2006;85(3):336-42 Park JY, Park KH, Bang S, Kim MH, Lee JE, Gang J, Koh SS, Song SY. CXCL5 overexpression is associated with late stage gastric cancer. J Cancer Res Clin Oncol. 2007 Nov;133(11):835-40 Keates S, Keates AC, Mizoguchi E, Bhan A, Kelly CP. Enterocytes are the primary source of the chemokine ENA-78 in normal colon and ulcerative colitis. Am J Physiol. 1997 Jul;273(1 Pt 1):G75-82 Strieter RM, Gomperts BN, Keane MP. The role of CXC chemokines in pulmonary fibrosis. J Clin Invest. 2007 Mar;117(3):549-56 Arenberg DA, Keane MP, DiGiovine B, Kunkel SL, Morris SB, Xue YY, Burdick MD, Glass MC, Iannettoni MD, Strieter RM. Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J Clin Invest. 1998 Aug 1;102(3):465-72 Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, 8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood. 2008 Oct 15;112(8):3455-64 Lukacs NW, Hogaboam CM, Kunkel SL, Chensue SW, Burdick MD, Evanoff HL, Strieter RM. Mast cells produce ENA-78, which can function as a potent neutrophil chemoattractant during allergic airway inflammation. J Leukoc Biol. 1998 Jun;63(6):746-51 Frick VO, Rubie C, Wagner M, Graeber S, Grimm H, Kopp B, Rau BM, Schilling MK. Enhanced ENA-78 and IL-8 expression in patients with malignant pancreatic diseases. 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Fertil Steril. 2003 Mar;79 Suppl 1:815-20 Li A, King J, Moro A, Sugi MD, Dawson DW, Kaplan J, Li G, Lu X, Strieter RM, Burdick M, Go VL, Reber HA, Eibl G, Hines OJ. Overexpression of CXCL5 is associated with poor survival in patients with pancreatic cancer. Am J Pathol. 2011 Mar;178(3):1340-9 Van Den Steen PE, Wuyts A, Husson SJ, Proost P, Van Damme J, Opdenakker G. Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and modulate their physiological activities. Eur J Biochem. 2003 Sep;270(18):3739-49 Starr AE, Bellac CL, Dufour A, Goebeler V, Overall CM. Biochemical characterization and N-terminomics analysis of leukolysin, the membrane-type 6 matrix metalloprotease (MMP25): chemokine and vimentin cleavages enhance cell migration and macrophage phagocytic activities. J Biol Chem. 2012 Apr 13;287(16):13382-95 Miyazaki H, Patel V, Wang H, Edmunds RK, Gutkind JS, Yeudall WA. Down-regulation of CXCL5 inhibits squamous carcinogenesis. Cancer Res. 2006 Apr 15;66(8):4279-84 This article should be referenced as such: Sugiyama K, Mukae H, Ishii H, Kakugawa T, Ishimoto H, Nakayama S, Shirai R, Fujii T, Mizuta Y, Kohno S. Elevated levels of interferon gamma-inducible protein-10 Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) Bulysheva AA, Yeudall WA. CXCL5 (chemokine (C-X-C motif) ligand 5). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11):749-752. 752