Download Gene Section CXCL5 (chemokine (C-X-C motif) ligand 5) in Oncology and Haematology

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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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.
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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)
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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
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