CXCL17 (chemokine (C-X-C motif) ligand 17)

2014-05-01   Aya Matsui , Takashi Murakami 

Department of Anatomy, Developmental Biology, Graduate School of Medicine, Tokyo Womens Medical University, Tokyo, Japan (AM); Laboratory of Tumor Biology, Faculty of Pharmacy, Takasaki University of Health, Welfare, Gunma, Japan (TM)

Identity

HGNC
LOCATION
19q13.2
LOCUSID
ALIAS
DMC,Dcip1,UNQ473,VCC-1,VCC1
FUSION GENES

DNA/RNA

Note

The CXCL17 gene is located on the long arm of chromosome 19, and it spans about 15 kb and includes four exons.
Atlas Image
The CXCL17 gene (NM_198477.1). Full-length CXCL17 comprises about 15 kb and includes four exons and three introns. Squares: exon region; two-way arrow: intron region; green: coding region; yellow: untranslated region.

Description

Expression of the CXCL17 gene has been observed in several tissues. In human tissues, Northern blot analysis showed that CXCL17 is expressed in the trachea, stomach, lung, skeletal muscle, and the fetal lung (Pisabarro et al., 2006; Weinstein et al., 2006). No Northern blotting signal is detected from the brain, heart, colon, thymus, spleen, kidney, liver, small intestine, placenta, and peripheral blood lymphocytes (Weinstein et al., 2006). Furthermore, investigation of CXCL17 expression using a comprehensive human gene expression microarray database showed that expression is restricted to mucosal sites including the digestive system, lung airways, the urethra, and several sites of the female reproductive system (Burkhardt et al., 2012).
In mouse tissues, CXCL17 is expressed in the lung, thyroid, submaxillary gland, epididymis and uterus, with faint signals in the ovary and prostate (Weinstein et al., 2006).
In rat tissues, real-time PCR using 22 different rat tissues demonstrated that CXCL17 was expressed mainly in the stomach, duodenum, lung, and salivary gland (Lee et al., 2013).

Proteins

Expression

Extensive analyses of CXCL17-secreting or -producing cells have yet to be performed. Some reports have demonstrated CXCL17 expression by immunostaining. Immunohistochemistry of the normal lung in adult humans demonstrated that CXCL17 was constitutively expressed on the bronchial and bronchiolar epithelium. Additionally, CXCL17 expression was also observed in the normal small intestine (duodenum) and colon. Specifically, CXCL17 production was localized to the villus and some crypt epithelial cells of the small intestine and colonic epithelial cells (Pisabarro et al., 2006). In mucosal tissues of the gastrointestinal tract, distinct cells were found that exhibited CXCL17-positivity with unique cell surface markers and morphological characteristics, and these cells were identified as CD68+ macrophages and CD138+ plasma cells.

Function

Chemokines are generally classified into one of four groups on the basis of protein structure (cysteine residues), and can also be classified on the basis of functional differences (Zlotnik and Yoshie, 2012). Chemokine groups based on functional characteristics include inflammatory, homeostatic, dual-function, plasma or precursor, and platelet chemokines. However, the functional and physiological role of CXCL17 remains unclear and has yet to be categorized.
Interestingly, C-X-C chemokines are divided into two types on the basis of angiogenic potential: pro-angiogenic types with an ELR motif and angiostatic types with a non-ELR motif. The ELR motif consists of the tripeptide glutamate (E)-leucine (L)-arginine (R). Pro-angiogenic types with an ELR motif which attract neutrophils are referred to as ELR+ chemokines, while angiostatic types that preferentially attract lymphocytes are referred to as ELR- chemokines (Vandercappellen et al., 2008; Strieter et al., 2005). In the case of CXCL17, the presence of the ELR motif has yet to be confirmed. However, CXCL17 can be functionally classified as an ELR+ chemokine since CXCL17 shows pro-angiogenic function and neutrophil migration (Weinstein et al., 2006; Vandercappellen et al., 2008; Zlotnik and Yoshie, 2012).
Although the function and role of CXCL17 has been extensively investigated, its main receptor has yet to be identified.

Implicated in

Entity name
Breast cancer
Note
Immunohistochemical analyses of clinical specimens showed that approximately 60% of cells were CXCL17-positive in human breast cancer (Matsui et al., 2012). Five out of seven mammary tumors showed considerable CXCL17 up-regulation (from 3-fold to more than 24-fold), in comparison with normal mammary tissues (Weinstein et al., 2006).
RT-PCR analysis using 13 human breast cancer cell lines showed CXCL17 expression in 8 cell lines: MDA-MB-361, MCF7, BT-20, BT-474, HCC-1419, HCC-1500, HCC-1937 and HCC-1954 (Matsui et al., 2012).
Entity name
Hepatocellular carcinoma
Note
CXCL17 is expressed in hepatocellular carcinoma (HCC) in humans, but is not expressed in normal liver tissues. The average rate for CXCL17-positive HCC was 83% (124 out of 148 samples) in an immunohistochemical study using clinical HCC specimens (Zhou et al., 2012). CXCL17 expression in HCC was much higher than that in adjacent non-cancerous tissue, and increased levels of CXCL17 expression were also shown in colon, gastric, breast, lung, bladder, and uterine cervical cancers (Zhou et al., 2012).
In HCC cell lines, CXCL17-overexpressing HepG2 cells showed increased cell proliferation compared to non-expressing control cells (Zhou et al., 2012). The SMMC7721 HCC cell line also showed similar results when CXCL17 was overexpressed (Mu et al., 2009). Moreover, colony formation, invasion and adhesion were promoted following forced expression of CXCL17 (Mu et al., 2009). When these cells were xenogenically transplanted into immunodeficient nude mice, tumor growth was significantly promoted in comparison with the control expression group. Interestingly, whereas control HCC cells subjected to cisplatin treatment (100 μM) induced apoptotic morphological changes within 12 hours (e.g., cell budding, chromatin condensation, nuclear shrinkage, and cellular fragmentation), CXCL17-expressing HCC cells resisted cisplatin-induced apoptotic cell death (Zhou et al., 2012).
Entity name
Colorectal cancer
Note
In critical specimens, expression of CXCL17 was 50%-positive in human colorectal cancer (Matsui et al., 2012; Weinstein et al., 2006). In human colorectal cancer cell lines, four out of nine cell lines (HT-29, KM12, LoVo and COLO205) showed strong expression of CXCL17 mRNA (Matsui et al., 2012). In a mice model, xenotransplantation of CXCL17 overexpressing DLD-1 and SW620 cells into SCID mice resulted in enhanced tumor formation and an increase in the number of intratumoral vessels (Matsui et al., 2012). These tumors were associated with infiltrating CD11b+Gr-1high neutrophil-like myeloid-derived cells. The neutrophil-like myeloid-derived cells were recruited at tumor sites by CXCL17. Indeed, SW620 cells transplanted with CXCL17-responding CD11b+Gr-1high cells resulted in significantly enhanced tumor formation and angiogenesis compared to control cells. Furthermore, analyses of metastatic potential using in vivo luminescent imaging demonstrated that CXCL17-positive cells such as HT-29, KM12 and COLO205 were hematogenous distant metastases, whereas CXCL17-negative cells such as DLD-1, SW620 and HCT-15 did not show any distant metastases (Matsui et al., 2012).
Entity name
Endometrial carcinoma
Note
Gene expression profiling using type I endometrial carcinoma patients demonstrated that 621 out of 28869 genes were differentially expressed between tumor and normal tissues. Among these 621 genes, 146 were up-regulated and 476 were down-regulated in the tumor. One of the up-regulated genes was CXCL17, although additional biological analyses were not reported (Saghir et al., 2010).
Entity name
Pancreatic cancer
Note
In gene expression analyses using different stages of pancreatic cancers (intraductal papillary mucinous adenoma (IPMA) and intraductal papillary mucinous carcinoma (IPMC)), CXCL17 expression was higher in IPMA compared to IPMC and normal ductal tissues (Hiraoka et al., 2011). In other words, this report suggested that expression of CXCL17 was induced at the early stage of carcinogenesis, and then decreased as carcinogenesis progressed. However, it has also been reported that CXCL17 expression in human pancreatic cancer was much higher than in adjacent non-cancerous tissue (Zhou et al., 2012). In human pancreatic cancer cell lines, two out of five cell lines (KP-2 and BxPC-3) showed CXCL17 mRNA expression (Matsui et al., 2012).
Entity name
Fibrosarcoma
Note
When mouse fibrosarcoma cells stably transfected with murine CXCL17 cDNA were injected subcutaneously into mice, these animals showed tumor growth retardation compared to parental cell transplantation (Hiraoka et al., 2011). It was subsequently demonstrated that abundant CD3+, CD4+ and CD8+ T cells and CD11b+CD11c+ dendritic cells infiltrated CXCL17-expressing tumors, suggesting that immune reactions were evoked in this animal model.
Entity name
Lung cancer
Note
Immunohistochemistry showed that about 30% of non-small cell lung carcinoma was CXCL17-positive (Matsui et al., 2012). RT-PCR analysis also demonstrated that CXCL17 mRNA expression was observed in three out of eight human lung cancer cell lines (NCI-H441, NCI-H1975 and NCI-H2228) (Matsui et al., 2012).
Entity name
Other tumors
Note
In RT-PCR analyses of human cancer cell lines, CXCL17 expression was demonstrated in one out of six renal cancer cell lines (RTK-2) and in two out of seven gastric cancer cell lines (MKN-45 and KATO III) (Matsui et al., 2012). Human melanoma cell lines investigated were all CXCL17-negative (Matsui et al., 2012).
Entity name
Tumorigenicity
Note
Tumorigenicity was examined in NIH3T3 cells that expressed CXCL17 cDNA. CXCL17-overexpressing NIH3T3 cells were reported to form tumors in immunodeficient mice (Weinstein et al., 2006; Matsui et al., 2012). However, CXCL17 expression itself did not induce focus formation and anchorage-independent cell growth using NIH3T3 cells and so CXCL17 lacked oncogenic transformation activity in vitro (Matsui et al., 2012).
Entity name
Angiogenesis
Note
In a two-dimensional assay using the mouse angioma endothelial cell line PY4.1, vascular tube formation in PY4.1 increased CXCL17 expression levels 28-fold. Adenoviral overexpression of CXCL17 in human-derived vascular endothelial cells (HUVECs) resulted in up-regulation of vascular endothelial growth factor A (VEGF-A) (Weinstein et al., 2006). In another report, HUVECs exposed to recombinant CXCL17 resulted in increased VEGF-A expression and cell migration (Matsui et al., 2012). Investigations of the human acute monocytic leukemia cell line THP-1 showed that CXCL17-treated THP-1 cells resulted in increased levels of VEGF-A in the conditioned medium (Lee et al., 2013).
Entity name
Immunity
Note
CXCL17 has the ability to induce cell migration (chemotaxis) as is the case with chemokines. It has been demonstrated that some immune cells exhibit chemotactic cell migration through CXCL17. For example, in a transwell migration assay using human peripheral blood mononuclear cells (PBMCs), CXCL17 specifically induced migration of CD14+ monocytes and CD11c+ immature dendritic cells, but not of CD3+ T cells, CD19+ B cells, CD56+ natural killer cells or CD16+ neutrophils (Pisabarro et al., 2006; Hiraoka et al., 2011). While CD14+ human monocyte-derived mature dendritic cells possessed CXCL17-induced chemotactic activity, immature Langerhans cells failed to acquire CXCL17-dependent chemotactic activity (Hiraoka et al., 2011). Furthermore, chemotaxis assays and flow cytometric analyses using murine splenocytes showed that CD11b+Gr-1highF4/80- cells are specifically migrated in a manner dependent on CXCL17 (Matsui et al., 2012). CXCL17-responding cells showed neutrophil-like myeloid-derived cell morphology and cell surface markers.
Entity name
Inflammation
Note
Chemokines can control the migration and localization of various cells in the body. However, some chemokines exhibit additional activities beyond the trafficking of cells. To date, CXCL17 has also been found to possess antimicrobial and anti-inflammatory activity. The antimicrobial activity of CXCL17 was demonstrated using Escherichia coli, Staphylococcus aureus, Salmonella enterica serovar Typhimurium 14028s, Lactobacillus casei, and Pseudomonas aeruginosa (Burkhardt et al., 2012). This report demonstrated that CXCL17 possessed antimicrobial properties, unlike the case with CXCL8 (a representative chemokine that lacks antimicrobial activity). Moreover, the antimicrobial mechanism by which CXCL17 induces permeabilization of bacterial membranes was also demonstrated. On the other hand, the anti-inflammatory activity of CXCL17 was demonstrated when cells pretreated with CXCL17 showed decreased inflammatory responses (Lee et al., 2013). J774 murine macrophage-like cells immediately express pro-inflammatory genes such as IL-6, TNFα and iNOS when cells are stimulated with LPS. These cytokines mediate strong inflammatory responses. However, pretreatment with CXCL17 significantly reduces LPS-induced expression of pro-inflammatory genes, and LPS-mediated inflammatory responses are attenuated.
Entity name
Others
Note
In a microarray-based whole-genome screening system using duodenal mucosa during acute cholera, expression of CXCL17 was up-regulated in cholera patients (Flach et al., 2007). In these acute cholera patients, mucosal CD8+ cells in the small intestine were localized in the lamina propria region. In contrast, these cells migrated from the lamina propria region to the epithelium in the convalescent stage. Details concerning the relationship between CXCL17 expression and changes in the localization pattern of the mucosal CD8+ cells remain to be determined. CXCL17 was produced in bronchoalveolar lavage fluids in patients with human idiopathic pulmonary fibrosis (IPF) (Burkhardt et al., 2012), suggesting that CXCL17 production may be associated with human pulmonary diseases.

Bibliography

Pubmed IDLast YearTitleAuthors
226112392012CXCL17 is a mucosal chemokine elevated in idiopathic pulmonary fibrosis that exhibits broad antimicrobial activity.Burkhardt AM et al
173079462007Broad up-regulation of innate defense factors during acute cholera.Flach CF et al
209557082011CXCL17 and ICAM2 are associated with a potential anti-tumor immune response in early intraepithelial stages of human pancreatic carcinogenesis.Hiraoka N et al
231150812013CXCL17, an orphan chemokine, acts as a novel angiogenic and anti-inflammatory factor.Lee WY et al
229528812012CXCL17 expression by tumor cells recruits CD11b+Gr1 high F4/80- cells and promotes tumor progression.Matsui A et al
196575642009Overexpression of VCC-1 gene in human hepatocellular carcinoma cells promotes cell proliferation and invasion.Mu X et al
164559612006Cutting edge: novel human dendritic cell- and monocyte-attracting chemokine-like protein identified by fold recognition methods.Pisabarro MT et al
209732582010Gene expression profiling and cancer-related pathways in type I endometrial carcinoma.Saghir FS et al
160461802005CXC chemokines in angiogenesis.Strieter RM et al
185792872008The role of CXC chemokines and their receptors in cancer.Vandercappellen J et al
169897742006VCC-1, a novel chemokine, promotes tumor growth.Weinstein EJ et al
224259832012VCC-1 over-expression inhibits cisplatin-induced apoptosis in HepG2 cells.Zhou Z et al
226334582012The chemokine superfamily revisited.Zlotnik A et al

Other Information

Locus ID:

NCBI: 284340
MIM: 611387
HGNC: 19232
Ensembl: ENSG00000189377

Variants:

dbSNP: 284340
ClinVar: 284340
TCGA: ENSG00000189377
COSMIC: CXCL17

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000189377ENST00000341918X6R584
ENSG00000189377ENST00000601181Q6UXB2

Expression (GTEx)

0
50
100
150
200
250
300
350

References

Pubmed IDYearTitleCitations
209557082011CXCL17 and ICAM2 are associated with a potential anti-tumor immune response in early intraepithelial stages of human pancreatic carcinogenesis.49
254112032015Cutting edge: GPR35/CXCR8 is the receptor of the mucosal chemokine CXCL17.34
215865972011Site-directed mutagenesis of the CC chemokine binding protein 35K-Fc reveals residues essential for activity and mutations that increase the potency of CC chemokine blockade.11
289434342017The role and clinical significance of the CXCL17-CXCR8 (GPR35) axis in breast cancer.10
307552602019CXCL17-derived CD11b+Gr-1+ myeloid-derived suppressor cells contribute to lung metastasis of breast cancer through platelet-derived growth factor-BB.8
164559612006Cutting edge: novel human dendritic cell- and monocyte-attracting chemokine-like protein identified by fold recognition methods.0
169897742006VCC-1, a novel chemokine, promotes tumor growth.0
196575642009Overexpression of VCC-1 gene in human hepatocellular carcinoma cells promotes cell proliferation and invasion.0
224259832012VCC-1 over-expression inhibits cisplatin-induced apoptosis in HepG2 cells.0
226112392012CXCL17 is a mucosal chemokine elevated in idiopathic pulmonary fibrosis that exhibits broad antimicrobial activity.0

Citation

Aya Matsui ; Takashi Murakami

CXCL17 (chemokine (C-X-C motif) ligand 17)

Atlas Genet Cytogenet Oncol Haematol. 2014-05-01

Online version: http://atlasgeneticsoncology.org/gene/47679/cxcl17