CXCR6

Official Full Name

C-X-C motif chemokine receptor 6

Organism

Homo sapiens

GeneID

10663

Background

The protein encoded by this gene is a G protein-coupled receptor with seven transmembrane domains that belongs to the CXC chemokine receptor family. This family also includes CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, and CXCR7. This gene, which maps to the chemokine receptor gene cluster, is expressed in several T lymphocyte subsets and bone marrow stromal cells. The encoded protein and its exclusive ligand, chemokine ligand 16 (CCL16), are part of a signalling pathway that regulates T lymphocyte migration to various peripheral tissues (the liver, spleen red pulp, intestine, lungs, and skin) and promotes cell-cell interaction with dendritic cells and fibroblastic reticular cells. CXCR6/CCL16 also controls the localization of resident memory T lymphocytes to different compartments of the lung and maintains airway resident memory T lymphocytes, which are an important first line of defense against respiratory pathogens. The encoded protein serves as an entry coreceptor used by HIV-1 and SIV to enter target cells, in conjunction with CD4. [provided by RefSeq, Aug 2020]

Synonyms

BONZO; CD186; CDw186; STRL33; TYMSTR;

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Detailed Information

Recent Research Progress

Chemokines and their receptors (CXCRs) have been proven to be closely involved in tumor progression and metastasis, of which CXCR6 is overexpressed in breast cancer (BC), gastric cancer (GC), osteosarcoma (OS), and in non-small cell lung cancer (NSCLC). CXCR6 promotes tumor development by stimulating tumor growth, recruits T cells and promotes epithelial-mesenchymal transition (EMT), and mediates inflammation-related migration and proliferation of various tumor cells.

CXCR6 and BC

BC is the leading cause of cancer in women worldwide. The study found that CXCR6 expression showed higher epithelial staining in BC nests and metastatic lymph nodes compared to normal breast tissue, suggesting that CXCR6 may be involved in the development of BC. In vitro and in vivo experiments have indicated that overexpression of CXCR6 in BC cells has a significant effect on increasing cell migration, invasion and metastasis. In contrast, reduction of CXCR6 expression by short hairpin RNAs (shRNAs) in these cells greatly reduced its invasion and metastasis ability. Mechanistic analysis showed that CXCL16/CXCR6 chemokine axis can regulate the activation of RhoA by activating extracellular signal-egulated kinase1/2 (ERK1/2) signaling pathway, thereby inhibiting the activity of cofilin, thereby enhancing the stability of F-actin, responsible for the invasion and metastasis of BC (Figure 1). In summary, the current data shows that the CXCR6/ERK1/2/RhoA/cofilin/F-actin pathway plays an important role in the development of BC.

Figure 1. Schematic diagram showing a novel regulatory mechanism for CXCL16/CXCR6 chemokine axis -induced BC progression. (Xiao G, et al. Oncotarget, 2015)

CXCR6 and GC

GC is the second leading cause of cancer-related deaths worldwide. Although several strategies have been adopted to treat GC for decades, it is still the fourth most common type of cancer in the world. It has been found that the expression level of CXCR6 was increased in GC compared with adjacent non-tumor tissues, and it was was closely associated with the metastatic lymph node in GC. Moreover, blockade of the CXCR6 signaling reduced migration and invasion of GC cells, followed by decreased expression of protein kinase B (AKT), matrix metalloprotein 2 (MMP-2) and MMP-9. Taken together, these findings indicate that CXCR6 promotes the development of GC cells by modulating AKT signaling.

CXCR6 and OS

OS is considered to be one of the most malignant tumors of the skeletal system in children and adolescents. The level of CXCR6 mRNA in OS tissues was significantly higher than that in normal bone tissues. Consistently, the mRNA and protein levels of CXCR6 in the OS cell lines MG-63, HOS and U2OS were higher than those in the normal bone cell hFOB 1.19. CXCR6 overexpression not only promoted cell proliferation, invasion and EMT, but also enhanced Akt phosphorylation in MG-63 cells. After inhibition of AKT -phosphorylation by AKT inhibitors, LY2940023, CXCR6 induced cell proliferation and invasion were significantly attenuated. In conclusion, studies have shown that CXCR6 enhances OS cell proliferation and invasion through the AKT pathway.

CXCR6 and non-small cell lung carcinoma

Regardless of gender, lung cancer (LuCa) is the leading cause of cancer-related deaths worldwide. Recent studies have found that CXCR6 expression was significantly higher in both subtypes of NSCLC (adenocarcinoma-AC and squamous cell carcinoma-SCC) as compared to non-neoplastic tissue. In addition, serum CXCL16 was significantly elevated in LuCa cases compared to healthy controls. Similar to CXCR6 tissue expression, serum CXCL16 levels were significantly higher in AC patients than in SCC patients. The biological significance of the axis was verified using SCC and AC cell lines. The expression of CXCR6 was higher in AC cells, and its migration and invasion potential was also higher than that of SCC. The difference in migration and invasion potential between AC and SCC was due to differential expression of metalloproteinases after CXCL16 stimulation. Hence, the results suggest that the clinical and biological significance of the CXCR6/CXCL16 axis in LuCa, which could be used as potential prognostic marker and therapeutic target.

In summary, there is increasing evidence that CXCL16 and its receptor CXCR6 are up-regulated in many types of cancer and can make more aggressive behavior by regulating proliferation and angiogenesis. Therefore, further exploration of the mechanism of the CXCL16/CXCR6 chemokine axis may help prevent metastasis and provide a more effective therapeutic strategy for cancer.

References:

Xiao G, et al. CXCL16/CXCR6 chemokine signaling mediates breast cancer progression by pERK1/2-dependent mechanisms. Oncotarget, 2015, 6(16): 14165-14178
Jin JJ, et al. CXCR6 predicts poor prognosis in gastric cancer and promotes tumor metastasis through epithelial-mesenchymal transition. Oncology Reports, 2017, 37: 3279-3286
Li Y, et al. Blockade of CXCR6 reduces invasive potential of gastric cancer cells through inhibition of AKT signaling. Immunopathology and Pharmacology, 2015, 28(2): 194–200
Ma YS, et al. CXCR6 promotes tumor cell proliferation and metastasis in osteosarcoma through the Akt pathway. Cellular Immunology, 2017, 311: 80–85
Mir H, et al. CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases. Oncotarget, 2015, 6(12): 9985-9998
Ke CW, et al. Association between CXCL16/CXCR6 expression and the clinicopathological features of patients with non-small cell lung cancer. Oncology Letters, 2017, 13: 4661-4668

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