CXCR4

Official Full Name

C-X-C motif chemokine receptor 4

Organism

Homo sapiens

GeneID

7852

Background

This gene encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. The protein has 7 transmembrane regions and is located on the cell surface. It acts with the CD4 protein to support HIV entry into cells and is also highly expressed in breast cancer cells. Mutations in this gene have been associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

Synonyms

FB22; HM89; LAP3; LCR1; NPYR; WHIM; CD184; LAP-3; LESTR; NPY3R; NPYRL; WHIMS; HSY3RR; NPYY3R; WHIMS1; D2S201E;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSIIFLTGIVGNGLVILVMGYQKKLRSMTDKYRLHLSVADLLFVITLPFWAVDAVANWYFGNFLCKAVHVIYTVNLYSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKVVYVGVWIPALLLTIPDFIFANVSEADDRYICDRFYPNDLWVVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKTTVILILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPILYAFLGAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS

Open

Disease

Acute myeloid leukaemia, Breast cancer, Chronic arterial occlusive disease, Diabetes mellitus, Human immunodeficiency virus disease, Innate/adaptive immunodeficiency, Kaposi sarcoma, Malignant haematopoietic neoplasm, Mature B-cell leukaemia, Mature B-cell lymphoma, Melanoma, Metastatic tumour, Multiple myeloma, Myelodysplastic syndrome, Neuroendocrine carcinoma, Neutropenia, Pancreatic cancer, Psoriasis, Renal cell carcinoma, Respiratory infection, Retinopathy, Sarcoma, Solid tumour/cancer, Transplanted organ/tissue

Approved Drug

2 +

Clinical Trial Drug

15 +

Discontinued Drug

3 +

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Detailed Information

Recent Research Progress

CXC Receptor 4 (CXCR4) is a G-protein-coupled receptor (GPCR) that is only activated by the chemokine CXCL12, also known as matrix-derived factor-1 or SDF-1. CXCR4 has been shown to be closely associated with many types of cancer, and the SDF-1/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and prognosis.

CXCR4 and glioblastoma

Glioblastoma is the most common malignant primary brain tumor in adults and invariably carries a poor prognosis. Epithelial-mesenchymal transition (EMT) has been reported to be identified as a key regulator of certain cancers. Recent studies have shown that the EMT process can be triggered by the SDF-1/CXCR4 axis in glioblastoma, and then participate in tumor cell invasion and proliferation by activating the PI3K/AKT and ERK pathways. These studies have laid a new foundation for the treatment of glioblastoma by antagonizing CXCR4.

CXCR4 and DLBCL

Diffuse large B-cell lymphoma (DLBCL) is a clinical and hereditary heterogeneous disease. CXCR4 is involved in the migration and trafficking of malignant B cells in several hematological malignancies. Recently, studies have found that the expression level of CXCR4 in DLBCL cell lines was positively correlated with migration in vitro. Expression of the receptor was also associated with increased engraftment and dissemination, and decreased survival time in NOD/SCID mice. In addition, administration of the specific CXCR4 antagonist, AMD3100, reduced the spread of DLBCL cells in a xenograft mouse model. Furthermore, CXCR4 expression has been reported to be an independent prognostic factor for shorter overall survival and progression-free survival in DLBCL patients. These results indicate that CXCR4 mediates the spread of DLBCL cells and serves as an independent prognostic marker for patients with DLBCL.

CXCR4 and ovarian cancer

Ovarian cancer is the most deadly gynecological malignancy. Understanding the molecular pathogenesis of ovarian cancer is critical to providing new targeted therapeutic strategies. Recently, studies have indicated that Notch activity affected tumor cell growth and survival, and actively regulated the expression of CXCR4 and SDF1. CXCR4/SDF1 signaling mediated the effect of the Notch pathway on ovarian cancer cell growth and SDF1-driven migration. Furthermore, Notch signaling activation can be detected in ovarian cancer specimens by immunohistochemistry analysis of the Notch transcriptional target, HES6 and is positively correlated with high expression levels of CXCR4 and SDF1. Taken together, the results suggest that Notch affects ovarian cancer cell biology via modulating CXCR4/SDF1 signaling and that Notch inhibition may be a fundamental therapeutic approach to block progression of ovarian cancer mediated by CXCR4/SDF1 axis.

CXCR4 and GC

Gastric cancer (GC) is one of the most fatal malignancies with the highest morbidity and mortality in Asian countries. Runt-associated transcription factor 2 (RUNX2) is a regulator of embryogenesis and development, but is also involved in the progression of certain human cancers. Studies have shown that RUNX2 was an independent prognostic indicator for patients with GC. RUNX2 significantly enhanced the in vitro migration and invasion of GC cells and enhanced the invasion and metastasis potential of GC cells in the in situ GC model of nude mice. Mechanically, RUNX2 directly binds to the promoter region of the gene encoding the chemokine receptor CXCR4 to enhance its transcription. CXCR4 knockdown or treatment with the CXCR4 inhibitor, AMD3100, attenuated RUNX2-promoted invasion and metastasis. These results indicate that RUNX2 promotes invasion and metastasis of human GC by transcriptionally up-regulating the chemokine receptor CXCR4. Therefore, the RUNX2-CXCR4 axis is a potential therapeutic target for GC.

In addition, CXCR4 overexpression was found in various tumor tissues such as breast cancer and osteosarcoma. In conclusion, the CXCR4 axis is involved in the aggressiveness of central nervous system cancer and the migration and metastasis of other tumor cells, and has significant prognostic value. Therefore, further study of the important role of CXCR4 in the mechanism of tumorigenesis is of great significance and value for the diagnosis and treatment of cancer.

References:

Yu Shi, et al. miR-663 Suppresses Oncogenic Function of CXCR4 in Glioblastoma. Clinical Cancer Research, 2015, 21(17); 4004–13
Peter J, et al. CXCR4 and Glioblastoma. Anti-Cancer Agents in Medicinal Chemistry, 2016, 16: 59-74
Lv Baoyu, et al. CXCR4 Signaling Induced Epithelial-Mesenchymal Transition by PI3K/AKT and ERK Pathways in Glioblastoma. Mol Neurobiol, 2015, 52: 1263–1268
Moreno, et al. CXCR4 expression enhances diffuse large B cell lymphoma dissemination and decreases patient survival. Journal of Pathology, 2015, 235: 445–455
R Chiaramontea,et al. Notch pathway promotes ovarian cancer growth and migration via CXCR4/SDF1 chemokine system. The International Journal of Biochemistry & Cell Biology, 2015, 66: 134–140
Guo ZhengJun, et al. Transcription factor RUNX2 up-regulates chemokine receptor CXCR4 to promote invasive and metastatic potentials of human gastric cancer. 2016, Oncotarget, 7: 15
Mego, et al. CXCR4-SDF-1 interaction potentially mediates trafficking of circulating tumor cells in primary breast cancer. BMC Cancer, 2016, 16:127
Guan Guofeng, et al. The HIF-1α/CXCR4 pathway supports hypoxia-induced metastasis of human osteosarcoma cells. Cancer Letters, 2015, 357: 254–264

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