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Cxcr7

Official Full Name
chemokine (C-X-C motif) receptor 7
Background
CXCR7, also known as RDC1, belongs to a subgroup of C-X-C chemokine receptors, which are part of a large protein family of G protein-coupled receptors (GPCR). CXCR7 binds with high-affinity to CXCL12/SDF-1 and CXCL11/I-TAC, which regulates the trafficking
Synonyms
CXCR7; chemokine (C-X-C motif) receptor 7; chemokine orphan receptor 1 , CMKOR1; C-X-C chemokine receptor type 7; GPR159; RDC1; G protein-coupled receptor; chemokine orphan receptor 1; G-protein coupled receptor 159; G-protein coupled receptor RDC1 homolo; G-protein coupled receptor RDC1 homolog; RDC-1; CMKOR1; CXC-R7; CXCR-7; RDC1-like G protein-coupled receptor

Recent Research Progress

CX Chemokine Receptor 7 (CXCR7) is involved in a variety of biological processes such as cell survival, adhesion and activity. Recently, CXCR7 has been identified as a novel receptor for matrix-derived factor-1 (SDF-1) and plays an important role in the development of cancer and related diseases.

CXCR7 and cancer

CXCR7 is an important component of the tumor microenvironment in a variety of human cancers. The chemokine receptor CXCR7 mediates cellular adhesion, migration, proliferation, and survival by binding its ligands SDF-1 and Interferon-inducible T cell α-chemoattractant (I-TAC). In recent years, accumulating evidences had demonstrated that expression of CXCR7 played a critical role in tumor cell proliferation, angiogenesis, invasion, and metastasis. According to the current literature, elevated expression of CXCR7 has been shown to contribute to Hepatocellular carcinoma (HCC) growth and invasion by activation of mitogen-activated protein kinase (MAPK) and angiogenic signaling pathways. It has been indicated that up-regulation of CXCR7 expression is associated with distant metastasis of Osteosarcoma (OS), whereas knockdown of CXCR7 blocks the development of OS cells by inhibiting PI3K/AKT and β-arrestin pathways. High expression of transforming growth factor-β1 (TGFβ1) and CXCR7 was found to be significantly associated with late lung adenocarcinoma. Inhibition of CXCR7 expression was found to significantly abolish breast cancer cell migration and invasion. CXCR7 has been shown to enhance ovarian cancer cell invasion via Mp-9 expression via the p38 MAPK pathway. In addition, it has been found that CXCR7 may play an important role in regulating tumor progression of Multiple myeloma (MM) by indirectly affecting the recruitment of AMCs to the MM tumor growth region in the medullary wall. These findings suggest that CXCR7 can be a potential therapeutic target for the treatment of cancer.

CXCR7 and other diseases

Li et al. showed that genetic defects in CXCR7 increased neointimal formation and impaired macrophage accumulation in hyperlipidemia mice after vascular injury. This is associated with elevated serum cholesterol levels and subsequent hyperlipidemia-induced mononucleosis. In contrast, administration of the CXCR7 ligand CCX771 to Apoe -/- mice inhibited lesion formation and ameliorated hyperlipidemia after vascular injury and during atherosclerosis. Treatment with CCX771 reduced circulating very low-density lipoprotein levels, but did not reduce low-density lipoprotein or high-density lipoprotein levels and increased the uptake of CXCR7-expressing white adipose tissue by very low-density lipoproteins. This effect of CCX771 was associated with enhanced lipase activity and decreased expression of Angptl4 in adipose tissue. In summary, CXCR7 regulates blood cholesterol by promoting its uptake in adipose tissue. This unexpected cholesterol lowering effect of CXCR7 is beneficial for atherosclerotic vascular disease, possibly by ameliorating hyperlipidemia-induced mononucleosis, and can be enhanced with synthetic CXCR7 ligands.

Diabetes is a common chronic metabolic disease that creates a huge social and economic burden. Recently, studies have shown that up-regulation of the SDF-1/CXCR7 axis signal improves endothelial progenitor cell (EPC) survival and function in diabetic conditions. This is mainly due to increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation, mediated by increased protein kinase B (Akt) and glycogen synthase kinase (GSK)-3β phosphorylation and inhibition of Fyn-mediated Nrf2 nuclear export and degradation in EPC. By maintaining Nrf2 nuclear localization, Nrf2 is enhanced and anti-oxidant gene expression is increased, protecting EPC from diabetes mellitus, ox-LDL and HG-induced oxidative damage as shown in Figure 1.

Figure 1. Schematic illustration of the protective effects of SDF-1/ CXCR7 on EPCs under diabetic conditions (Dai, et al. Circulation Research, 2017)

In summary, it has been widely reported that CXCR7 expression is induced in various types of cancer and increases with increasing malignancy compared to healthy tissues. Therefore, further study of the biological significance of CXCR7 will have significant clinical significance and value for the prevention and treatment of cancer.

References:

  1. Madhumita Chatterjee, et al. Macrophage Migration Inhibitory Factor Limits Activation-Induced Apoptosis of Platelets via CXCR7-Dependent Akt Signaling. Circulation Research, 2014, 115:939-949
  2. Li Xiaofeng, et al. Activation of CXCR7 Limits Atherosclerosis and Improves Hyperlipidemia by Increasing Cholesterol Uptake in Adipose Tissue. Circulation, 2014, 129:1244-1253
  3. L Lin, et al. CXCR7 stimulates MAPK signaling to regulate hepatocellular carcinoma progression. Cell Death and Disease, 2014, 5:e1488
  4. Abdel Kareem Azab, et al. CXCR7-dependent angiogenic mononuclear cell trafficking regulates tumor progression in multiple myeloma. Blood, 2014, 124(12):1905-1914
  5. Wu YC, et al. CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer. Oncogene, 2016, 35:2123–2132
  6. Na Chai, et al. FOXM1 promotes proliferation in human hepatocellular carcinoma cells by transcriptional activation of CCNB1. Biochemical and Biophysical Research Communications, 2018, 500:924e929
  7. Zhou ShaoMei, et al. miR-100 suppresses the proliferation and tumor growth of esophageal squamous cancer cells via targeting CXCR7. Oncology Reports, 2016, 35:3453-3459
  8. Li JunTang, et al. MiRNA-101 inhibits breast cancer growth and metastasis by targeting CX chemokine receptor 7. Oncotarget, 2015, 6(31): 30818-30830
  9. Wu YC, et al. CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer. Oncogene, 2016, 35:2123–2132
  10. Yu Yuecheng, et al. SDF-1/CXCR7 Axis Enhances Ovarian Cancer Cell Invasion by MMP-9 Expression Through p38 MAPK Pathway. DNA And Cell Biology, 2014, 33(8): 543–549
  11. Zhang Hengwei, et al. Gene expression profile analyze the molecular mechanism of CXCR7 regulating papillary thyroid carcinoma growth and metastasis. Journal of Experimental & Clinical Cancer Research, 2015, 34:16
  12. Dai Xiaozhen, et al. Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia. Circulation Research, 2017, 120:e7-e23
  13. Amanda C. Stacer, et al. Endothelial CXCR7 Regulates Breast Cancer Metastasis. Oncogene. 2016, 35(13):1716–1724
  14. Li XinXiang, et al. Silencing of CXCR7 gene represses growth and invasion and induces apoptosis in colorectal cancer through ERK and β-arrestin pathways. International Journal Of Oncology, 2014, 45:1649-1657

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