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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review CCR1 (chemokine (C-C motif) receptor 1) Qiang Gao, Jia Fan Liver Cancer Institute, Zhong Shan Hospital and Shanghai Medical School, Fudan University, Shanghai, P R China (QG, JF) Published in Atlas Database: April 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/CCR1ID44379ch3p21.html DOI: 10.4267/2042/44930 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology Description Identity Sequence length: 6633 bp; coding sequence: CDS 721139. 2 exons; number of SNPs: 97. Other names: CD191, CKR-1, CKR1, CMKBR1, HM145, MIP1aR, SCYAR1 HGNC (Hugo): CCR1 Location: 3p21.31 Transcription 2690 bp mRNA, no alternative splicing. Pseudogene DNA/RNA No pseudogenes have been reported for CCR1. Note CCR1, a member of the beta chemokine receptor family, is a seven transmembrane protein similar to G protein-coupled receptors. CCR1 is the first human CC chemokine receptor to be identified at the cDNA level. It has a functional viral homolog, US28, which is a human cytomegalovirus.The ligands of this receptor include macrophage inflammatory protein 1 alpha (MIP-1 alpha), regulated on activation normal T expressed and secreted protein (RANTES), monocyte chemoattractant protein 3 (MCP-3), and myeloid progenitor inhibitory factor-1 (MPIF-1). This gene and other chemokine receptor genes, including CCR2, CCRL2, CCR3, CCR5 and CCXCR1, form a gene cluster on chromosome 3p. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1) Protein Note Chemokine receptors are cytokine receptors found on the surface of certain cells, which interact with a type of cytokine called a chemokine. They each have a 7 transmembrane structure and couple to G-protein for signal transduction within a cell, making them members of a large protein family of G protein-coupled receptors. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium (Ca2+) ions (calcium signaling). This causes cell responses, including the onset of a process known as chemotaxis that traffics the cell to a desired location within the organism. 1 CCR1 (chemokine (C-C motif) receptor 1) Gao Q, Fan J Predicted structure and amino acid sequence of CCR1. The typical serpentine structure is depicted with three extracellular (top) and three intracellular (bottom) loops and seven transmembrane domains. The shaded horizontal band represents the cell membrane. Amino acids are listed with a single letter code. Chemokine receptors share many common structural features; they are composed of about 350 amino acids that are divided into a short and acidic N-terminal end, seven helical transmembrane domains with three intracellular and three extracellular hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues that act as phosphorylation sites during receptor regulation. The first two extracellular loops of chemokine receptors are linked together by disulfide bonding between two conserved cysteine residues. The N-terminal end of a chemokine receptor binds to chemokine(s) and is important for ligand specificity. G-proteins couple to the C-terminal end, which is important for receptor signaling following ligand binding. lymphocytes; blood derived mast cells, dendritic cells, basophils and eosinophils; bone marrow stromal cells; microvascular endothelial cells; vascular smooth muscle cells. Localisation Cell membrane; multi-pass membrane protein. Function Receptor for a C-C type chemokine. Binds to CCL3 (MIP-1-alpha), CCL5 (RANTES), CCL7 (MCP-3), CCL9 (MIP-1-gamma), CCL14 (HCC-1), CCL15 (MIP-1-delta), CCL16 (HCC-4) and CCL23 (MIP-3), and, less efficiently, to MIP-1-beta or MCP-1 and subsequently transduces a signal by increasing the intracellular calcium ions level. The major function of CCR1 is to regulate leukocyte trafficking in hematopoiesis and in innate and adaptive immunity. Other functions include angiogenic activity, ischemia/reperfusion injury, immune-cell differentiation, phagocyte activation, and affecting stem cell proliferation. Description 355 amino acids; 41173 Da. Expression Monocyte/macrophages; T cells; platelets; tonsil B Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1) 2 CCR1 (chemokine (C-C motif) receptor 1) Gao Q, Fan J ligands, RANTES and MIP-1alpha, respectively, were demonstrated in MM cell lines and primary MM cells. Osteoclasts (OCL) secrete high levels of CCL3 and MM cells the express CCR1, the interaction between which plays a key role in the pathogenesis of MMrelated osteolytic bone disease. Through CCL3-CCR1 axis OCL cells promote OCL formation and, in turn, OCL enhance MM cell proliferation. In murine models of MM, MIP-1alpha, an OCL stimulatory factor produced by primary MM cells, increases bone destruction and tumor burden, by interacting with chemokine receptors CCR1 and CCR5 that widely expressed in human OCL precursors, myeloma cell lines, and purified marrow plasma cells from MM patients. Neutralizing antibodies to CCR1 or CCR5 inhibited MIP-1alpha-induced OCL formation. Furthermore, MCP-3, which binds CCR1 but not CCR5, and the CCR1-specific antagonist, BX471, markedly inhibited OCL formation stimulated with MIP-1alpha. Anti-CCR1, anti-CCR5, or BX471 also inhibited the upregulation of beta1 integrin myeloma cells induced by MIP-1alpha, as well as the adherence of myeloma cells to stromal cells and IL-6 production by stromal cells in response to myeloma cells. The oncogene c-maf is translocated in approximately 5%-10% of MM. By gene expression profiling, three cmaf target genes, cyclin D2, integrin beta7 and CCR1, were identified. Homology CCR1 protein contains considerable amino acid sequence homology to other C-C chemokines: CCR2B (56%), CCR3 (54%), CCR4 (49%), CCR5 (55%). Implicated in Hematolymphoid neoplasia Prognosis CCR1 expression correlates with overall survival in the non-germinal center subtype of diffuse large B-cell lymphoma. In follicular lymphoma, high levels of CCR1 are associated with a shorter survival interval, and CCR1 is a marker of an immune switch between macrophages and a T cell-dominant response. Oncogenesis CCR1 is expressed in intraepithelial B cells of human tonsil and granulocytic/monocytic cells in the bone marrow. Immunohistochemical analysis of 944 cases of hematolymphoid neoplasia identified CCR1 expression in a subset of B- and T-cell lymphomas, plasma cell myeloma, acute myeloid leukemia, and classical Hodgkin lymphoma. In 13 patients with chronic lymphocytic leukemia (CLL), 9 with hairy cell leukemia (HCL), 5 with mantle cell lymphoma (MCL), 5 with marginal zone B-cell lymphoma (MZL), 6 with small lymphocytic lymphoma (SLL), and 5 with follicular cell lymphoma (FCL), flow cytometry analysis demonstrated that CCR1 was expressed in 70% of patients with CLL and 40% of those with HCL but was lacking in patients with MCL, MZL, SLL, and circulating normal B cells. Circulating CD3+ T cells derived from healthy individuals and acute myelogenous leukemia patients with therapy-induced cytopenia after conventional chemotherapy or allogeneic stem cell transplantation showed no qualitative differences in CCR1 expression, that is, low expression for all the three groups. Hepatocellular carcinoma Oncogenesis Hepatic myofibroblast LI90 cells express and secrete MCP-1/CCL2. Through its receptors CCR1 and CCR2 as well, LI90 induces human hepatocellular carcinoma (HCC) Huh7 cell migration and invasion, which are strongly inhibited by heparin, beta-D-xyloside and antisyndecan-1 and -4 antibodies. RANTES/CCL5 strongly stimulates the migration and the invasion of Huh7 cells by stimulating the tyrosine phosphorylation of focal adhesion kinase as well as activating matrix metalloproteinase-9, and to a lesser extent that of Hep3B cells. The RANTES-induced migration and invasion of Huh7 cells are also strongly inhibited by anti-CCR1 antibodies and heparin, as well as by beta-dxyloside treatment of the cells, suggesting that CCR1 and glycosaminoglycans are involved in these events. We found that the miRNA-mediated knockdown expression of CCR1 significantly inhibited the invasive ability of and reduced the secretion of MMP-2 in hepatocellular carcinoma HCCLM3 cells, but only had a minor effect on the cellular proliferation. CCR1 expression was also detected on primary HCC cells and to a lesser degree, on endothelial cells in HCC tissues but not in normal liver tissues. Similarly, CCL3 expression was detected in HCC cells, endothelial cells, and to a lesser degree, fibroblast-like cells in HCC tissue, whereas only occasional vascular endothelial cells and inflammatory cells in normal liver tissues were weakly positive for CCL3. IL-1 enhances the Multiple myeloma Prognosis In 80 multiple myeloma (MM) patients with bone marrow samples, patients with active disease showed a significantly lower expression of CCR1, CCR2, as well as CXCR4 than patients with non-active disease. This chemokine receptor expression profile correlated with serum beta2-microglobulin, C-reactive protein and hemoglobin. Multivariate analysis identified the chemokine receptor expression profile as an independent prognostic factor. Oncogenesis Human MM cells express at least three different chemokine receptors that are functionally involved in MM cell migration, i.e. CCR1, CCR2 and CXCR4, some also CCR6 and CXCR3. cDNA arrays identified CCR1 and CCR2 are overexpressed in myeloma cells compared to autologous B-lymphoblastoid cell lines. The expression of CCR1 and the migration to their Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1) 3 CCR1 (chemokine (C-C motif) receptor 1) Gao Q, Fan J local production of CCL3, which interact with CCR1 expressed on HCC cells, in an autocrine and/or paracrine manner. In a murine HCC model, injected tumor cells were transfected with HSV-thymidine kinase gene and then treated with ganciclovir (GCV). GCV treatment induced massive tumor cell apoptosis accompanied with intratumoral CCR1+CCR5+ dendritic cell infiltration. Tumor-infiltrating T cells and macrophages expressed CCL3, suggesting CCR1CCL3 play a crucial role in the regulation of intratumoral dendritic cell accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes. CCL3 and CCR1 are also expressed in 2 different models of HCC, i.e., N-nitrosodiethylamine (DEN)-induced HCC and HCC induced by hepatitis B virus. After DEN treatment, tumor foci number and sizes were remarkably reduced in CCR1- and CCL3-deficient mice, comparing with wild-type (WT) mice. Also, tumor angiogenesis markedly diminished, intratumoral Kupffer cells number reduced, MMP9 gene expression attenuated and MMP9+ cell numbers decreased in CCL3- and CCR1-deficient mice, as compared with WT mice. These observations suggest the contribution of the CCR1-CCL3 axis to HCC progression. Oral squamous cell carcinoma Oncogenesis Expression of CCL3 and CCR1 is significant higher in oral squamous cell carcinoma compared with the normal controls. The percentages of CCL3+ and CCR1+ cells were observed to be similar in parenchyma and stroma in cases without lymph node metastasis when compared with lymph node metastasis positive cases. Ovarian cancer Oncogenesis mRNA for CCR1, -2a, -2b, -3, -4, -5, and -8 was detected in cells from human ovarian cancer ascites. Further, flowcytometry showed CD14+ macrophages within ascites consistently expressed CCR1, -2, and -5, and >60% of all T cells expressed CCR1. Although ovarian cancer ascitic and blood monocyte/macrophages express CCR1, they failed to migrate in response to the RANTES. Compared with that of normal blood, cell surface expression level for CCR1 was higher in ascites. In a monocytic cell line in vitro, CCR1 mRNA expression was increased 5-fold by hypoxia. In 25 patients with ovarian cancer, CCR1 was detected in samples from 75% of patients, where CCR1 localised to macrophages and lymphocytes, and there was a correlation between numbers of CD8+ cells and CCR1+ cells. Colorectal cancer Prognosis The expression of CCR1 is higher in colorectal carcinoma than normal tissues, and correlates with lymph node metastasis, deep invasion, poor differentiation and advanced Dukes' stage. Oncogenesis Inactivation of TGF-beta family signaling within colon cancer increases CCL9 and promotes recruitment of the matrix metalloproteinase-expressing stromal cells that carry CCR1. Lack of CCR1 prevents the accumulation of MMP-expressing cells at the invasive front and suppresses tumor invasion. In a murine model of invasive colorectal cancer in which TGF-beta family signaling is blocked, CD34+ CCR1+ immature myeloid cell is recruited from the bone marrow to the tumor invasive front where expression of CCL9 is increased. These immature myeloid cells express MMP9, MMP2 and CCR1 and migrate toward the ligand CCL9. Lack of CCR1 prevents accumulation of CD34+ immature myeloid cell at the invasive front and suppresses tumor invasion. Prostate cancer Oncogenesis Androgen receptor negative human prostate cancer cell line DU-145 cells selectively expressed CXCR4 and CCR1 at high levels compared with DU-145/AR cells that express androgen receptor. DU-145 showed vigorous migratory responses to CXCL12 and CCL3. In contrast, neither CXCL12 nor CCL3 affected the migration of DU-145/AR cells. Breast cancer Oncogenesis The expression of CCR5 was higher than that of CCR1 in the peripheral blood mononuclear cells (PBMC) of healthy women, while the PBMC of the breast cancer patients showed overexpression of CCR1 and downregulation of CCR5. The differential effects of MIP-1alpha and MIP-1beta on the PBMC of healthy women and breast cancer patients correlated with the expression levels of CCR1 and CCR5 in these monocytes. In murine model of breast cancer, CCL5 (RANTES) was produced by the tumor cells, and its receptors, CCR1 and CCR5, were expressed by the infiltrating leukocytes. In mice treatment with MetCCL5, an antagonist of CCR1 and CCR5, the volume and weight of tumors were significantly decreased compared with control-treated tumors. The total cell number obtained after collagenase Non-small cell lung cancer Oncogenesis CCR1 expression correlated with the aggressive phenotype of the non-small cell lung cancer (NSCLC) cells. CCR1 knockdown significantly suppressed the invasiveness of NSCLC cells and significantly reduced the expression of matrix metalloproteinase-9, but had only a minor effect on cell proliferation. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1) 4 CCR1 (chemokine (C-C motif) receptor 1) Gao Q, Fan J Robinson SC, Scott KA, Wilson JL, Thompson RG, Proudfoot AE, Balkwill FR. A chemokine receptor antagonist inhibits experimental breast tumor growth. Cancer Res. 2003 Dec 1;63(23):8360-5 digestion was decreased in Met-CCL5-treated tumors as was the proportion of infiltrating macrophages. Furthermore, chemokine antagonist treatment increased stromal development and necrosis. Hurt EM, Wiestner A, Rosenwald A, Shaffer AL, Campo E, Grogan T, Bergsagel PL, Kuehl WM, Staudt LM. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell. 2004 Feb;5(2):191-9 Glioma Oncogenesis Co-cultured human glioma U87 cells induced an activated phenotype in HUVECs. These tumouractivated endothelial cells coordinately expressed matching pairs of receptors/ligands were found to be, including CCR1-RANTES axis. Ko J, Jang SW, Kim YS, Kim IS, Sung HJ, Kim HH, Park JY, Lee YH, Kim J, Na DS. Human LZIP binds to CCR1 and differentially affects the chemotactic activities of CCR1dependent chemokines. FASEB J. 2004 May;18(7):890-2 Osteogenic sarcoma Trentin L, Cabrelle A, Facco M, Carollo D, Miorin M, Tosoni A, Pizzo P, Binotto G, Nicolardi L, Zambello R, Adami F, Agostini C, Semenzato G. Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas. Blood. 2004 Jul 15;104(2):502-8 Oncogenesis The activities of phospholipase C (PLC), protein kinase C delta (PKCdelta) and NF-kappaB were enhanced by Lkn-1 (CCL15) stimulation on CCR1+ human osteogenic sarcoma cells. Inhibitors of G protein, PLC, PKCdelta and NF-kappaB inhibited the chemotactic activity of Lkn-1 on CCR1+ osteogenic sarcoma cells indicating that Lkn-1-induced chemotaxis involving these signaling pathways. Oba Y, Lee JW, Ehrlich LA, Chung HY, Jelinek DF, Callander NS, Horuk R, Choi SJ, Roodman GD. MIP-1alpha utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells. Exp Hematol. 2005 Mar;33(3):272-8 Ribeiro S, Horuk R. The clinical potential of chemokine receptor antagonists. Pharmacol Ther. 2005 Jul;107(1):44-58 References Akashi T, Koizumi K, Nagakawa O, Fuse H, Saiki I. 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