Gene Summary

Gene:CCR3; C-C motif chemokine receptor 3
Aliases: CKR3, CD193, CMKBR3, CC-CKR-3
Summary:The protein encoded by this gene is a receptor for C-C type chemokines. It belongs to family 1 of the G protein-coupled receptors. This receptor binds and responds to a variety of chemokines, including eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). It is highly expressed in eosinophils and basophils, and is also detected in TH1 and TH2 cells, as well as in airway epithelial cells. This receptor may contribute to the accumulation and activation of eosinophils and other inflammatory cells in the allergic airway. It is also known to be an entry co-receptor for HIV-1. This gene and seven other chemokine receptor genes form a chemokine receptor gene cluster on the chromosomal region 3p21. Alternatively spliced transcript variants have been described. [provided by RefSeq, Sep 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:C-C chemokine receptor type 3
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 02 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • rac1 GTP-Binding Protein
  • Salivary Gland Cancer
  • Chromosome 3
  • Breast Cancer
  • Biomarkers, Tumor
  • Endothelial Cells
  • Gene Expression Profiling
  • Oligonucleotide Array Sequence Analysis
  • Receptors, CCR3
  • Neoplastic Cell Transformation
  • Chemokine CCL5
  • Receptors, CCR5
  • Cell Proliferation
  • Ovarian Cancer
  • bcl-X Protein
  • RHOB
  • Genetic Predisposition
  • Cell Movement
  • Single Nucleotide Polymorphism
  • Chemokines
  • Gene Expression
  • Skin Cancer
  • Receptors, CCR1
  • Lung Cancer
  • Neoplasm Metastasis
  • Reproducibility of Results
  • Chemokine CCL11
  • Young Adult
  • Immunohistochemistry
  • Receptors, Chemokine
  • Human Umbilical Vein Endothelial Cells
  • Neoplasm Invasiveness
  • p38 Mitogen-Activated Protein Kinases
  • Chemokines, CC
  • Cancer Gene Expression Regulation
  • Prostate Cancer
  • Messenger RNA
  • Uterine Cancer
  • Liver Cancer
  • Wound Healing
  • Signal Transduction
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CCR3 (cancer-related)

Ishida Y, Kido A, Akahane M, et al.
Mesenchymal stem cells up-regulate the invasive potential of prostate cancer cells via the eotaxin-3/CCR3 axis.
Pathol Res Pract. 2018; 214(9):1297-1302 [PubMed] Related Publications
This study aimed to clarify the role of mesenchymal stem cells (MSCs) as a component of the cancer microenvironment. We investigated the homing-related chemokine expression levels of MSCs treated with a prostate cancer cell line (PC-3) -conditioned medium. Among several homing chemokines, an antibody array revealed that expression of eotaxin-3 (but not eotxin-1 and -2) was highly enhanced in MSCs treated with PC-3-conditioned medium. A gene expression array showed significantly increased expression of CCR3, a receptor of eotaxin-3, in PC-3. In a matrigel invasion assay, interferon-gamma, a specific inhibitor of eotaxin-related homing, significantly reduced the transmigration of PC-3 cells, under co-cultured condition with MSCs, in a dose-dependent manner (P < 0.05). Consistent with these results, anti-CCR3 antibody successfully reduced PC-3 migration under the co-cultured condition. These findings suggest that MSCs to modulation of the invasive potential of prostate cancer cells via the eotaxin-3/CCR3 axis.

González-Arriagada WA, Lozano-Burgos C, Zúñiga-Moreta R, et al.
Clinicopathological significance of chemokine receptor (CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4) expression in head and neck squamous cell carcinomas.
J Oral Pathol Med. 2018; 47(8):755-763 [PubMed] Related Publications
BACKGROUND: Head and neck squamous cell carcinoma shows high prevalence of lymph node metastasis at diagnosis, and despite the advances in treatment, the overall 5-year survival is still under 50%. Chemokine receptors have a role in the development and progression of cancer, but their effect in head and neck carcinoma remains poorly characterised. This study aimed to assess the prognostic value of CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4 in head and neck squamous cell carcinomas.
METHODS: Immunohistochemical expression of chemokine receptors was evaluated in a retrospective cohort of 76 cases of head and neck squamous cell carcinoma. Clinicopathological associations were analysed using the chi-square test, survival curves were analysed according to the Kaplan-Meier method, and the Cox proportional hazard model was applied for multivariate survival analysis.
RESULTS: The chemokine receptors were highly expressed in primary carcinomas, except for CCR1 and CCR3. Significant associations were detected, including the associations between CCR5 expression and lymph node metastasis (N stage, P = .03), advanced clinical stage (P = .003), poor differentiation of tumours (P = .05) and recurrence (P = .01). The high expression of CCR5 was also associated with shortened disease-free survival (HR: 2.85, 95% CI: 1.09-8.14, P = .05), but the association did not withstand the Cox multivariate survival analysis. At univariate analysis, high expression of CCR7 was associated with disease-free survival and low levels of CXCR4 were significantly associated with both disease-specific and disease-free survival.
CONCLUSIONS: These findings show that chemokine receptors may have an important role in head and neck squamous cell carcinoma progression, regional lymph node metastasis and recurrence.

Dedoni S, Campbell LA, Harvey BK, et al.
The orphan G-protein-coupled receptor 75 signaling is activated by the chemokine CCL5.
J Neurochem. 2018; 146(5):526-539 [PubMed] Free Access to Full Article Related Publications
The chemokine CCL5 prevents neuronal cell death mediated both by amyloid β, as well as the human immunodeficiency virus viral proteins gp120 and Tat. Because CCL5 binds to CCR5, CCR3 and/or CCR1 receptors, it remains unclear which of these receptors plays a role in neuroprotection. Indeed, CCL5 also has neuroprotective activity in cells lacking these receptors. CCL5 may bind to a G-protein-coupled receptor 75 (GPR75), which encodes for a 540 amino-acid orphan receptor of the Gqα family. In this study, we have used SH-SY5Y human neuroblastoma cells to characterize whether CCL5 could activate a Gq signaling through GPR75. Both qPCR and flow cytometry show that these cells express GPR75 but do not express CCR5, CCR3 or CCR1 receptors. SY-SY5Y cells were then used to examine CCL5-mediated signaling. We report that CCL5 promotes a time- and concentration-dependent phosphorylation of protein kinase B (AKT), glycogen synthase kinase 3β, and extracellular signal-regulated kinase (ERK) 1/2. Specific antagonists of CCR5, CCR3, and CCR1 did not prevent CCL5 from increasing phosphorylated AKT or ERK. Moreover, CCL5 promotes a time-dependent internalization of GPR75. Lastly, knocking down GPR75 expression by a CRISPR-Cas9 approach inhibited the ability of CCL5 to activate pERK in SH-SY5Y cells. Therefore, we propose that GPR75 is a novel receptor for CCL5 that could explain some of the pharmacological action of this chemokine. These findings may help in the development of small molecule GPR75 agonists that mimic CCL5. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see:

Vaniotis G, Rayes RF, Qi S, et al.
Collagen IV-conveyed signals can regulate chemokine production and promote liver metastasis.
Oncogene. 2018; 37(28):3790-3805 [PubMed] Related Publications
Liver metastases remain a major cause of death from gastrointestinal tract cancers as well as from other malignancies such as breast and lung carcinomas and melanoma. Understanding the underlying biology is essential for the design of effective targeted therapies. We previously reported that collagen IV α1/α2 overexpression in non-metastatic lung carcinoma (M27

Lan Q, Lai W, Zeng Y, et al.
CCL26 Participates in the PRL-3-Induced Promotion of Colorectal Cancer Invasion by Stimulating Tumor-Associated Macrophage Infiltration.
Mol Cancer Ther. 2018; 17(1):276-289 [PubMed] Related Publications
Both phosphatase of regenerating liver-3 (PRL-3) and tumor-associated macrophages (TAM) influence cancer progression. Whether PRL-3 plays a critical role in colorectal cancer invasion and metastasis by inducing TAM infiltration remains unclear. In the current study, we investigated the effects of chemokine ligand 26 (CCL26) on TAM infiltration and colorectal cancer invasion and the underlying mechanism in colorectal cancer cells by overexpressing or silencing PRL-3. We found that PRL-3 upregulated CCL26 expression correlatively and participated in cell migration, according to the results of gene ontology analysis. In addition, IHC analysis results indicated that the PRL-3 and CCL26 levels were positively correlated and elevated in stage III and IV colorectal cancer tissues and were associated with a worse prognosis in colorectal cancer patients. Furthermore, we demonstrated that CCL26 induced TAM infiltration by CCL26 binding to the CCR3 receptor. When LoVo-P and HT29-C cells were cocultured with TAMs, CCL26 binding to the CCR3 receptor enhanced the invasiveness of LoVo-P and HT29-C cells by mobilizing intracellular Ca

Valverde-Villegas JM, de Medeiros RM, Almeida SEM, Chies JAB
Immunogenetic profiling of 23 SNPs of cytokine and chemokine receptor genes through a minisequencing technique: Design, development and validation.
Int J Immunogenet. 2017; 44(3):135-144 [PubMed] Related Publications
The minisequencing technique offers accuracy and robustness to genotyping of polymorphic DNA variants, being an excellent option for the identification and analyses of prognostic/susceptibility markers in human diseases. Two multiplex minisequencing assays were designed and standardized to screen 23 candidate SNPs in cytokine, chemokine receptor and ligand genes previously associated with susceptibility to cancer and autoimmune disorders as well as to infectious diseases outcome. The SNPs were displayed in two separate panels (panel 1-IL2 rs2069762, TNFα rs1800629, rs361525; IL4 rs2243250; IL6 rs1800795; IL10 rs1800896, rs1800872; IL17A rs8193036, rs2275913 and panel 2-CCR3 rs309125, CCR4 rs6770096, rs2228428; CCR6 rs968334; CCR8 rs2853699; CXCR3 rs34334103, rs2280964;CXCR6 rs223435, rs2234358; CCL20 rs13034664, rs6749704; CCL22 rs4359426; CXCL10/IP-10 rs3921, rs56061981). A total of 305 DNA samples from healthy individuals were genotyped by minisequencing. To validate the minisequencing technique and to encompass the majority of the potential genotypes for all 23 SNPs, 20 of these samples were genotyped by Sanger sequencing. The results of both techniques were 100% in agreement. The technique of minisequencing showed high accuracy and robustness, avoiding the need for high quantities of DNA template samples. It was easily to be conducted in bulk samples derived from a highly admixed human population, being therefore an excellent option for immunogenetic studies.

Jin L, Liu WR, Tian MX, et al.
CCL24 contributes to HCC malignancy via RhoB- VEGFA-VEGFR2 angiogenesis pathway and indicates poor prognosis.
Oncotarget. 2017; 8(3):5135-5148 [PubMed] Free Access to Full Article Related Publications
CCL24 is one chemotactic factor extensively studied in airway inflammation and colorectal cancer but less studied in hepatocellular carcinoma (HCC) retrospectively. So HCC tissue microarray (TMA) was used to estimate relationship between CCL24 and prognosis, cell experiments were conducted to study its influence for HCC cell biological behavior. CCL24 was injected to nude mice to monitor tumor formation and pulmonary metastasis; qRT-PCR, western blot and Immunohistochemistry were used to explore potential mechanism. CCL24 plays roles in target cells via its downstream CCR3, or it is regulated by Type 2 helper T cells (Th2 cell) factors, so immune related experiments were conducted. Meanwhile, Rho GTPase family have close relation not only with T cell priming, but with neovascularization; CCL24 contributes to neovascularization in age-related macular degeneration via CCR3, so Rho GTPase family, Th2 cell factors, Human Umbilical Vein Endothelial Cells were used to uncover their trafficking. Ultimate validation was confirmed by small interfering RNA. Results showed CCL24 expression was higher in caner tissues than adjacent normal tissues, it could contribute to proliferation, migration, and invasion in HCCs, could accelerate pulmonary metastasis, promote HUVECs tube formation. Th2 cell factors were irrelevant with CCL24 in HCCs; and RhoB, VEGFA, and VEGFR2 correlated with CCL24 in both mRNA and protein level. Downstream RhoB-VEGFA signaling pathway was validated by siRhoB and siVEGFA inhibition. In a word, CCL24 contributes to HCC malignancy via RhoB-VEGFA-VEGFR2 angiogenesis pathway and indicates poor prognosis, which urges us to study further CCL24 effects on diagnosis and potential therapy for HCC.

Mays AC, Feng X, Browne JD, Sullivan CA
Chemokine and Chemokine Receptor Profiles in Metastatic Salivary Adenoid Cystic Carcinoma.
Anticancer Res. 2016; 36(8):4013-8 [PubMed] Related Publications
AIM: To characterize the chemokine pattern in metastatic salivary adenoid cystic carcinoma (SACC).
MATERIALS AND METHODS: Real-time polymerase chain reaction (RT-PCR) was used to compare chemokine and chemokine receptor gene expression in two SACC cell lines: SACC-83 and SACC-LM (lung metastasis). Chemokines and receptor genes were then screened and their expression pattern characterized in human tissue samples of non-recurrent SACC and recurrent SACC with perineural invasion.
RESULTS: Expression of chemokine receptors C5AR1, CCR1, CCR3, CCR6, CCR7, CCR9, CCR10, CXCR4, CXCR6, CXCR7, CCRL1 and CCRL2 were higher in SACC-83 compared to SACC-LM. CCRL1, CCBP2, CMKLR1, XCR1 and CXCR2 and 6 chemokine genes (CCL13, CCL27, CXCL14, CMTM1, CMTM2, CKLF) were more highly expressed in tissues of patients without tumor recurrence/perineural invasion compared to those with tumor recurrence. CCRL1 (receptor), CCL27, CMTM1, CMTM2, and CKLF (chemokine) genes were more highly expressed in SACC-83 and human tissues of patients without tumor recurrence/perineural invasion.
CONCLUSION: CCRL1, CCL27, CMTM1, CMTM2 and CKLF may play important roles in the development of tumor metastases in SACC.

Gong DH, Fan L, Chen HY, et al.
Intratumoral expression of CCR3 in breast cancer is associated with improved relapse-free survival in luminal-like disease.
Oncotarget. 2016; 7(19):28570-8 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The association chemokine receptor CCR3 with breast cancer subtypes and relapse-free survival is unknown.
RESULTS: The overall expression (either intratumoral or peritumoral) of CCR3 was not associated with tumor size, lymph node status, age, and subtype. When we confined the analysis in samples without peritumoral stromal CCR3 expression, intratumoral expression of CCR3 was associated with breast cancer subtype (P=0.04). Tumors with high expression of CCR3 were more likely to be luminal-like rather than TNBC or HER2-enriched cancers. Moreover, high mRNA expression of CCR3 was related with improved relapse-free survival in luminal-A/B (P<0.001). The subsequent sensitivity analysis using the systemically untreated patients confirmed that higher mRNA expression of CCR3 was a robust prognostic factor for luminal-A (P=0.0025) and luminal-B (P=0.088), but not for HER2-enriched (P=0.21) and TNBC (P=0.86). In the independent cohort, the positive association between increased expression of CCR3 and improved distant relapse-free survival was also observed.
METHODS: We determined the expression level of CCR3 in 150 cases with breast cancer by using immunohistochemistry (IHC) assay, for both intratumoral and peritumoral stroma, and investigated the effect of CCR3 expression on relapse-free survival according to subtype using cases from publicly available datasets, in the whole group (N=3557) and in the patients without adjuvant systemic treatment (N=1005), respectively. Moreover, the survival outcomes were validated in another independent cohort including 508 breast cancer patients treated with neoadjuvant chemotherapy.
CONCLUSIONS: Our data indicate that intratumoral expression of CCR3 in breast cancer is associated with improved relapse-free survival in patients with luminal-like disease.

Tang S, Xiang T, Huang S, et al.
Ovarian cancer stem-like cells differentiate into endothelial cells and participate in tumor angiogenesis through autocrine CCL5 signaling.
Cancer Lett. 2016; 376(1):137-47 [PubMed] Related Publications
Cancer stem cells (CSCs) are well known for their self-regeneration and tumorigenesis potential. In addition, the multi-differentiation potential of CSCs has become a popular issue and continues to attract increased research attention. Recent studies demonstrated that CSCs are able to differentiate into functional endothelial cells and participate in tumor angiogenesis. In this study, we found that ovarian cancer stem-like cells (CSLCs) activate the NF-κB and STAT3 signal pathways through autocrine CCL5 signaling and mediate their own differentiation into endothelial cells (ECs). Our data demonstrate that CSLCs differentiate into ECs morphologically and functionally. Anti-CCL5 antibodies and CCL5-shRNA lead to markedly inhibit EC differentiation and the tube formation of CSLCs, both in vitro and in vivo. Recombinant human-CCL5 significantly promotes ovarian CSLCs that differentiate into ECs and form microtube network. The CCL5-mediated EC differentiation of CSLCs depends on binding to receptors, such as CCR1, CCR3, and CCR5. The results demonstrated that CCL5-CCR1/CCR3/CCR5 activates the NF-κB and STAT3 signal pathways, subsequently mediating the differentiation of CSLCs into ECs. Therefore, this study was conducted based on the theory that CSCs improve tumor angiogenesis and provides a novel strategy for anti-angiogenesis in ovarian cancer.

Zhang Q, Qin J, Zhong L, et al.
CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer.
Cancer Res. 2015; 75(20):4312-21 [PubMed] Related Publications
The tumor-promoting chemokine CCL5 has been implicated in malignant transformation of breast epithelial cells, with studies to date focusing mainly on basal-type breast cancers. In this study, we investigated the consequences of CCL5 deletion in the MMTV-PyMT transgenic mouse model of luminal breast cancer. In this model, primary tumor burden and pulmonary metastases were reduced significantly in CCL5-deficient subjects, an effect found to be associated with a deficit of Th2 (IL4⁺CD4⁺ T) cells. Mechanistic investigations revealed that CCL5 activates CCR3, a highly expressed chemokine receptor on CD4⁺ T cells, and also boosts Gfi1 expression to promote the differentiation of Th2 cells, which enhance the prometastatic activity of tumor-associated myeloid cells. Clinically, polarization toward this immunosuppressive Th2 phenotype was also evident in patients with advanced luminal breast cancer. Thus, our findings showed that CCL5/CCR3 signaling promotes metastasis by inducing Th2 polarization of CD4⁺ T cells, with implications for prognosis and immunotherapy of luminal breast cancer.

Zhao W, Xu Y, Xu J, et al.
Subsets of myeloid-derived suppressor cells in hepatocellular carcinoma express chemokines and chemokine receptors differentially.
Int Immunopharmacol. 2015; 26(2):314-21 [PubMed] Related Publications
Tumors induce the recruitment and expansion of myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells that can be further sub-divided into polymorphonuclear Ly6G(+) PMN-MDSCs and monocytic Ly6G(-) Mo-MDSCs. To identify chemokines and chemokine-related genes that are differentially expressed within the tumor microenvironment in these two MDSC subsets, we established an orthotopic hepatocellular carcinoma model in immunocompetent mice. Splenic PMN-MDSCs and Mo-MDSCs were isolated to >95% homogeneity by flow cytometry. Using a real-time PCR array, we investigated the expression of 84 genes encoding chemokines and cytokines, chemokine receptors, and related signaling molecules involved with chemotaxis. Clustering analysis suggested that a core set of chemokine-related genes is expressed in both PMN-MDSC and Mo-MDSC populations, but that the expression profile is broader for Mo-MDSCs. Furthermore, 11 genes are more highly expressed in PMN-MDSCs and 12 genes are more highly expressed in Mo-MDSCs. Among these, PMN-MDSCs express Cxcr1, Cxcr2 and Il1b at 33.03- to 109.76-fold higher levels than in Mo-MDSCs, and Mo-MDSCs express eight genes (Ccr2, Ccr5, Cmklr1, Cx3cr1, Ccr3, Ccl9, Cmtm3 and Cxcl16) at 30.2 to 515.5-fold higher levels than in PMN-MDSCs. These results suggest that the profile of chemokines and chemokine-related genes is more expansive for Mo-MDSCs than for PMN-MDSCs. The differential expression of chemokines and chemokine-associated genes may regulate the presence and activity of PMN-MDSCs and Mo-MDSCs in the tumor microenvironment.

Poswar Fde O, Farias LC, Fraga CA, et al.
Bioinformatics, interaction network analysis, and neural networks to characterize gene expression of radicular cyst and periapical granuloma.
J Endod. 2015; 41(6):877-83 [PubMed] Related Publications
INTRODUCTION: Bioinformatics has emerged as an important tool to analyze the large amount of data generated by research in different diseases. In this study, gene expression for radicular cysts (RCs) and periapical granulomas (PGs) was characterized based on a leader gene approach.
METHODS: A validated bioinformatics algorithm was applied to identify leader genes for RCs and PGs. Genes related to RCs and PGs were first identified in PubMed, GenBank, GeneAtlas, and GeneCards databases. The Web-available STRING software (The European Molecular Biology Laboratory [EMBL], Heidelberg, Baden-Württemberg, Germany) was used in order to build the interaction map among the identified genes by a significance score named weighted number of links. Based on the weighted number of links, genes were clustered using k-means. The genes in the highest cluster were considered leader genes. Multilayer perceptron neural network analysis was used as a complementary supplement for gene classification.
RESULTS: For RCs, the suggested leader genes were TP53 and EP300, whereas PGs were associated with IL2RG, CCL2, CCL4, CCL5, CCR1, CCR3, and CCR5 genes.
CONCLUSIONS: Our data revealed different gene expression for RCs and PGs, suggesting that not only the inflammatory nature but also other biological processes might differentiate RCs and PGs.

Chen Q, Zheng T, Lan Q, et al.
Single-nucleotide polymorphisms in genes encoding for CC chemokines were not associated with the risk of non-Hodgkin lymphoma.
Cancer Epidemiol Biomarkers Prev. 2013; 22(7):1332-5 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chemokines play a pivotal role in immune regulation and response, and previous studies suggest an association between immune deficiency and non-Hodgkin lymphoma (NHL).
METHODS: We evaluated the association between NHL and polymorphisms in 18 genes (CCL1, CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL18, CCL20, CCL24, CCL26, CCR1, CCR3, CCR4, CCR6, CCR7, CCR8, and CCR9) encoding for the CC chemokines using data from a population-based case-control study of NHL conducted in Connecticut women.
RESULTS: CCR8 was associated with diffuse large B-cell lymphoma (DLBCL; P = 0.012), and CCL13 was associated with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL; P = 0.003) at gene level. After adjustment for multiple comparisons, none of the genes or single-nucleotide polymorphisms (SNP) were associated with risk of overall NHL or NHL subtypes.
CONCLUSIONS: Our results suggest that the genes encoding for CC chemokines are not significantly associated with the risk of NHL, and further studies are needed to verify these findings.
IMPACT: Our data indicate that CC chemokine genes were not associated with NHL risk.

Du L, Xu WT, Fan QM, et al.
Tumorigenesis and spontaneous metastasis by luciferase-labeled human xenograft osteosarcoma cells in nude mice.
Chin Med J (Engl). 2012; 125(22):4022-30 [PubMed] Related Publications
BACKGROUND: Osteosarcoma (OS) is the most common primary malignant tumor of bone. Mouse models of human OS can invariably provide greater insight into the complex mechanisms that underlie the development and pathogenesis of this aggressive tumor. Bioluminescence technology favored tracing cancer cells in vivo. In this study, an OS model was described and evaluated using human OS cell line, Saos2, labeled with luciferase (Saos2-luc).
METHODS: Saos2 cells were infected by lentivirus loading a firefly luciferase gene. Luciferase expression of Saos2-luc cells was characterized both in vitro and in vivo. Specific biologic and oncologic features of Saos2-luc cells were analyzed. The OS was established as orthotopic xenografts in nude mice. Both orthotopic tumors and spontaneous lung metastasis were analyzed.
RESULTS: Tumorigenesis and spontaneous lung metastasis in nude mice could be monitored in vivo through in vivo imaging system. The enhancement in proliferation, migration and invasion abilities and the attenuation in adhesion ability were observed in Saos2-luc cells compared with Saos2 cells. Furthermore, there were the up-regulation of Osteocalcin, CCR10, CXCR1 and ID1 and the down-regulation of ALP, collagen I, CCR1, CCR3, CXCR3, NID and N-cadherin in Saos2-luc cells compare to Saos2 cells. The rate of spontaneous lung metastasis in Saos2-luc cells was higher than that in Saos2 cells, although without significant difference.
CONCLUSIONS: Lentivirus transfection may cause alteration of gene expression profiles and further biological functions. This model can be used in the elucidation of molecular mechanisms of tumorigenesis and the screening of new therapeutic agents.

Santos FP, O'Brien S
Small lymphocytic lymphoma and chronic lymphocytic leukemia: are they the same disease?
Cancer J. 2012 Sep-Oct; 18(5):396-403 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, characterized by peripheral blood B-cell lymphocytosis as well as lymphadenopathy, organomegaly, cytopenias, and systemic symptoms. Chronic lymphocytic leukemia cells have a distinctive immunophenotype, and the disease has a characteristic pattern of histological infiltration in the lymph node and bone marrow. The clinical course of CLL is heterogeneous, with some patients presenting with very indolent disease and other patients having a more aggressive malignancy. It is known that genetic abnormalities underlie this difference in clinical presentation. Some patients may present solely with lymphadenopathy, organomegaly, and presence of infiltrating monoclonal B cells with the same immunophenotype as CLL cells, but lacking peripheral blood lymphocytosis. This disease is called small lymphocytic lymphoma (SLL) and has been considered for almost 2 decades to be the tissue equivalent of CLL. Both CLL and SLL are currently considered different manifestations of the same entity by the fourth edition of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. It is suspected that differential expression of chemokine receptors (e.g., reduced expression of R1 and CCR3 in SLL cells), integrins (e.g., CLL cells have lower expression of integrin αLβ2), and genetic abnormalities (a higher incidence of trisomy 12 and lower incidence of del(13q) is found in SLL) may explain some of the clinical differences between these 2 disorders. However, there is still a lack of knowledge on the precise biological basis underlying the different clinical presentations of CLL and SLL. It is expected that future studies will shed light on the pathophysiology of both disorders.

Long H, Xie R, Xiang T, et al.
Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-κB-mediated MMP-9 upregulation.
Stem Cells. 2012; 30(10):2309-19 [PubMed] Related Publications
The concept of cancer stem cells (CSCs) proposes that solely CSCs are capable of generating tumor metastases. However, how CSCs maintain their invasion and migration abilities, the most important properties of metastatic cells, still remains elusive. Here we used CD133 to mark a specific population from human ovarian cancer cell line and ovarian cancer tissue and determined its hyperactivity in migration and invasion. Therefore, we labeled this population as cancer stem-like cells (CSLCs). In comparison to CD133- non-CSLCs, chemokine CCL5 and its receptors, CCR1, CCR3, and CCR5, were consistently upregulated in CSLCs, and most importantly, blocking of CCL5, CCR1, or CCR3 effectively inhibits the invasive capacity of CSLCs. Mechanistically, we identified that this enhanced invasiveness is mediated through nuclear factor κB (NF-κB) activation and the consequently elevated MMP9 secretion. Our results suggested that the autocrine activation of CCR1 and CCR3 by CCL5 represents one of major mechanisms underlying the metastatic property of ovarian CSLCs.

Velasco-Velázquez M, Jiao X, De La Fuente M, et al.
CCR5 antagonist blocks metastasis of basal breast cancer cells.
Cancer Res. 2012; 72(15):3839-50 [PubMed] Related Publications
The roles of the chemokine CCL5 and its receptor CCR5 in breast cancer progression remain unclear. Here, we conducted microarray analysis on 2,254 human breast cancer specimens and found increased expression of CCL5 and its receptor CCR5, but not CCR3, in the basal and HER-2 genetic subtypes. The subpopulation of human breast cancer cell lines found to express CCR5 displayed a functional response to CCL5. In addition, oncogene transformation induced CCR5 expression, and the subpopulation of cells that expressed functional CCR5 also displayed increased invasiveness. The CCR5 antagonists maraviroc or vicriviroc, developed to block CCR5 HIV coreceptor function, reduced in vitro invasion of basal breast cancer cells without affecting cell proliferation or viability, and maraviroc decreased pulmonary metastasis in a preclinical mouse model of breast cancer. Taken together, our findings provide evidence for the key role of CCL5/CCR5 in the invasiveness of basal breast cancer cells and suggest that CCR5 antagonists may be used as an adjuvant therapy to reduce the risk of metastasis in patients with the basal breast cancer subtype.

Cho YB, Lee WY, Choi SJ, et al.
CC chemokine ligand 7 expression in liver metastasis of colorectal cancer.
Oncol Rep. 2012; 28(2):689-94 [PubMed] Related Publications
The main cause of death for colorectal cancer (CRC) patients is the development of metastatic lesions at sites distant from the primary tumor. Therefore, it is important to find biomarkers that are related to the metastasis and to study the possible mechanisms. Recent data have shown that soluble attractant molecules called chemokines support the metastasis of certain cancers to certain organs. To identify molecular regulators that are differentially expressed in liver metastasis of CRC, PCR array analysis was performed and CC chemokine ligand 7 (CCL7) showed remarkable overexpression in liver metastatic tumor tissues. To validate the results of the PCR array, 30 patients with primary CRC and liver metastases were selected. Immunohistochemistry and real-time PCR analysis showed that CCL7 was expressed in normal colonic epithelium and the expression was higher in liver metastases compared to primary CRC (p<0.001). Real-time PCR showed that the expression of CCR1, CCR2 and CCR3 was also higher in liver metastases compared to primary CRC (p=0.001, p=0.033 and p<0.001, respectively). In conclusion, correlation of CCL7 overexpression and its receptor expression with colon cancer liver metastasis suggests that CCL7 as a novel target in liver metastasis of CRC may be of potential clinical value for the prevention of hepatic recurrences.

de Souza A, el-Azhary RA, Camilleri MJ, et al.
In search of prognostic indicators for lymphomatoid papulosis: a retrospective study of 123 patients.
J Am Acad Dermatol. 2012; 66(6):928-37 [PubMed] Related Publications
BACKGROUND: Lymphomatoid papulosis (LyP) is a benign recurrent papulonodular skin eruption with histologically malignant features that sometimes (10%-20%) progresses to lymphoma.
OBJECTIVE: We retrospectively evaluated the clinical course of patients with LyP and identify prognostic factors possibly indicating a malignant course.
METHODS: Clinical, histopathologic, and immunologic features and molecular genetics were examined and correlated with clinical course and outcomes. Immunophenotyping and chemokine profiling were performed in select skin biopsy samples. A follow-up questionnaire was sent to patients. Clinical course and association with neoplastic disorders were correlated with LyP subtypes, molecular genetics, and immunophenotyping studies.
RESULTS: Of 123 patients with LyP (1991-2008) followed up a mean of 4 years (range, 2 months to 14 years), 17 (14%) had an associated hematologic malignancy, 8 of which were mycosis fungoides. Histopathologic analyses demonstrated classic LyP type A (n = 69), B (n = 13), or C (n = 6), and a slight predominance of T-cell CD8 marker expression for type A. More than one type of lesion was present in 9 patients with a higher incidence of hematologic malignancies. T-cell receptor gene rearrangement positivity was about two times higher, with LyP associated with hematologic malignancy (82% vs 44%; odds ratio 5.7; P = .02). Chemokine studies in a subset of 25 patients showed chemokine receptor (CCR) CCR4(+) and thymus and activation-related chemokine (TARC(+)) in all LyP types and CCR3(+) and chemokine-related receptor (CXCR) CXCR3(+) in types B and C.
LIMITATIONS: Retrospective study design is a limitation.
CONCLUSIONS: Positive T-cell receptor gene rearrangement or diagnosis of mixed-type LyP may be a prognostic indicator of disease more prone to progress to lymphoma.

Setty MK, Devadas K, Ragupathy V, et al.
XMRV: usage of receptors and potential co-receptors.
Virol J. 2011; 8:423 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: XMRV is a gammaretrovirus first identified in prostate tissues of Prostate Cancer (PC) patients and later in the blood cells of patients with Chronic Fatigue Syndrome (CFS). Although XMRV is thought to use XPR1 for cell entry, it infects A549 cells that do not express XPR1, suggesting usage of other receptors or co-receptors.
METHODS: To study the usage of different receptors and co- receptors that could play a role in XMRV infection of lymphoid cells and GHOST (GFP- Human osteosarcoma) cells expressing CD4 along with different chemokine receptors including CCR1, CCR2, etc., were infected with XMRV. Culture supernatants and cells were tested for XMRV replication using real time quantitative PCR.
RESULTS: Infection and replication of XMRV was seen in a variety of GHOST cells, LNCaP, DU145, A549 and Caski cell lines. The levels of XMRV replication varied in different cell lines showing differential replication in different cell lines. However, replication in A549 which lacks XPR1 expression was relatively higher than DU145 but lower than, LNCaP. XMRV replication varied in GHOST cell lines expressing CD4 and each of the co- receptors CCR1-CCR8 and bob. There was significant replication of XMRV in CCR3 and Bonzo although it is much lower when compared to DU145, A549 and LNCaP.
CONCLUSION: XMRV replication was observed in GHOST cells that express CD4 and each of the chemokine receptors ranging from CCR1- CCR8 and BOB suggesting that infectivity in hematopoietic cells could be mediated by use of these receptors.

Wang Y, Wang W, Wang L, et al.
Regulatory mechanisms of interleukin-8 production induced by tumour necrosis factor-α in human hepatocellular carcinoma cells.
J Cell Mol Med. 2012; 16(3):496-506 [PubMed] Free Access to Full Article Related Publications
Interleukin (IL)-8 plays the critical role in the initiation of micro-environmental inflammation responsible for tumour growth and patient prognosis. This study aimed at investigating the molecular mechanisms of IL-8 production from human hepatocellular carcinoma (HCC) cells. The levels of IL-8 and phosphorylation of p38 mitogen-activated protein kinase (MAPK), ERK1/2 and Akt in MHCC-97H cells were measured by ELISA, Western blot and immunofluorescence. NF-κB p65 protein nuclear translocation was determined by non-radioactive NF-κB p50/p65 transcription factor activity kit and cell bio-behaviours were detected by the real-time cell-monitoring system. Tumour necrosis factor-α (TNF-α) significantly induced phosphorylation of p38 MAPK, ERK, Akt and production of IL-8 from HCC cells, which were prevented by SB203580 (p38 MAPK inhibitor), PD98059 (ERK inhibitor), LY294002 and Wortmannin (PI3K inhibitor) and SB328437 (CCR3 inhibitor). TNF-α could significantly increase the translocation of NF-κB p65 protein into the nucleus in a dose-dependent manner, while SB203580 partially inhibited. In inflammatory micro-environment, HCC auto-produced IL-8 through p38 MAPK, ERK and PI3K/Akt signalling pathways, where the p38 MAPK is a central factor to activate the NF-κB pathway and regulate the expression of IL-8 production. There was a potential cross-talking between receptors.

Miyagaki T, Sugaya M, Murakami T, et al.
CCL11-CCR3 interactions promote survival of anaplastic large cell lymphoma cells via ERK1/2 activation.
Cancer Res. 2011; 71(6):2056-65 [PubMed] Related Publications
CCR3 is a specific marker of anaplastic large cell lymphoma (ALCL) cells. ALCL cells also express CCL11, a ligand for CCR3, leading to the hypothesis that CCL11 may play an autocrine role in ALCL progression. In this study, we investigated a role of CCL11 in cell survival and growth of human Ki-JK cells, established from an ALCL patient, and murine EL-4 lymphoma cells. Both Ki-JK and EL-4 cells expressed cell surface CCR3. CCL11 increased cell survival rates of Ki-JK cells in a dose-dependent manner, whereas it promoted EL-4 cell proliferation. Furthermore, CCL11 induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in both Ki-JK cells and EL-4 cells. Cell survival and tumor proliferation promoted by CCL11 was completely blocked by inhibition of ERK phosphorylation. CCL11 induced expression of antiapoptotic proteins, Bcl-xL and survivin, in Ki-JK cells. CCL11 also enhanced tumor growth of EL-4 and Ki-JK cells in vivo. Consistent with these results, tumor cells of cutaneous ALCL expressed CCR3 and increased levels of phosphorylated ERK1/2, Bcl-xL, and survivin in situ. Thus, our findings prompt a novel therapeutic approach to treat relapses of an aggressive form of lymphoma based on the discovery that a cell surface marker of disease functions as a critical autocrine growth receptor.

Wolff HA, Rolke D, Rave-Fränk M, et al.
Analysis of chemokine and chemokine receptor expression in squamous cell carcinoma of the head and neck (SCCHN) cell lines.
Radiat Environ Biophys. 2011; 50(1):145-54 [PubMed] Free Access to Full Article Related Publications
The purpose of this work was to analyze chemokine and chemokine receptor expression in untreated and in irradiated squamous cell carcinoma of the head and neck (SCCHN) tumor cell lines, aiming at the establishment of assays to test for the relevance of chemokine and chemokine receptor expression in the response of SCCHN to radiotherapy and radiochemotherapy. Five low passage and 10 established SCCHN lines, as well as two normal cell lines, were irradiated at 2 Gy or sham-irradiated, and harvested between 1 and 48 h after treatment. For chemokines with CC and CXC structural motifs and their receptors, transcript levels of target and reference genes were quantified relatively by real-time PCR. In addition, CXCL1 and CXCL12 protein expression was analyzed by ELISA. A substantial variation in chemokine and chemokine receptor expression between SCCHN was detected. Practically, all cell lines expressed CCL5 and CCL20, while CCL2 was expressed in normal cells and in some of the tumor cell lines. CXCL1, CXCL2, CXCL3, CXCL10, and CXCL11 were expressed in the vast majority of the cell lines, while the expression of CXCL9 and CXCL12 was restricted to fibroblasts and few tumor cell lines. None of the analyzed cell lines expressed the chemokines CCL3, CCL4, or CCL19. Of the receptors, transcript expression of CCR1, CCR2, CCR3, CCR5, CCR7, CCXR2, and CCXR3 was not detected, and CCR6, CXCR1, and CXCR4 expression was restricted to few tumor cells. Radiation caused up- and down-regulation with respect to chemokine expressions, while for chemokine receptor expressions down-regulations were prevailing. CXCL1 and CXCL12 protein expression corresponded well with the mRNA expression. We conclude that the substantial variation in chemokine and chemokine receptor expression between SCCHN offer opportunities for the establishment of assays to test for the relevance of chemokine and chemokine receptor expression in the response of SCCHN to radiotherapy and radiochemotherapy.

Clements D, Markwick LJ, Puri N, Johnson SR
Role of the CXCR4/CXCL12 axis in lymphangioleiomyomatosis and angiomyolipoma.
J Immunol. 2010; 185(3):1812-21 [PubMed] Related Publications
Lymphangioleiomyomatosis (LAM) is a progressive disease caused by accumulation of metastatic (LAM) cells in the lungs, lymphatics, and the tumor angiomyolipoma (AML). LAM cells have biallelic loss of either tuberous sclerosis complex gene (but predominantly TSC-2) and resultant dysregulation of the mammalian target of rapamycin (mTOR) pathway. Chemokines are associated with neoplastic cell growth, survival, and homing to specific organs and may play similar roles in LAM. Our objective was to study comprehensively the expression and function of chemokine receptors and how their function interacts with dysregulation of the mTOR pathway in LAM and AML. We used RT-PCR and FACS to study receptor expression in primary AML cells and immunohistochemistry to investigate expression in tissues. Chemokine receptor function was analyzed in AML cells by Western blotting of signaling proteins and cell proliferation and apoptosis assays. Primary AML cells, LAM, and AML tissues expressed CCR3, CXCR4, CXCR6, and CXC3CR1. In AML cells, their ligands CXCL12 CX3CL1, CCL11, CCL24, and CCL28 caused robust phosphorylation of p42/44 MAPK and Akt. CXCL12 was expressed in type II pneumocytes covering LAM nodules and caused AML cell growth and protection from apoptosis, which was blocked by AMD3100, a CXCR4 inhibitor. The mTOR inhibitor rapamycin, but not AMD3100, inhibited growth of AML tumor xenografts. We conclude that the CXCL12/CXCR4 axis promotes, but is not absolutely required for, AML/LAM cell growth and survival.

Miyagaki T, Sugaya M, Fujita H, et al.
Eotaxins and CCR3 interaction regulates the Th2 environment of cutaneous T-cell lymphoma.
J Invest Dermatol. 2010; 130(9):2304-11 [PubMed] Related Publications
CC chemokine receptor 3 (CCR3), the sole receptor for eotaxins, is expressed on eosinophils and T helper type 2 (Th2) cells. In Hodgkin's disease, eotaxin-1 secreted by fibroblasts collects Th2 cells and eosinophils within the tissue. Similarly, many Th2 cells infiltrate the lesional skin of cutaneous T-cell lymphoma (CTCL). In this study, we investigated the role of eotaxins in the development of the Th2 environment of CTCL. We revealed that fibroblasts from lesional skin of CTCL expressed higher amounts of eotaxin-3 messenger RNA (mRNA) compared with those from normal skin. Lesional skin of CTCL at advanced stages contained significantly higher levels of eotaxin-3 and CCR3 mRNA, compared with early stages of CTCL. IL-4 mRNA was expressed in some cases at advanced stages. Immunohistochemistry revealed that keratinocytes, endothelial cells, and dermal fibroblasts in lesional skin of CTCL showed a stronger expression of eotaxin-3 than did normal skin. CCR3(+) lymphocytes and IL-4 expression were observed in some cases of advanced CTCL. Furthermore, both serum eotaxin-3 and eotaxin-1 levels of CTCL patients at advanced stages were significantly higher than those of healthy individuals. The concentrations of these chemokines correlated with serum soluble IL-2 receptor levels. These results suggest that interaction of eotaxins and CCR3 regulates the Th2-dominant tumor environment, which is closely related to the development of CTCL.

Yang D, Tong L, Wang D, et al.
Roles of CC chemokine receptors (CCRs) on lipopolysaccharide-induced acute lung injury.
Respir Physiol Neurobiol. 2010; 170(3):253-9 [PubMed] Related Publications
The aim of the present study was to evaluate the effects of the CC chemokine receptor (CCR) 2b and CCR1 antagonist RS504393 as well as the roles of CCRs on lipopolysaccharide (LPS)-induced acute lung injury (ALI). In A549 cell line, treatment with RS504393 significantly inhibited the expression of CCR1, CCR2 and interleukin (IL)-8 after either LPS or tumor necrosis factor-alpha stimulation. An ALI model with intranasal LPS administration was used on C57BL/6J, CCR1, CCR2 and CCR3 knockout mice. Treatment with RS504393 had a noteworthy preventative effect on LPS-induced over-expression of IL-1beta, plasminogen activator inhibitor and CCR2. In CCR1 and CCR2-deficient animals, LPS-induced less increase of lung weight, bronchoalveolar lavage (BAL) leukocytes and IL-6 compared to the C57BL/6J and CCR3 knockout mice. This was most prominent in the CCR2 knockout mice where no LPS-induced lung edema and no increase of IL-6 in BAL fluid occurred. Our results indicate that CCR2, and to some extent CCR1, play pivotal roles in the development of ALI.

Goode EL, Maurer MJ, Sellers TA, et al.
Inherited determinants of ovarian cancer survival.
Clin Cancer Res. 2010; 16(3):995-1007 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Due to variation of outcome among cases, we sought to examine whether overall survival in ovarian cancer was associated with common inherited variants in 227 candidate genes from ovarian cancer-related pathways including angiogenesis, inflammation, detoxification, glycosylation, one-carbon transfer, apoptosis, cell cycle regulation, and cellular senescence.
EXPERIMENTAL DESIGN: Blood samples were obtained from 325 women with invasive epithelial ovarian cancer diagnosed at the Mayo Clinic from 1999 to 2006. During a median follow-up of 3.8 years (range, 0.1-8.6 years), 157 deaths were observed. Germline DNA was analyzed at 1,416 single nucleotide polymorphisms (SNP). For all patients, and for 203 with serous subtype, we assessed the overall significance of each gene and pathway, and estimated risk of death via hazard ratios (HR) and 95% confidence intervals (CI), adjusting for known prognostic factors.
RESULTS: Variation within angiogenesis was most strongly associated with survival time overall (P = 0.03) and among patients with serous cancer (P = 0.05), particularly for EIF2B5 rs4912474 (all patients HR, 0.69; 95% CI, 0.54-0.89; P = 0.004), VEGFC rs17697305 (serous subtype HR, 2.29; 95% CI, 1.34-3.92; P = 0.003), and four SNPs in VHL. Variation within the inflammation pathway was borderline significant (all patients, P = 0.09), and SNPs in CCR3, IL1B, IL18, CCL2, and ALOX5 which correlated with survival time are worthy of follow-up.
CONCLUSION: An extensive multiple-pathway assessment found evidence that inherited differences may play a role in outcome of ovarian cancer patients, particularly in genes within the angiogenesis and inflammation pathways. Our work supports efforts to target such mediators for therapeutic gain.

Jung DW, Che ZM, Kim J, et al.
Tumor-stromal crosstalk in invasion of oral squamous cell carcinoma: a pivotal role of CCL7.
Int J Cancer. 2010; 127(2):332-44 [PubMed] Related Publications
Recent studies have shown that stromal fibroblasts have a more profound influence on the initiation and progression of carcinoma than was previously appreciated. This study aimed at investigating the reciprocal relationship between cancer cells and their associated fibroblasts at both the molecular and cellular level in oral squamous cell carcinoma (OSCC). To identify key molecular regulators expressed by carcinoma-associated fibroblasts (CAF) that promote cancer cell invasion, microarrays were performed by comparing cocultured OSCC cells and CAF with monoculture controls. Microarray and real-time PCR analysis identified marked upregulation of the chemokine (C-C motif) ligand 7 (CCL7) in cocultured CAF. ELISA showed an elevated level of CCL7 secretion from CAF stimulated by coculture with OSCC cells. CCL7 promoted the invasion and migration of OSCC cells, and the invasiveness was inhibited by treatment with CCL7 neutralizing antibody. OSCC cells were shown to express CCR1, CCR2 and CCR3, receptors for CCL7, by RT-PCR. In addition, treatment with anti-CCR1 or anti-CCR3 antibody inhibited CCL7-induced OSCC cell migration, implicating that CCL7 promotes cancer cell migration through CCR1 and CCR3 on OSCC cells. Cytokine antibody array analysis of the supernatant from OSCC cell culture revealed that interleukin-1alpha was an inducer of CCL7 secretion by CAF. This study confirms the reciprocal relationship of the molecular crosstalk regulating the invasion of OSCC and describes new potential targets for future therapy.

Chuang JY, Yang WH, Chen HT, et al.
CCL5/CCR5 axis promotes the motility of human oral cancer cells.
J Cell Physiol. 2009; 220(2):418-26 [PubMed] Related Publications
CCL5 (previously called RANTES) is in the CC-chemokine family and plays a crucial role in the migration and metastasis of human cancer cells. On the other hand, the effect of CCL5 is mediated via CCR receptor. RT-PCR and flow cytometry studies demonstrated CCR5 but not CCR1 and CCR3 mRNA in oral cancer cell lines, especially higher in those with high invasiveness (SCC4) as compared with lower levels in HSC3 cells and SCC9 cells. Stimulation of oral cancer cells with CCL5 directly increased the migration and metalloproteinase-9 (MMP-9) production. MMP-9 small interfering RNA inhibited the CCL5-induced MMP-9 expression and thereby significantly inhibited the CCL5-induced cell migration. Activations of phospholipase C (PLC), protein kinase Cdelta (PKCdelta), and NF-kappaB pathways after CCL5 treatment was demonstrated, and CCL5-induced expression of MMP-9 and migration activity was inhibited by the specific inhibitor of PLC, PKCdelta, and NF-kappaB cascades. In addition, migration-prone sublines demonstrate that cells with increasing migration ability had more expression of MMP-9, CCL5, and CCR5. Taken together, these results indicate that CCL5/CCR5 axis enhanced migration of oral cancer cells through the increase of MMP-9 production.

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