Gene Summary

Gene:CCR1; C-C motif chemokine receptor 1
Aliases: CKR1, CD191, CKR-1, HM145, CMKBR1, MIP1aR, SCYAR1
Summary:This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. 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). Chemokines and their receptors mediated signal transduction are critical for the recruitment of effector immune cells to the site of inflammation. Knockout studies of the mouse homolog suggested the roles of this gene in host protection from inflammatory response, and susceptibility to virus and parasite. This gene and other chemokine receptor genes, including CCR2, CCRL2, CCR3, CCR5 and CCXCR1, are found to form a gene cluster on chromosome 3p. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:C-C chemokine receptor type 1
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 01 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.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: CCR1 (cancer-related)

Liang Q, Tang C, Tang M, et al.
TRIM47 is up-regulated in colorectal cancer, promoting ubiquitination and degradation of SMAD4.
J Exp Clin Cancer Res. 2019; 38(1):159 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tripartite motif 47 (TRIM47), a member of the TRIM family proteins, plays a key role in many types of cancers including colorectal cancer (CRC). We found that levels of TRIM47 mRNA and protein were increased significantly in colorectal tumors compared with nontumor tissues and the increased levels were associated with advanced tumor stage and poor outcome.
METHODS: We used quantitative polymerase chain reaction and western blot to measure levels of TRIM47 mRNA and protein in human colorectal cancer and paired normal tissues. TRIM47 was knocked down and overexpressed in colorectal cancer cells, and the effects on cell proliferation, migration and growth of xenograft tumors in nude mice were assessed. The signaling pathways were examined by western blot and immunoprecipitation assays.
RESULTS: TRIM47 promoted CRC proliferation and metastasis in vitro and in vivo as an oncogene. Mechanistically, TRIM47 interacted physically with SMAD4, increasing its ubiquitination and degradation. Loss of SMAD4 leaded to up-regulation of CCL15 expression and caused growth and invasion in human CRC cells through the CCL15-CCR1 signaling. Moreover, TRIM47 overexpression played a role in CRC chemoresistance in response to 5-FU therapy.
CONCLUSIONS: Our study demonstrated a functional role of the TRIM47-SMAD4-CCL15 axis in CRC progression and suggested a potential target for CRC therapy.

Martínez-Laperche C, Buces E, Aguilera-Morillo MC, et al.
A novel predictive approach for GVHD after allogeneic SCT based on clinical variables and cytokine gene polymorphisms.
Blood Adv. 2018; 2(14):1719-1737 [PubMed] Free Access to Full Article Related Publications
Despite considerable advances in our understanding of the pathophysiology of graft-versus-host disease (GVHD), its prediction remains unresolved and depends mainly on clinical data. The aim of this study is to build a predictive model based on clinical variables and cytokine gene polymorphism for predicting acute GVHD (aGVHD) and chronic GVHD (cGVHD) from the analysis of a large cohort of HLA-identical sibling donor allogeneic stem cell transplant (allo-SCT) patients. A total of 25 SNPs in 12 cytokine genes were evaluated in 509 patients. Data were analyzed using a linear regression model and the least absolute shrinkage and selection operator (LASSO). The statistical model was constructed by randomly selecting 85% of cases (training set), and the predictive ability was confirmed based on the remaining 15% of cases (test set). Models including clinical and genetic variables (CG-M) predicted severe aGVHD significantly better than models including only clinical variables (C-M) or only genetic variables (G-M). For grades 3-4 aGVHD, the correct classification rates (CCR1) were: 100% for CG-M, 88% for G-M, and 50% for C-M. On the other hand, CG-M and G-M predicted extensive cGVHD better than C-M (CCR1: 80% vs. 66.7%, respectively). A risk score was calculated based on LASSO multivariate analyses. It was able to correctly stratify patients who developed grades 3-4 aGVHD (

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:

Liu X, Jin G, Qian J, et al.
Digital gene expression profiling analysis and its application in the identification of genes associated with improved response to neoadjuvant chemotherapy in breast cancer.
World J Surg Oncol. 2018; 16(1):82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study aimed to screen sensitive biomarkers for the efficacy evaluation of neoadjuvant chemotherapy in breast cancer.
METHODS: In this study, Illumina digital gene expression sequencing technology was applied and differentially expressed genes (DEGs) between patients presenting pathological complete response (pCR) and non-pathological complete response (NpCR) were identified. Further, gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed. The genes in significant enriched pathways were finally quantified by quantitative real-time PCR (qRT-PCR) to confirm that they were differentially expressed. Additionally, GSE23988 from Gene Expression Omnibus database was used as the validation dataset to confirm the DEGs.
RESULTS: After removing the low-quality reads, 715 DEGs were finally detected. After mapping to KEGG pathways, 10 DEGs belonging to the ubiquitin proteasome pathway (HECTD3, PSMB10, UBD, UBE2C, and UBE2S) and cytokine-cytokine receptor interactions (CCL2, CCR1, CXCL10, CXCL11, and IL2RG) were selected for further analysis. These 10 genes were finally quantified by qRT-PCR to confirm that they were differentially expressed (the log
CONCLUSION: Our results suggested that these 10 genes belonging to these two pathways might be useful as sensitive biomarkers for the efficacy evaluation of neoadjuvant chemotherapy in breast cancer.

Fujimoto H, Saito Y, Ohuchida K, et al.
Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1
J Immunol. 2018; 200(9):3291-3303 [PubMed] Related Publications
Disturbed balance between immune surveillance and tolerance may lead to poor clinical outcomes in some malignancies. In paired analyses of adenocarcinoma and normal mucosa from 142 patients, we found a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma. The increased frequency of Tregs correlated with the local infiltration and extension of the tumor. There was concurrent maturation arrest, upregulation of programmed death-1 expression, and functional impairment in CD8

Zhu Y, Gao XM, Yang J, et al.
C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma.
Cancer Sci. 2018; 109(3):710-723 [PubMed] Free Access to Full Article Related Publications
In the hepatocellular carcinoma (HCC) microenvironment, chemokine receptors play a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN-induced HCC metastasis remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and that high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion and pulmonary metastasis in HCC. We find that C-C chemokine receptor type 1 (CCR1) and C-X-C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN-promoted migration and invasion. Moreover, OPN upregulates the expression of CCR1 through activating phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor 1α (HIF-1α) in HCC cells. Furthermore, blockade of OPN-CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN-CCR1 axis in HCC is important for accelerating tumor metastasis and that CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.

Luo X, Shi F, Qiu H, et al.
Identification of potential key genes associated with diffuse large B-cell lymphoma based on microarray gene expression profiling.
Neoplasma. 2017; 64(6):824-833 [PubMed] Related Publications
The study aimed to screen potential key genes, and their targeted miRNAs and transcription factors (TFs) that were related to diffuse large B-cell lymphoma (DLBCL), and explore potential therapeutic targets for the progression of DLBCL. Dataset GSE56315 extracted from human tonsils was downloaded from Gene Expression Omnibus. Limma package was used to identify differential expression genes (DEG) between DLBCL and normal human tonsils samples, and the function and pathway enrichment analyses were performed. Then, functional interaction (FI) networks analyses of DEGs were implemented, and modules were extracted. Additionally, DLBCL-related miRNAs were predicted based on miR2disease database. Thereafter, TF-target DEGs and miRNAs targeted genes were respectively obtained. Finally, the integrated network of TF-target-miRNA was constructed. A total of 4,495 DEGs were identified between DLBCL and NHT samples. Among them, 114 up-regulated DEGs were contained in 8 modules of FI network, while 189 down-regulated DEGs were contained in 12 sub-modules. In addition, most DEGs were enriched in the function of "DNA binding" and pathways of "chemokine signaling pathway", "phosphatidylinositol signaling system" and "RNA degradation". Moreover, 19 miRNAs related with DLBCL were downloaded from Mirwalk2. Furthermore, miRNAs of miR-21-5p, miR-155 and miR-17-5p, the TF of STAT1, and DEGs such as NUF2, CCR1, PIK3R1, SMC1A, FOXK1 and CNOT6L had high degrees in the integrated networks of TF-target-miRNA. DEGs like NUF2, CCR1, PIK3R1, SMC1A, FOXK1 and CNOT6L might be closely associated with the pathogenesis of DLBCL.

Vandyke K, Zeissig MN, Hewett DR, et al.
HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1.
Cancer Res. 2017; 77(20):5452-5463 [PubMed] Related Publications
Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2α may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2α upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells

Ho KH, Chen PH, Hsi E, et al.
Identification of IGF-1-enhanced cytokine expressions targeted by miR-181d in glioblastomas via an integrative miRNA/mRNA regulatory network analysis.
Sci Rep. 2017; 7(1):732 [PubMed] Free Access to Full Article Related Publications
The insulin-like growth factor (IGF)-1 signaling is relevant in regulating cell growth and cytokine secretions by glioblastomas. MicroRNAs determine the cell fate in glioblastomas. However, relationships between IGF-1 signaling and miRNAs in glioblastoma pathogenesis are still unclear. Our aim was to validate the IGF-1-mediated mRNA/miRNA regulatory network in glioblastomas. Using in silico analyses of mRNA array and RNA sequencing data from The Cancer Genome Atlas (TCGA), we identified 32 core enrichment genes that were highly associated with IGF-1-promoted cytokine-cytokine receptor interactions. To investigate the IGF-1-downregulated miRNA signature, microarray-based approaches with IGF-1-treated U87-MG cells and array data in TCGA were used. Four miRNAs, including microRNA (miR)-9-5p, miR-9-3p, miR-181d, and miR-130b, exhibited an inverse correlation with IGF-1 levels. The miR-181d, that targeted the most IGF-1-related cytokine genes, was significantly reduced in IGF-1-treated glioma cells. Statistical models incorporating both high-IGF-1 and low-miR-181d statuses better predicted poor patient survival, and can be used as an independent prognostic factor in glioblastomas. The C-C chemokine receptor type 1 (CCR1) and interleukin (IL)-1b demonstrated inverse correlations with miR-181d levels and associations with patient survival. miR-181d significantly attenuated IGF-1-upregulated CCR1 and IL-1b gene expressions. These findings demonstrate a distinct role for IGF-1 signaling in glioma progression via miR-181d/cytokine networks.

Chen R, Lee WY, Zhang XH, et al.
Epigenetic Modification of the CCL5/CCR1/ERK Axis Enhances Glioma Targeting in Dedifferentiation-Reprogrammed BMSCs.
Stem Cell Reports. 2017; 8(3):743-757 [PubMed] Free Access to Full Article Related Publications
The success of stem cell-mediated gene therapy in cancer treatment largely depends on the specific homing ability of stem cells. We have previously demonstrated that after in vitro induction of neuronal differentiation and dedifferentiation, bone marrow stromal cells (BMSCs) revert to a primitive stem cell population (De-neu-BMSCs) distinct from naive BMSCs. We report here that De-neu-BMSCs express significantly higher levels of chemokines, and display enhanced homing abilities to glioma, the effect of which is mediated by the activated CCL5/CCR1/ERK axis. Intriguingly, we find that the activated chemokine axis in De-neu-BMSCs is epigenetically regulated by histone modifications. On the therapeutic front, we show that De-neu-BMSCs elicit stronger homing and glioma-killing effects together with cytosine deaminase/5-fluorocytosine compared with unmanipulated BMSCs in vivo. Altogether, the current study provides an insight into chemokine regulation in BMSCs, which may have more profound effects on BMSC function and their application in regenerative medicine and cancer targeting.

Yamamoto T, Kawada K, Itatani Y, et al.
Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-Associated Neutrophils through CCL15-CCR1 Axis.
Clin Cancer Res. 2017; 23(3):833-844 [PubMed] Related Publications
PURPOSE: We have reported loss of SMAD4 promotes expression of CCL15 from colorectal cancer to recruit CCR1
EXPERIMENTAL DESIGN: In a mouse model, we examined whether SMAD4 could affect the metastatic activity of colorectal cancer cells to the lung through the CCL15-CCR1 axis. We immunohistochemically analyzed expression of SMAD4, CCL15, and CCR1 with 107 clinical specimens of colorectal cancer lung metastases. We also characterized the CCR1
RESULTS: In a mouse model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1
CONCLUSIONS: CCL15-CCR1 axis may be a therapeutic target to prevent colorectal cancer lung metastasis. CCL15 can be a biomarker indicating poor prognosis of colorectal cancer patients with lung metastases. Clin Cancer Res; 23(3); 833-44. ©2016 AACR.

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.

Maiga A, Lemieux S, Pabst C, et al.
Transcriptome analysis of G protein-coupled receptors in distinct genetic subgroups of acute myeloid leukemia: identification of potential disease-specific targets.
Blood Cancer J. 2016; 6(6):e431 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) is associated with poor clinical outcome and the development of more effective therapies is urgently needed. G protein-coupled receptors (GPCRs) represent attractive therapeutic targets, accounting for approximately 30% of all targets of marketed drugs. Using next-generation sequencing, we studied the expression of 772 GPCRs in 148 genetically diverse AML specimens, normal blood and bone marrow cell populations as well as cord blood-derived CD34-positive cells. Among these receptors, 30 are overexpressed and 19 are downregulated in AML samples compared with normal CD34-positive cells. Upregulated GPCRs are enriched in chemokine (CCR1, CXCR4, CCR2, CX3CR1, CCR7 and CCRL2), adhesion (CD97, EMR1, EMR2 and GPR114) and purine (including P2RY2 and P2RY13) receptor subfamilies. The downregulated receptors include adhesion GPCRs, such as LPHN1, GPR125, GPR56, CELSR3 and GPR126, protease-activated receptors (F2R and F2RL1) and the Frizzled family receptors SMO and FZD6. Interestingly, specific deregulation was observed in genetically distinct subgroups of AML, thereby identifying different potential therapeutic targets in these frequent AML subgroups.

Huang M, Li G, Pan T, et al.
A novel multi-target RNAi adenovirus inhibits hepatoma cell proliferation, migration, and induction of angiogenesis.
Oncotarget. 2016; 7(36):57705-57713 [PubMed] Free Access to Full Article Related Publications
The pathogenesis of hepatocellular carcinoma (HCC) is a multi-step process involving many genes. Consequently, single gene targeting therapy has limited efficacy, making combination therapy targeting multiple genes a necessity. Based on our previous findings, we constructed a single vector mediating simultaneous expression of multiple short hairpin RNAs (shRNAs) against human vascular endothelial growth factor receptor 2 (VEGFR2), chemokine C-C motif receptor 1 (CCR1), and epithelial cell adhesion molecule (EpCAM), three genes closely related to HCC progression that act through separate pathways. The shRNA vector efficiently downregulated the mRNA and protein of all three molecules in Huh7 hepatoma cells. The vector also inhibited cell proliferation and migration and reduced angiogenesis. Furthermore, this shRNA vector can be recombined into adenovirus, a gene therapy vector, for better in vivo application. It thus offers a potentially effective future gene therapy approach to treating human liver cancer.

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.

Gao Y, Zhou Z, Lu S, et al.
Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma.
Stem Cells. 2016; 34(4):1112-22 [PubMed] Related Publications
Mesenchymal stem cells (MSCs) possess the ability to migrate toward tumor sites and are regarded as promising gene delivery vehicles for cancer therapeutics. However, the factors that mediate this tropism have yet to be completely elucidated. In this study, through cytokine array analysis, chemokine CCL15 was found to be the most abundant protein differentially expressed in hepatocellular carcinoma (HCC) cell lines compared with a normal liver cell line. Serum CCL15 levels in HCC patients determined by enzyme linked immunosorbent assay were shown to be profoundly elevated compared with healthy controls. Immunohistochemical analysis indicated that CCL15 expression was much stronger in HCC tumor tissues than in adjacent nontumor tissues. Transwell migration assay suggested that CCL15 may be involved in chemotaxis of human MSCs (hMSCs) toward HCC in vitro and that this chemotactic effect of CCL15 is mediated via CCR1 receptors on hMSCs. Orthotopic animal models of HCC were established to investigate the role of CCL15 in hMSCs migration toward HCC in vivo. Both histological and flow cytometric analysis showed that significantly fewer hMSCs localized within 97H-CCL15-shRNA xenografts compared with 97H-green fluorescent protein xenografts after intravenous delivery. Finally, the possible effects of hMSCs on HCC tumor growth were also evaluated. Coculture experiments showed that hMSCs had no apparent effect on the proliferation of HCC cells in vitro In addition, systemic administration of hMSCs did not affect HCC tumor progression in vivo. Our data in this study help to elucidate the mechanism underlying the homing capacity of hMSCs toward HCC.

Li Y, Wu J, Zhang P
CCL15/CCR1 axis is involved in hepatocellular carcinoma cells migration and invasion.
Tumour Biol. 2016; 37(4):4501-7 [PubMed] Related Publications
The identification of new biomarkers for the early detection of hepatocellular carcinoma is critical in the development of tumor-targeted therapy, which is possibly advantageous on the prognosis of this disease. Results from our previous study indicated that CCL15 can be a specific proteomic biomarker of hepatocellular carcinoma, which plays an important role in tumorigenesis and tumor invasion. In this study, we found that CCL15 can induce hepatocellular carcinoma cell migration and invasion. Furthermore, CCR1, the receptor of CCL15, was demonstrated to play a critical role in metastatic hepatocellular carcinoma. CCR1 short hairpin RNA significantly inhibited CCL15-induced chemotaxis and invasion of HepG2 cells. Moreover, CCR1 knockdown significantly limited the activity and expression of matrix metalloproteinase-2 (MMP-2) and MMP-9. These findings suggest that CCR1 plays critical roles in hepatocellular carcinoma metastasis, which indicates that CCR1 may be a potential molecular target in hepatocellular carcinoma therapy.

Akram IG, Georges R, Hielscher T, et al.
The chemokines CCR1 and CCRL2 have a role in colorectal cancer liver metastasis.
Tumour Biol. 2016; 37(2):2461-71 [PubMed] Related Publications
C-C chemokine receptor type 1 (CCR1) and chemokine C-C motif receptor-like 2 (CCRL2) have not yet been sufficiently investigated for their role in colorectal cancer (CRC). Here, we investigated their expression in rat and human CRC samples, their modulation of expression in a rat liver metastasis model, as well as the effects on cellular properties resulting from their knockdown. One rat and five human colorectal cancer cell lines were used. CC531 rat colorectal cells were injected via the portal vein into rats and re-isolated from rat livers after defined periods. Following mRNA isolation, the gene expression was investigated by microarray. In addition, all cell lines were screened for mRNA expression of CCR1 and CCRL2 by reverse transcription polymerase chain reaction (RT-PCR). Cell lines with detectable expression were used for knockdown experiments; and the respective influence was determined on the cells' proliferation, scratch closure, and colony formation. Finally, specimens from the primaries of 50 patients with CRC were monitored by quantitative RT-PCR for CCR1 and CCRL2 expression levels. The microarray studies showed peak increases of CCR1 and CCRL2 in the early phase of liver colonization. Knockdown was sufficient at mRNA but only moderate at protein levels and resulted in modest but significant inhibition of proliferation (p < 0.05), scratch closure, and colony formation (p < 0.05). All human CRC samples were positive for CCR1 and CCRL2 and showed a significant pairwise correlation (p < 0.0004), but there was no correlation with tumor stage or age of patients. In summary, the data point to an important role of CCR1 and CCRL2 under conditions of organ colonization and both chemokine receptors qualify as targets of treatment during early colorectal cancer liver metastasis.

Barbai T, Fejős Z, Puskas LG, et al.
The importance of microenvironment: the role of CCL8 in metastasis formation of melanoma.
Oncotarget. 2015; 6(30):29111-28 [PubMed] Free Access to Full Article Related Publications
We have attempted to characterize the changes occurring on the host side during the progression of human melanoma. To investigate the role of tumor microenvironment, we set up such an animal model, which was able to isolate the host related factors playing central role in metastasis formation. One of these 'factors', CCL12, was consequently selected and its behavior was examined alongside its human homologue (CCL8). In our animal model, metastasis forming primary melanoma in the host exhibited increased level of CCL12 mRNA expression. In clinical samples, when examining the tumor and the host together, the cumulative (tumor and host) CCL8 expression was lower in the group in which human primary melanoma formed lung metastasis compared to non-metastatic primary tumors. We could not detect significant difference in CCL8 receptor (CCR1) expression between the two groups. Increased migration of the examined tumor cell lines was observed when CCL8 was applied as a chemoattractant. The tumor cells and their interactions can be influenced the expression of CCL8 by dermal fibroblasts, as a significant change in the metastatic microenvironment. Furthermore, we examined changes in miRNA profile resulted by CCL8 and miR146a appears to be a promising prognostic marker for following this process.

Wada A, Ito A, Iitsuka H, et al.
Role of chemokine CX3CL1 in progression of multiple myeloma via CX3CR1 in bone microenvironments.
Oncol Rep. 2015; 33(6):2935-9 [PubMed] Related Publications
Several chemokines/chemokine receptors such as CXCL12, CCL3, CXCR4 and CCR1 attract multiple myelomas to specific microenvironments. In the present study, we investigated whether the CX3CL1/CX3CR1 axis is involved in the interaction of the multiple myeloma cells with their microenvironment. The expression of CX3CR1 (also known as fractalkine) was detected in three of the seven human myeloma cell lines. CX3CL1-induced phosphorylation of Akt and ERK1/2 was detected in the CX3CR1-positive cell lines, but not in the CX3CR1-negative cell lines. In addition, CX3CL1-induced cell adhesion to fibronectin and vascular cell adhesion molecule-1 (VCAM-1) in the human myeloma RPMI-8226 cell line. We also investigated whether a relationship existed between myeloma cells and osteoclasts that may function via the CX3CL1/CX3CR1 axis. Conditioned medium from CX3CL1-stimulated RPMI-8226 cells drastically increased the osteoclast differentiation. Collectively, the results from the present study support the concept of the CX3CL1-mediated activation of the progression of the multiple myeloma via CX3CR1. Thus, CX3CR1 may represent a potential therapeutic target for the treatment of multiple myeloma in a bone 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.

Heo SK, Noh EK, Yoon DJ, et al.
Rosmarinic acid potentiates ATRA-induced macrophage differentiation in acute promyelocytic leukemia NB4 cells.
Eur J Pharmacol. 2015; 747:36-44 [PubMed] Related Publications
Rosmarinic acid (RA, an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid) has a number of biological activities, but little is known about anti-leukemic activities of RA combined with all-trans retinoic acid (ATRA) against acute promyelocytic leukemia (APL) cells. We examined the differentiation marker, CD11b, in bone marrow cells (BMC) of an APL patient, in NB4 cells (APL cell line), and in normal BMC and peripheral blood mononuclear cells (PBMC) of healthy subjects by flow cytometric analysis. ATRA/RA induced expression of CD11b in the BMC of the APL patient and in NB4 cells, but not in normal BMC or PBMC. Therefore, we realized that RA potentiated ATRA-induced macrophage differentiation in APL cells. Further characterization of the induced macrophages showed that they exhibited morphological changes and were able to phagocytose and generate reactive oxygen species. Th also had typical expression of C-C chemokine receptor type 1 (CCR1), CCR2, and intercellular adhesion molecule-1 (ICAM-1). Moreover, the expression of CD11b(+) and CD14(+) cells depended on ERK-NF-κB axis activation. Together, these results indicate that RA potentiates ATRA-induced macrophage differentiation in APL cells. Thus, RA may play an important role as an appurtenant differentiation agent for functional macrophage differentiation in APL. Additionally, the differentiated macrophages might have a normal life span and, they could die. These data indicate that co-treatment with RA and ATRA has potential as an anti-leukemic therapy in APL.

Hirai H, Fujishita T, Kurimoto K, et al.
CCR1-mediated accumulation of myeloid cells in the liver microenvironment promoting mouse colon cancer metastasis.
Clin Exp Metastasis. 2014; 31(8):977-89 [PubMed] Free Access to Full Article Related Publications
To understand colon cancer metastasis, we earlier analyzed a mouse model that developed liver metastasis of cancer cells disseminated from the spleen. We suggested that CCR1(+) bone marrow (BM)-derived cells are recruited to the microenvironment of disseminated colon cancer cells, and produce metalloproteinases MMP9 and MMP2, helping metastatic colonization. In the present study, we have examined these myeloid cells expressing CCR1 and/or MMPs in detail. To this end, we have established bacterial artificial chromosome (BAC)-based transgenic mouse lines in which membrane-targeted Venus fluorescent protein (mVenus) was expressed under the control of Ccr1 gene promoter. Then, myeloid cells obtained from the BM and liver metastatic foci were analyzed by the combination of flow cytometry and cytology/immunohistochemistry, in situ RNA hybridization, or quantitative RT-PCR. We have found four distinct types of myeloid cells recruited to the metastatic foci; neutrophils, eosinophils, monocytes and fibrocytes. These cell types exhibited distinct expression patterns for CCR1, MMP2 and MMP9. Namely, neutrophils found in the early phase of cancer cell dissemination expressed CCR1 exclusively and MMP9 preferentially, whereas fibrocytes accumulated in later phase expressed MMP2 exclusively. Either genetic inactivation of Ccr1 or antibody-mediated neutrophil depletion reduced subsequent recruitment of fibrocytes. The recruitment of CCR1(+) neutrophils in early phase of colon cancer dissemination appears to cause that of fibrocytes in late phase. These results implicate the key role of CCR1 in colon cancer metastasis in this mouse model, and explain why both MMP9 and MMP2 are essential as genetically demonstrated previously. The results also suggest relevant mechanisms in humans.

Guerrero AD, Moyes JS, Cooper LJ
The human application of gene therapy to re-program T-cell specificity using chimeric antigen receptors.
Chin J Cancer. 2014; 33(9):421-33 [PubMed] Free Access to Full Article Related Publications
The adoptive transfer of T cells is a promising approach to treat cancers. Primary human T cells can be modified using viral and non-viral vectors to promote the specific targeting of cancer cells via the introduction of exogenous T-cell receptors (TCRs) or chimeric antigen receptors (CARs). This gene transfer displays the potential to increase the specificity and potency of the anticancer response while decreasing the systemic adverse effects that arise from conventional treatments that target both cancerous and healthy cells. This review highlights the generation of clinical-grade T cells expressing CARs for immunotherapy, the use of these cells to target B-cell malignancies and, particularly, the first clinical trials deploying the Sleeping Beauty gene transfer system, which engineers T cells to target CD19+ leukemia and non-Hodgkin's lymphoma.

McCorkle JR, Leonard MK, Kraner SD, et al.
The metastasis suppressor NME1 regulates expression of genes linked to metastasis and patient outcome in melanoma and breast carcinoma.
Cancer Genomics Proteomics. 2014 Jul-Aug; 11(4):175-94 [PubMed] Free Access to Full Article Related Publications
NME1 is a well-documented metastasis suppressor gene, with suppressor activity demonstrated across a wide spectrum of human cancers including melanoma and carcinomas of the breast, stomach and thyroid. A primary aim of the current study was to identify profiles of genes whose expression is regulated by NME1 in cell lines of melanoma and thyroid carcinoma origin. Impact of NME1 was determined by forcing its expression transiently in cell lines using a novel Ad5-based adenoviral vector (Ad5-NME1), followed 48 h later by analysis of RNA expression profiles using the U133A microarray chip. Robust NME1 expression was achieved following infection with the Ad5-NME1 adenovirus in the human metastasis-derived cell lines WM1158 (melanoma) and WRO82 (follicular thyroid carcinoma), resulting in wide-ranging effects on gene expression in both settings. A substantial proportion of the NME1-regulated genes identified in the analyses were of clear potential relevance to metastasis, such as matrix metalloproteinase-1 (MMP1), angiopoietin-2 (ANGPT2), SERPINB9 and colony stimulating factor receptor-2B (CSFR2B). Nine genes were identified (false discovery rate <0.1) that were regulated by NME1 in both the WM1158 and WRO82 cell lines, each possessing one or more such metastasis-relevant activities as stress fiber formation and focal adhesion (PPM1E, ZYX, PFN1), chemotaxis (CCR1) epithelial-mesenchymal signaling (WNT6), differentiation and morphogenesis (TBX4, ZFP36L2), and G protein modulation (GPR52 and PFN1). In addition, a number of the NME1-regulated genes were shown to be of prognostic value for distant disease-free survival and overall survival in melanoma and breast cancer. The combined expression of three NME1-regulated genes CSFR2B, MSF4A1 and SERPINB9 provided a strongly synergistic correlation with distant disease-free survival in the basal subtype of breast cancer (p<3.5e(-5), hazard ratio=0.33). Our study demonstrates that analysis of NME1-dependent gene expression is a powerful approach for identifying potential modulators of metastatic potential in multiple cancer types, which in turn may represent useful therapeutic targets. The study also highlights NME1-dependent genes as potential prognostic/diagnostic indices, which are profoundly lacking at present in melanoma.

Baba T, Naka K, Morishita S, et al.
MIP-1α/CCL3-mediated maintenance of leukemia-initiating cells in the initiation process of chronic myeloid leukemia.
J Exp Med. 2013; 210(12):2661-73 [PubMed] Free Access to Full Article Related Publications
In the initiation process of chronic myeloid leukemia (CML), a small number of transformed leukemia-initiating cells (LICs) coexist with a large number of normal hematopoietic cells, gradually increasing thereafter and eventually predominating in the hematopoietic space. However, the interaction between LICs and normal hematopoietic cells at the early phase has not been clearly delineated because of the lack of a suitable experimental model. In this study, we succeeded in causing a marked leukocytosis resembling CML from restricted foci of LICs in the normal hematopoietic system by direct transplantation of BCR-ABL gene-transduced LICs into the bone marrow (BM) cavity of nonirradiated mice. Herein, we observed that BCR-ABL(+)lineage(-)c-kit(-) immature leukemia cells produced high levels of an inflammatory chemokine, MIP-1α/CCL3, which promoted the development of CML. Conversely, ablation of the CCL3 gene in LICs dramatically inhibited the development of CML and concomitantly reduced recurrence after the cessation of a short-term tyrosine kinase inhibitor treatment. Finally, normal hematopoietic stem/progenitor cells can directly impede the maintenance of LICs in BM in the absence of CCL3 signal.

Itatani Y, Kawada K, Fujishita T, et al.
Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis.
Gastroenterology. 2013; 145(5):1064-1075.e11 [PubMed] Related Publications
BACKGROUND & AIMS: Loss of the tumor suppressor SMAD4 correlates with progression of colorectal cancer (CRC). In mice, colon tumors that express CCL9 recruit CCR1(+) myeloid cells, which facilitate tumor invasion and metastasis by secreting matrix metalloproteinase 9.
METHODS: We used human CRC cell lines to investigate the ability of SMAD4 to regulate expression of CCL15, a human ortholog of mouse CCL9. We used immunohistochemistry to compare levels of CCL15 and other proteins in 141 samples of human liver metastases.
RESULTS: In human CRC cell lines, knockdown of SMAD4 increased CCL15 expression, and overexpression of SMAD4 decreased it. SMAD4 bound directly to the promoter region of the CCL15 gene to negatively regulate its expression; transforming growth factor-β increased binding of SMAD4 to the CCL15 promoter and transcriptional repression. In livers of nude mice, SMAD4-deficient human CRC cells up-regulated CCL15 to recruit CCR1(+) cells and promote metastasis. In human tumor samples, there was a strong inverse correlation between levels of CCL15 and SMAD4; metastases that expressed CCL15 contained 3-fold more CCR1(+) cells than those without CCL15. Patients with CCL15-expressing metastases had significantly shorter times of disease-free survival than those with CCL15-negative metastases. CCR1(+) cells in the metastases expressed the myeloid cell markers CD11b and myeloperoxidase, and also matrix metalloproteinase 9.
CONCLUSIONS: In human CRC cells, loss of SMAD4 leads to up-regulation of CCL15 expression. Human liver metastases that express CCL15 contain higher numbers CCR1(+) cells; patients with these metastases have shorter times of disease-free survival. Reagents designed to block CCL15 recruitment of CCR1(+) cells could prevent metastasis of CRC to liver.

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.

Niesen CE, Xu J, Fan X, et al.
Transcriptomic profiling of human peritumoral neocortex tissues revealed genes possibly involved in tumor-induced epilepsy.
PLoS One. 2013; 8(2):e56077 [PubMed] Free Access to Full Article Related Publications
The molecular mechanism underlying tumor-induced epileptogenesis is poorly understood. Alterations in the peritumoral microenvironment are believed to play a significant role in inducing epileptogenesis. We hypothesize that the change of gene expression in brain peritumoral tissues may contribute to the increased neuronal excitability and epileptogenesis. To identify the genes possibly involved in tumor-induced epilepsy, a genome-wide gene expression profiling was conducted using Affymetrix HG U133 plus 2.0 arrays and RNAs derived from formalin-fixed paraffin embedded (FFPE) peritumoral cortex tissue slides from 5-seizure vs. 5-non-seizure low grade brain tumor patients. We identified many differentially expressed genes (DEGs). Seven dysregulated genes (i.e., C1QB, CALCRL, CCR1, KAL1, SLC1A2, SSTR1 and TYRO3) were validated by qRT-PCR, which showed a high concordance. Principal Component Analysis (PCA) showed that epilepsy subjects were clustered together tightly (except one sample) and were clearly separated from the non-epilepsy subjects. Molecular functional categorization showed that significant portions of the DEGs functioned as receptor activity, molecular binding including enzyme binding and transcription factor binding. Pathway analysis showed these DEGs were mainly enriched in focal adhesion, ECM-receptor interaction, and cell adhesion molecules pathways. In conclusion, our study showed that dysregulation of gene expression in the peritumoral tissues may be one of the major mechanisms of brain tumor induced-epilepsy. However, due to the small sample size of the present study, further validation study is needed. A deeper characterization on the dysregulated genes involved in brain tumor-induced epilepsy may shed some light on the management of epilepsy due to brain tumors.

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