CCR6

Gene Summary

Gene:CCR6; C-C motif chemokine receptor 6
Aliases: BN-1, DCR2, DRY6, CCR-6, CD196, CKRL3, GPR29, CKR-L3, CMKBR6, GPRCY4, STRL22, CC-CKR-6, C-C CKR-6
Location:6q27
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 gene is preferentially expressed by immature dendritic cells and memory T cells. The ligand of this receptor is macrophage inflammatory protein 3 alpha (MIP-3 alpha). This receptor has been shown to be important for B-lineage maturation and antigen-driven B-cell differentiation, and it may regulate the migration and recruitment of dentritic and T cells during inflammatory and immunological responses. Alternatively spliced transcript variants that encode the same protein have been described for this gene. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:C-C chemokine receptor type 6
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
Show (15)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 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.

  • Messenger RNA
  • Receptors, Chemokine
  • Survival Rate
  • Single Nucleotide Polymorphism
  • Immunohistochemistry
  • Up-Regulation
  • Cancer Gene Expression Regulation
  • Enzyme-Linked Immunosorbent Assay
  • Colorectal Cancer
  • Transfection
  • Neoplastic Cell Transformation
  • Liver Cancer
  • CD Antigens
  • Case-Control Studies
  • Mutation
  • Xenograft Models
  • Cell Proliferation
  • Receptors, CCR6
  • Biomarkers, Tumor
  • RTPCR
  • Neoplasm Invasiveness
  • Disease Progression
  • Chemokine CCL20
  • Receptors, CCR7
  • Cutaneous T-cell lymphoma
  • Staging
  • Down-Regulation
  • Immunoenzyme Techniques
  • B-Lymphocytes
  • Chemokines, CC
  • Macrophage Inflammatory Proteins
  • Chromosome 6
  • Cell Movement
  • Neoplasm Metastasis
  • Gene Expression Profiling
  • Lung Cancer
  • MicroRNAs
  • Chemokines
  • Statistics, Nonparametric
  • Taxoids
  • Chemotaxis
  • Cervical Cancer
Tag cloud generated 16 March, 2017 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: CCR6 (cancer-related)

Lu E, Su J, Zhou Y, et al.
CCL20/CCR6 promotes cell proliferation and metastasis in laryngeal cancer by activating p38 pathway.
Biomed Pharmacother. 2017; 85:486-492 [PubMed] Related Publications
Chemokine and its receptors play important roles in laryngeal cancer development and progression. CCR6 is the receptor of CCL20 chemokine, but its function in laryngeal cancer is not known. The aim of this study is to explore the roles of CCR6 and its regulation mechanism in laryngeal cancer. We found CCR6 expression was higher in laryngeal cancer tissues compared with their normal controls, so did in laryngeal cancer cells. Cellular function indicated that down-regulation of CCR6 in laryngeal cancer cells could suppress cell proliferation and metastasis. Further research showed that CCR6 could activate p38, which was related with the changes of microRNA (miRNA) profile in laryngeal cancer cells. We also found that CCR6 was positively associated with miR-20a-5p, miR-489 and negatively related to miR-29-3p, miR-632 and miR-1276 in laryngeal cancer tissues.

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.

Kawaguchi K, Suzuki E, Yamaguchi A, et al.
Altered expression of major immune regulatory molecules in peripheral blood immune cells associated with breast cancer.
Breast Cancer. 2017; 24(1):111-120 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The purpose of this study was to clarify the alterations of major immune regulators in peripheral blood mononuclear cells (PBMCs) of cancer patients and to analyze the association with the disease progression in breast cancer patients.
METHODS: The study included 6 healthy volunteers (HVs), 12 primary breast cancer (PBC) patients, and 30 metastatic breast cancer (MBC) patients. The expression of immune regulators such as, CCR6, CD4, CD8, CD14, CD40, CD56, CD80, CTLA4, CXCR4, FOXP3, IDO-1, IDO-2, NKG2D, NRP-1, PD-1, and PD-L1 mRNA in PBMCs was measured by quantitative RT-PCR. Analysis of variance with contrasts was performed to find expression patterns of the three groups (HVs, PBC, MBC).
RESULTS: We clarified the alterations of mRNA of major immune regulators PD-L1, FOXP3, CD80, CD40, and CD14 in PBMCs of cancer patients and the association of these alternations with disease progression. Furthermore, PD-L1 expression was correlated with serum interferon-γ production.
CONCLUSION: Our data suggested that mRNA expressions of PD-L1, FOXP3, CD80, CD40 and CD14 in PBMCs are affected by disease progression. Understanding the roles of these various interactions will be of importance to future studies aiming to uncover biomarkers for predicting response to immune therapy.

Bock S, Murgueitio MS, Wolber G, Weindl G
Acute myeloid leukaemia-derived Langerhans-like cells enhance Th1 polarization upon TLR2 engagement.
Pharmacol Res. 2016; 105:44-53 [PubMed] Related Publications
Langerhans cells (LCs) represent a highly specialized subset of epidermal dendritic cells (DCs), yet not fully understood in their function of balancing skin immunity. Here, we investigated in vitro generated Langerhans-like cells obtained from the human acute myeloid leukaemia cell line MUTZ-3 (MUTZ-LCs) to study TLR- and cytokine-dependent activation of epidermal DCs. MUTZ-LCs revealed high TLR2 expression and responded robustly to TLR2 engagement, confirmed by increased CD83, CD86, PD-L1 and IDO expression, upregulated IL-6, IL-12p40 and IL-23p19 mRNA levels IL-8 release. TLR2 activation reduced CCR6 and elevated CCR7 mRNA expression and induced migration of MUTZ-LCs towards CCL21. Similar results were obtained by stimulation with pro-inflammatory cytokines TNF-α and IL-1β whereas ligands of TLR3 and TLR4 failed to induce a fully mature phenotype. Despite limited cytokine gene expression and production for TLR2-activated MUTZ-LCs, co-culture with naive CD4(+) T cells led to significantly increased IFN-γ and IL-22 levels indicating Th1 differentiation independent of IL-12. TLR2-mediated effects were blocked by the putative TLR2/1 antagonist CU-CPT22, however, no selectivity for either TLR2/1 or TLR2/6 was observed. Computer-aided docking studies confirmed non-selective binding of the TLR2 antagonist. Taken together, our results indicate a critical role for TLR2 signalling in MUTZ-LCs considering the leukemic origin of the generated Langerhans-like cells.

Marmary Y, Adar R, Gaska S, et al.
Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation.
Cancer Res. 2016; 76(5):1170-80 [PubMed] Related Publications
Head and neck cancer patients treated by radiation commonly suffer from a devastating side effect known as dry-mouth syndrome, which results from the irreversible loss of salivary gland function via mechanisms that are not completely understood. In this study, we used a mouse model of radiation-induced salivary hypofunction to investigate the outcomes of DNA damage in the head and neck region. We demonstrate that the loss of salivary function was closely accompanied by cellular senescence, as evidenced by a persistent DNA damage response (γH2AX and 53BP1) and the expression of senescence-associated markers (SA-βgal, p19ARF, and DcR2) and secretory phenotype (SASP) factors (PAI-1 and IL6). Notably, profound apoptosis or necrosis was not observed in irradiated regions. Signs of cellular senescence were also apparent in irradiated salivary glands surgically resected from human patients who underwent radiotherapy. Importantly, using IL6 knockout mice, we found that sustained expression of IL6 in the salivary gland long after initiation of radiation-induced DNA damage was required for both senescence and hypofunction. Additionally, we demonstrate that IL6 pretreatment prevented both senescence and salivary gland hypofunction via a mechanism involving enhanced DNA damage repair. Collectively, these results indicate that cellular senescence is a fundamental mechanism driving radiation-induced damage in the salivary gland and suggest that IL6 pretreatment may represent a promising therapeutic strategy to preserve salivary gland function in head and neck cancer patients undergoing radiotherapy.

Ouyang W, Zhang S, Yang B, et al.
β-catenin is regulated by USP9x and mediates resistance to TRAIL-induced apoptosis in breast cancer.
Oncol Rep. 2016; 35(2):717-24 [PubMed] Related Publications
To investigate the regulatory mechanisms of decoy receptor expression in TRAIL-resistant breast cancer MCF-7 cells, cytotoxicity and apoptosis assays were applied to examine sensitivity to TRAIL in breast cancer cells. Immunofluorescence and immunoprecipitation were used to detect the co-localization and interaction of USP9x and β-catenin. Luciferase assay was used to examine activity of the DcR1/DcR2/OPG reporter. Overexpression/silencing of β-catenin was performed to confirm β-catenin mediated transcription of the decoy receptors. Additionally, silencing of USP9x was performed to prove that USP9X stabilizes β-catenin and mediates TRAIL-resistance. It was found that USP9x interacted with β-catenin and inhibited the degradation of β-catenin through the deubiquitination of β-catenin. Luciferase reporter assays showed induction of DcR1/DcR2/OPG reporter activity observed upon co-transfection of β-catenin and Tcf-4. The overexpression/silencing of β-catenin further confirmed the role of β-catenin in the regulation of transcription of the decoy receptors. Silencing of USP9x directly evidenced that USP9x affected the protein expression level of β-catenin, the transcription level of the decoy receptors, and reversed TRAIL-resistance of MCF-7 cells. In conclusion, USP9x interacted with and stabilized β-catenin through deubiquitination to mediate transcription of the decoy receptors in breast cancer cells. Our results offer new insights into the mechanisms of resistance to TRAIL, and USP9x could potentially be a therapeutic target for TRAIL-resistant breast cancers.

Coperchini F, Pignatti P, Carbone A, et al.
TNF-α increases the membrane expression of the chemokine receptor CCR6 in thyroid tumor cells, but not in normal thyrocytes: potential role in the metastatic spread of thyroid cancer.
Tumour Biol. 2016; 37(4):5569-75 [PubMed] Related Publications
The chemokine receptor CCR6, selectively bound by CCL20, is involved in the metastatic spread of cancer cells. Tumor necrosis factor-α (TNF-α) displays a complex pro-tumorigenic actions, but it is unknown whether this cytokine could modulate the expression of chemokine receptors in thyroid tumors. The membrane expression of CCR6 was assessed by flow cytometry and immunofluorescence, in primary cultures of normal human thyroid (NHT) cells and in thyroid cancer cell lines (TPC-1 and BCPAP), both in basal conditions and after stimulation with TNF-α. In basal conditions, CCR6+ cells were virtually absent in NHT cells (0.4 ± 0.4 %), while they were detected in TPC-1 (23.6 ± 6.6 %) and in BCPAP (12.9 ± 9.4 %) tumor cells (ANOVA F: 10.534; p < 0.005). The incubation with TNF-α significantly increased the percentage of CCR6+ cells in TPC-1 (23.6 ± 6.6 % vs. 33.1 ± 8.7; p < 0.033) and in BCPAP (12.9 ± 9.4 % vs. 18.1 ± 11.5; p < 0.030), but not in NHT (0.4 ± 0.4 % vs. 0.2 ± 0.3; NS) cells. The magnitude of the TNF-α effect was similar for TPC-1 and BCPAP (∼40 % vs. baseline) cells. TPC-1 cells were characterized by a greater amount of CCR6 per cell as compared with BCPAP cells, both in basal conditions (148.3 ± 33.7 fluorescence intensity vs. 102.5 ± 22.1 p < 0.016) and after TNF-α stimulation (147.8 ± 46.3 fluorescence intensity vs. 95.3 ± 18.5; p < 0.025). Cell migration assays showed that TNF-α treatment significantly increased the rate of migrated cells in those cells in which it also increased the membrane expression of CCR6 (TPC-1 and BCPAP) as compared to basal condition (p < 0.05 for both TPC-1 and BCPAP cells). No effect was observed in NHT cells in which TNF-α stimulation had no effect in terms of CCR6 expression. We first report that TNF-α enhances the expression of CCR6 in thyroid tumor cells, thus providing evidence that TNF-α increases the metastatic potential of thyroid tumors.

Song B, Ma Y, Liu X, et al.
IL-22 promotes the proliferation of cancer cells in smoking colorectal cancer patients.
Tumour Biol. 2016; 37(1):1349-56 [PubMed] Related Publications
Chronic cigarette smoking increases the risk of developing colorectal cancer (CRC) and causes higher mortality of CRC patients. To improve our understanding of the underlying mechanism and devise treatment strategies specifically targeted at chronic smoking CRC patients, we examined the immune system of healthy and CRC patients who are complete nonsmokers or chronic primary smokers. We found that the serum concentrations of CRC nonsmokers and CRC smokers were skewed toward Th17-type cytokines, including interleukin (IL)-17 and IL-22. Notably, smoking CRC subjects had significantly higher levels of IL-22 than nonsmoking CRC patients. We also observed higher percentages of CCR4(+)CCR6(+) Th17 cells in circulating blood and higher secretion of IL-17 and IL-22 by peripheral blood mononuclear cells (PBMCs) of nonsmoking CRC and smoking CRC patients, compared to healthy individuals. Again, we observed elevated IL-17 and IL-22 secretion by CRC smokers than nonsmokers. Since IL-22 has been shown to stimulate tumorigenesis, which was also replicated in our experiments using cancer cell line model, we tested whether CRC patients' cell culture supernatant could also support tumor growth using this model. We found that both HT29 cells and LoVo cells had the highest proliferation in the supernatant from smoking CRC patients. Moreover, the proliferation of LoVo cells in smoking CRC supernatant was significantly higher than that in nonsmoking CRC supernatant. In addition, we found that the IL-22 concentration in normal gut tissue of the smoking CRC patients was significantly increased compared to that in nonsmoking CRC subjects, while no significant differences were observed in tumor tissues. Our results suggest that chronic smokers may have higher risk for CRC and worse prognosis due to dysregulated IL-22 production.

Liu JY, Li F, Wang LP, et al.
CTL- vs Treg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma.
Br J Cancer. 2015; 113(5):747-55 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumoural infiltration of T lymphocytes is determined by local patterns of specific chemokine expression. In this report, we examined the roles of CCL4 and CCL20 in the accumulation of CD8(+) cytotoxic T lymphocytes (CTLs) and regulatory T (Treg) lymphocytes in oesophageal squamous cell carcinoma (ESCC), and determined the correlations between chemokine expressions and ESCC patients' survival.
METHODS: Reverse transcriptase-PCR and immunohistochemistry (IHC) staining were performed to examine the expressions of interested genes. Flow cytometry was adopted to check the expressions of CCL4- and CCL6-specific receptors, CCR5 and CCR6, on CTLs and Treg cells. In addition, transwell assay was carried on.
RESULTS: The CCL4 expression was significantly correlated with the expression of CTL markers (CD8 and Granzyme B), whereas CCL20 was positively correlated with Treg markers (FoxP3 and IL-10). Consistently, CCR5 was found to be mainly expressed on CD8(+) T lymphocytes, while CCR6 showed prevalence on Treg lymphocytes and the frequencies of CCR5(+)CD8(+) CTLs and CCR6(+) Treg cells were higher in TIL compared with PBMC. Respectively, CCL4 and CCL20 recruited CD8(+) and regulatory T cells in vitro. Importantly, high levels of CCL4 in the lesions of ESCC patients predicted prolonged survival. Furthermore, CCL4(high)/CCL20(low) group demonstrated better overall survival, whereas CCL4(low)/CCL20(low) and CCL4(low)/CCL20(high) groups showed the worst overall survival.
CONCLUSIONS: Our data showed that CCL4 and CCL20 recruit functionally different T lymphocyte subsets into oesophageal carcinoma, indicating CCL4 and CCL20 are potential predictors of ESCC patients' survival.

Zhang J, Zhu D, Lv Q, et al.
The key role of astrocyte elevated gene-1 in CCR6-induced EMT in cervical cancer.
Tumour Biol. 2015; 36(12):9763-7 [PubMed] Related Publications
In recent years, astrocyte elevated gene-1 (AEG-1) has been recommended as an important mediator that is involved in the epithelial-to-mesenchymal transition (EMT) process. However, the mechanisms underlying the chemokine (C-C motif) ligand 20 (CCL20)/chemokine (C-C motif) receptor 6 (CCR6)-AEG-1 pathway-mediated EMT in cervical cancer (CC) have not been well featured till now. We used immunohistochemistry and immunoblotting to assess the expression of AEG-1 in 94 cervical cancer tissues and cells. Subsequently, cervical cancer SiHa cells were treated with si-AEG-1 and then subjected to in vitro assays. We observed that AEG-1 proteins were highly expressed in cervical cancer tissues and closely correlated with International Federation of Gynecology and Obstetrics (FIGO) stage and metastasis. Importantly, we validated the expression of AEG-1, p-Erk1/2, p-Akt, vimentin, N-cadherin, and matrix metalloproteinase 2 (MMP2) increased in SiHa with CCL20 treatment in a concentration-dependent manner. When cells were treated with si-AEG-1, the expression of p-Erk1/2, p-Akt, vimentin, N-cadherin, and MMP2 was also downregulated. Using the cell cycle assay, the knockdown of AEG-1 inhibited the entry of G1 into S phase. In conclusion, AEG-1 mediates CCL20/CCR6-induced EMT development via both Erk1/2 and Akt signaling pathway in cervical cancer, which indicates that CCL20/CCR6-AEG-1-EMT pathway could be suggested as a useful target to affect the progression of cervical cancer.

Han G, Wu D, Yang Y, et al.
CrkL meditates CCL20/CCR6-induced EMT in gastric cancer.
Cytokine. 2015; 76(2):163-9 [PubMed] Related Publications
BACKGROUND: In recent years, Crk-like adapter protein (CrkL) has been identified as a key regulator in the epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms underlying the CC chemokine receptor 6 (CCR6) and chemokine (C-C motif) ligand 20 (CCL20)-induced EMT in gastric cancer are still unclear.
METHODS: We conducted the immunohistochemistry and immunoblotting to detect the expression of CCR6 and CrkL in 90 cases of gastric cancer tissues and five kinds of cell lines. And then, gastric cancer cells were subjected to small interfering RNA (siRNA) treatment and in vitro assay.
RESULTS: Both CCR6 and CrkL were aberrantly expressed in gastric cancer specimens and closely correlated with differentiation of cell lines. The expression of CCR6 and CrkL was also significantly associated with metastasis, stage, and poor prognosis of gastric cancer. In addition, we validated CCL20 activated the expression of p-CrkL, p-Erk1/2, p-Akt, vimentin, N-cadherin and MMP2 in MGC803 cells in a dose-dependent manner. However, si-CrkL abrogated the CCL20-induced p-Erk1/2, vimentin, N-cadherin and MMP2 expression. Most importantly, the knockdown of CrkL decreased migration and invasion of MGC803 cells.
CONCLUSIONS: CrkL mediates CCL20/CCR6-induced EMT via Akt pathway, instead of Erk1/2 pathway in development of gastric cancer, which indicated CCL20/CCR6-CrkL-Erk1/2-EMT pathway may be targeted to antagonize the progression of gastric cancer.

Wang GZ, Cheng X, Li XC, et al.
Tobacco smoke induces production of chemokine CCL20 to promote lung cancer.
Cancer Lett. 2015; 363(1):60-70 [PubMed] Related Publications
Tobacco kills nearly 6 million people each year, and 90% of the annual 1.59 million lung cancer deaths worldwide are caused by cigarette smoke. Clinically, a long latency is required for individuals to develop lung cancer since they were first exposed to smoking. In this study, we aimed to identify clinical relevant inflammatory factors that are critical for carcinogenesis by treating normal human lung epithelial cells with tobacco carcinogen nicotine-derived nitrosaminoketone (NNK) for a long period (60 days) and systematic screening in 84 cytokines/chemokines. We found that a chemokine CCL20 was significantly up-regulated by NNK, and in 78/173 (45.1%) patients the expression of CCL20 was higher in tumor samples than their adjacent normal lung tissues. Interestingly, CCL20 was up-regulated in 48/92 (52.2%) smoker and 29/78 (37.2%) nonsmoker patients (p = 0.05), and high CCL20 was associated with poor prognosis. NNK induced the production of CCL20, which promoted lung cancer cell proliferation and migration. In addition, an anti-inflammation drug, dexamethasone, inhibited NNK-induced CCL20 production and suppressed lung cancer in vitro and in vivo. These results indicate that CCL20 is crucial for tobacco smoke-caused lung cancer, and anti-CCL20 could be a rational approach to fight against this deadly disease.

Hu Y, Wang C, Li Y, et al.
MiR-21 controls in situ expansion of CCR6⁺ regulatory T cells through PTEN/AKT pathway in breast cancer.
Immunol Cell Biol. 2015; 93(8):753-64 [PubMed] Related Publications
Our recent evidence showed that prior expansion of CCR6(+) Foxp3(+) regulatory T cells (Tregs) was important for their dominant enrichment in tumor tissue, which was closely related to poor prognosis of breast cancer patients. However, the underlying regulation mechanism of expansion of CCR6(+) Tregs in situ remains largely unknown. In this study, we reported that miR-21 was highly expressed in CCR6(+) Tregs in tumor tissues from a murine breast cancer model. And silencing of miR-21 could significantly reduce the proliferation of CCR6(+) Tregs in vitro. Adoptive cell-transfer assay further showed that silencing of miR-21 could alter the enrichment of CCR6(+) Tregs in the tumor mass and endow effectively antitumor effect of CD8(+) T cells using a murine breast cancer model. Mechanistic evidence showed that silencing of miR-21 enhanced the expression of its target phosphatase and tensin homolog deleted on chromosome ten (PTEN) and subsequently altered the activation of Akt pathway, which was ultimately responsible for reduced proliferation activity of CCR6(+) Tregs. Finally, we further revealed that miR-21 was also highly expressed on CCR6(+) Tregs in clinical breast cancer patients. Therefore, miR-21 can act as a fine tuner in the regulation of PTEN/Akt pathway transduction in the expansion of CCR6(+) Tregs in tumor sites and provided a novel insight into the development of therapeutic strategies for promoting T-cell immunity by regulating distinct subset of Tregs through targeting specific miRNAs.

Woo JK, Kang JH, Jang YS, et al.
Evaluation of preventive and therapeutic activity of novel non-steroidal anti-inflammatory drug, CG100649, in colon cancer: Increased expression of TNF-related apoptosis-inducing ligand receptors enhance the apoptotic response to combination treatment with TRAIL.
Oncol Rep. 2015; 33(4):1947-55 [PubMed] Related Publications
Non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested as the potential new class of preventive or therapeutic antitumor agents. The aim of the present study was to evaluate the antitumor activity of the novel NSAID, CG100649. CG100649 is a novel NSAID dual inhibitor for COX-2 and carbonic anhydrase (CA)-I/-II. In the present study, we investigated the alternative mechanism by which CG100649 mediated suppression of the colon cancer growth and development. The anchorage‑dependent and -independent clonogenic assay showed that CG100649 inhibited the clonogenicity of human colon cancer cells. The flow cytometric analysis showed that CG100649 induced the G2/M cell cycle arrest in colon cancer cells. Animal studies showed that CG100649 inhibited the tumor growth in colon cancer xenograft in nude mice. Furthermore, quantitative PCR and FACS analysis demonstrated that CG100649 upregulated the expression of TNF-related apoptosis-inducing ligand (TRAIL) receptors (DR4 and DR5) but decreased the expression of decoy receptors (DcR1 and DcR2) in colon cancer cells. The results showed that CG100649 treatment sensitized TRAIL‑mediated growth suppression and apoptotic cell death. The combination treatment resulted in significant repression of the intestinal polyp formation in APCmin/+ mice. Our data clearly demonstrated that CG100649 contains preventive and therapeutic activity for colon cancer. The present study may be useful for identification of the potential benefit of the NSAID CG100649, for the achievement of a better treatment response in colon cancer.

Zhang CY, Qi Y, Li XN, et al.
The role of CCL20/CCR6 axis in recruiting Treg cells to tumor sites of NSCLC patients.
Biomed Pharmacother. 2015; 69:242-8 [PubMed] Related Publications
Inflammatory chemokine CCL20 and its receptor CCR6 have been reported to correlate with colorectal cancer patients' metastasis. However, the role of CCL20 in patients with NSCLC is not well defined. In this study, we detected the expression of CCL20 in tumor samples and corresponding adjacent ones (n=71) from patients with NSCLC using RT-PCR and observed that CCL20 showed higher expression in tumor samples (0.28±0.17) than in adjacent ones (0.20±0.13) (n=71, P=0.0056), which was also verified in protein level using IHC. Analysis results showed that CCL20 expression was positively associated with CD4 (n=80, P=0.0046), Foxp3 (n=80, P=0.0020) and IL-10 (n=61, P=0.0003) in tumor samples. And the flow data showed that Treg cells accumulated in TIL (MFI: 961±760) compared with PBMC (MFI: 683±460) (n=40, P=0.0046); and the percentage of CCR6 - the sole receptor of CCL20 - on Treg cells was higher in TIL (MFI: 1311±1268) than in PBMC (MFI: 976±780) (n=40, P=0.0219). It was interesting to find that the expression of CCL20 in tumor sites was almost 1.5-fold higher in samples from high-stage patients (III-IV stage, 0.34±0.17) compared with those from low-stage patients (I-II stage, 0.22±0.11) (P=0.0056). Furthermore, the higher expression of CCL20 was associated with a lower overall survival (P=0.0198). The IHC data showed that tumor cells were the main source of CCL20, and after treated cell line A549 with docetaxel, we found that the secretion of CCL20 was decreased heavily (n=3, P=0.0046). Our results demonstrated that CCL20 cooperated with CCR6 could recruit Treg cells to tumor sites, and chemotherapy medicine docetaxel could decrease the expression of CCL20.

Verim A, Turan S, Farooqi AA, et al.
Association between laryngeal squamous cell carcinoma and polymorphisms in tumor necrosis factor related apoptosis induce ligand (TRAIL), TRAIL receptor and sTRAIL levels.
Asian Pac J Cancer Prev. 2014; 15(24):10697-703 [PubMed] Related Publications
The laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors occurring in the head and neck. Tumor necrosis factor related apoptosis induce ligand (TRAIL) and TRAIL-receptors (DR4, DR5, DcR1, DcR2) are known as important members of TRAIL-mediated biochemical signaling pathway. Associations between polymorphisms in these genes and clinicopathological characteristics of human laryngeal carcinoma are not well defined. This study therefore aimed to investigate a possible relationship among the TRAIL and TRAIL-DR4 polymorphisms and sTRAIL levels in the risk or progression of LSCC. A total of 99 patients with laryngeal cancer and 120 healthy subjects were enrolled in the study. DR4 C626G and TRAIL 1595 C/T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and sTRAIL levels were measured by ELISA. There were significant differences in the distribution of DR4 C626G genotypes and frequencies of the alleles between laryngeal cancer patients and controls (p<0.001) but not in TRAIL 1595 C/T. We found the increased frequency of the DR4 C626G homozygote CC genotype in patients than in controls (p<0.001). Haplotype analysis revealed that there was also a statistically significant relationship between TRAIL and TRAIL-DR4 polymorphisms and laryngeal cancer. Serum sTRAIL levels in the laryngeal patients with CC genotype who had advanced tumour stage were lower than those of patients with early tumor stage (p=0.014). Our findings suggest that DR4 C626G genotypes and sTRAIL levels might be associated with progression of laryngeal cancer in the Turkish population.

Meng F, Li W, Li C, et al.
CCL18 promotes epithelial-mesenchymal transition, invasion and migration of pancreatic cancer cells in pancreatic ductal adenocarcinoma.
Int J Oncol. 2015; 46(3):1109-20 [PubMed] Related Publications
CCL18 is a chemokine that is primarily expressed in monocytes, macrophages and immature dendritic cells and plays a crucial role in immune and inflammation responses. Recently, CCL18 was found to play pivotal roles in the development of several kinds of cancers, but its expression status and role during the tumorigenesis of pancreatic cancer remain unknown. In this study, we performed immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) to evaluate the expression of CCL18 in human pancreatic ductal adenocarcinoma (PDAC) tissues and preoperative serum, respectively. The results showed that both cancer epithelial cells and mesenchymal macrophages in PDAC tissues positively expressed CCL18. Serum CCL18 levels were significantly higher in patients with PDAC in comparison to healthy controls. The expression of CCL18 in both cancer epithelial cells and mesenchymal cells was correlated with lymph node metastasis, histopathological grading and overall survival in 62 PDAC patients. In vitro assays showed that the gene and protein expression of CCL18 from U937 and THP-1 cell- derived macrophages were significantly higher than that from unstimulated U937 cells and THP-1 cells. In contrast, pancreatic cancer cell lines showed little to no CCL18 expression even after IL4 stimulation. Intriguingly, pancreatic cancer cell lines expressed the potential CCL18 receptors PITPNM3, CCR6 and GPR3. Furthermore, treatment with recombinant human CCL18 promoted the migration and invasion of pancreatic cancer cells, but had no effect on cell proliferation. Consistent with these results, CCL18 induced the expression of the epithelial-mesenchymal transition (EMT) related gene SNAIL1. Our findings suggest that the serum level of CCL18 is a potential biomarker for the diagnosis and prognosis of PDAC, and that the combined functions of CCL18 in mesenchymal and cancer cells might accelerate the progression of PDAC by promoting the epithelial-mesenchymal transition, invasion and migration of pancreatic cancer cells.

Yu R, Albarenque SM, Cool RH, et al.
DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer.
Cancer Biol Ther. 2014; 15(12):1658-66 [PubMed] Free Access to Full Article Related Publications
Current treatment modalities for pancreatic carcinoma afford only modest survival benefits. TRAIL, as a potent and specific inducer of apoptosis in cancer cells, would be a promising new treatment option. However, since not all pancreatic cancer cells respond to TRAIL, further improvements and optimizations are still needed. One strategy to improve the effectiveness of TRAIL-based therapies is to specifically target one of the 2 cell death inducing TRAIL-receptors, TRAIL-R1 or TRAIL-R2 to overcome resistance. To this end, we designed constructs expressing soluble TRAIL (sTRAIL) variants that were rendered specific for either TRAIL-R1 or TRAIL-R2 by amino acid changes in the TRAIL ectodomain. When we expressed these constructs, including wild-type sTRAIL (sTRAIL(wt)), TRAIL-R1 (sTRAIL(DR4)) and TRAIL-R2 (sTRAIL(DR5)) specific variants, in 293 producer cells we found all to be readily expressed and secreted into the supernatant. These supernatants were subsequently transferred onto target cancer cells and apoptosis measured. We found that the TRAIL-R1 specific variant had higher apoptosis-inducing activity in human pancreatic carcinoma Colo357 cells as well as PancTu1 cells that were additionally sensitized by targeting of XIAP. Finally, we tested TRAIL-R1 specific recombinant TRAIL protein (rTRAIL(DR4)) on Colo357 xenografts in nude mice and found them to be more efficacious than rTRAIL(wt). Our results demonstrate the benefits of synthetic biological approaches and show that TRAIL-R1 specific variants can potentially enhance the therapeutic efficacy of TRAIL-based therapies in pancreatic cancer, suggesting that they can possibly become part of individualized and tumor specific combination treatments in the future.

Anees M, Horak P, Schiefer AI, et al.
The potential evasion of immune surveillance in mucosa associated lymphoid tissue lymphoma by DcR2-mediated up-regulation of nuclear factor-κB.
Leuk Lymphoma. 2015; 56(5):1440-9 [PubMed] Related Publications
This study investigated expression profiles of tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) pathway components and mechanisms underlying TRAIL-induced apoptosis in mucosa associated lymphoid tissue (MALT) lymphoma. Genetic aberrations including translocations and trisomies were assessed by reverse transcription polymerase chain reaction and fluorescence in situ hybridization. Expression of TRAIL, death receptors 4 and 5, decoy receptors 1 and 2, and FADD-like interleukin-1β-converting enzyme (FLICE) inhibitory protein was analyzed by immunohistochemistry. All 32 patients under study showed some alterations in TRAIL pathway mainly involving loss of death receptors (37.5%), gain of decoy receptors (3.1%) or both (59.4%). Decoy receptor 2 (DcR2) was highly expressed in patients with normal cytogenetic status as compared to those with cytogenetic aberrations (p = 0.005). Moreover, DcR2 expression correlated significantly with nuclear factor-κB (NF-κB) expression (R = 0.372, p = 0.047). High expression of DcR2 in patients with normal cytogenetic status and its significant correlation with NF-κB expression provides a potential clue to evasion of immune surveillance in cytogenetically normal MALT lymphomas.

Zeng W, Chang H, Ma M, Li Y
CCL20/CCR6 promotes the invasion and migration of thyroid cancer cells via NF-kappa B signaling-induced MMP-3 production.
Exp Mol Pathol. 2014; 97(1):184-90 [PubMed] Related Publications
CCL20, an important member of the CC-chemokine family, is the only ligand that activates CCR6. The levels of CCL20 and CCR6 are elevated in many human cancers, and CCL20/CCR6 interaction participates in the development and progression of cancer. In this present study, we found that CCR6 was overexpressed in thyroid cancer cells. Activation of CCR6 by CCL20 promoted the invasion and migration of human thyroid cancer SW1736 cells, while knockdown of CCR6 repressed the effect of CCL20. Furthermore, CCL20/CCR6 interaction induced the activation of NF-κB, and stimulated the expression and secretion of MMP-3. In addition, BAY117082, a special inhibitor of NF-κB, suppressed the expression and secretion of MMP-3 stimulated by CCL20/CCR6. Together, these results suggest that CCL20/CCR6 enhances thyroid cancer cell invasion and migration. The possible molecular mechanisms involved NF-κB activation and NF-κB-dependent MMP-3 upregulation. Thus, molecular therapies that aim at CCL20 and CCR6 may offer promising intervention strategies for thyroid cancer.

Liu J, Ke F, Xu Z, et al.
CCR6 is a prognostic marker for overall survival in patients with colorectal cancer, and its overexpression enhances metastasis in vivo.
PLoS One. 2014; 9(6):e101137 [PubMed] Free Access to Full Article Related Publications
The chemokine receptor CCR6 has been recently shown to be associated with colorectal cancer (CRC) progression. However, the direct evidence for whether CCR6 in tumors is a prognostic marker for the survival of patients with CRC and whether it plays a critical role in CRC metastasis in vivo is lacking. Here we show that the levels of CCR6 were upregulated in CRC cell lines and primary CRC clinical samples. CCR6 upregulation was closely correlated with disease stages and the survival time of CRC patients. Knockdown of CCR6 inhibited the migration of CRC cells in vitro. Overexpression of CCR6 in CRC cells increased their proliferation, migration, and colony formation in vitro and promoted their metastatic potential in vivo. CCR6 activated Akt signaling, upregulated metastasis genes and downregulated metastasis suppressor genes. Selective targeting of CCR6 in tumors dramatically inhibited the growth of CRC in mice. Thus, the tumor expression of CCR6 plays a critical role in CRC metastasis, upregulated CCR6 predicts poor survival in CRC patients, and targeting CCR6 expression in tumors may be a potential therapeutic strategy for CRC.

Hashikawa K, Yasumoto S, Nakashima K, et al.
Microarray analysis of gene expression by microdissected epidermis and dermis in mycosis fungoides and adult T-cell leukemia/lymphoma.
Int J Oncol. 2014; 45(3):1200-8 [PubMed] Related Publications
The characteristic histopathological feature of mycosis fungoides (MF) and adult T-cell leukemia/lymphoma (ATLL) is epidermotropism. To identify the mechanism for epidermotropism of lymphoma cells, total RNAs were obtained from skin biopsies of epidermis and dermis of MF and ATLL patients by means of laser capture microdissection, and used for subsequent complementary DNA (cDNA) microarray experiments. This procedure has made it possible for us to observe and evaluate the regional environment of MF and ATLL. Hierarchical cluster analysis revealed that the cDNAs could be clearly differentiated into MF and ATLL. CCL27 was expressed in the dermis generated from keratinocytes, CCR4/CCR6/CCR7/CCR10/cutaneous lymphocyte-associated antigen (CLA) lymphoma cells in the dermis, and CCL21 in the extracellular matrix (stroma). Lymphotoxin (LT) β and CCL21 expression was significantly higher and that of CCR10 relatively for MF, while CCR4 and CLA expression was relatively higher for ATLL. In the epithelium, keratinocytes expressed CCL20/CCL27, and lymphoma cells CCR4/CCR6/CCR10, while CCR4, CCR6, CCL20 and CCL27 expression was relatively higher for ATLL than MF. The dermis of MF, but not that of ATLL, showed correlation between CCR7 and CCL21. These findings support the suggestion that chemokines and chemokine receptors are involved in the pathogenesis of MF and ATLL, indicate that cutaneous homing seems to be different for MF and ATLL, and point to the possibility that cutaneous T-cell lymphomas originate in regulatory T cells, especially in the case of ATLL.

Nandi B, Pai C, Huang Q, et al.
CCR6, the sole receptor for the chemokine CCL20, promotes spontaneous intestinal tumorigenesis.
PLoS One. 2014; 9(5):e97566 [PubMed] Free Access to Full Article Related Publications
Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been associated with colorectal cancer growth and metastasis, however, a causal role for CCL20 signaling through CCR6 in promoting intestinal carcinogenesis has not been demonstrated in vivo. In this study, we aimed to determine the role of CCL20-CCR6 interactions in spontaneous intestinal tumorigenesis. CCR6-deficient mice were crossed with mice heterozygous for a mutation in the adenomatous polyposis coli (APC) gene (APCMIN/+ mice) to generate APCMIN/+ mice with CCR6 knocked out (CCR6KO-APCMIN/+ mice). CCR6KO-APCMIN/+ mice had diminished spontaneous intestinal tumorigenesis. CCR6KO-APCMIN/+ also had normal sized spleens as compared to the enlarged spleens found in APCMIN/+ mice. Decreased macrophage infiltration into intestinal adenomas and non-tumor epithelium was observed in CCR6KO-APCMIN/+ as compared to APCMIN/+ mice. CCL20 signaling through CCR6 caused increased production of CCL20 by colorectal cancer cell lines. Furthermore, CCL20 had a direct mitogenic effect on colorectal cancer cells. Thus, interactions between CCL20 and CCR6 promote intestinal carcinogenesis. Our results suggest that the intestinal tumorigenesis driven by CCL20-CCR6 interactions may be driven by macrophage recruitment into the intestine as well as proliferation of neoplastic epithelial cells. This interaction could be targeted for the treatment or prevention of malignancy.

Kryczek I, Lin Y, Nagarsheth N, et al.
IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L.
Immunity. 2014; 40(5):772-84 [PubMed] Free Access to Full Article Related Publications
Little is known about how the immune system impacts human colorectal cancer invasiveness and stemness. Here we detected interleukin-22 (IL-22) in patient colorectal cancer tissues that was produced predominantly by CD4(+) T cells. In a mouse model, migration of these cells into the colon cancer microenvironment required the chemokine receptor CCR6 and its ligand CCL20. IL-22 acted on cancer cells to promote activation of the transcription factor STAT3 and expression of the histone 3 lysine 79 (H3K79) methytransferase DOT1L. The DOT1L complex induced the core stem cell genes NANOG, SOX2, and Pou5F1, resulting in increased cancer stemness and tumorigenic potential. Furthermore, high DOT1L expression and H3K79me2 in colorectal cancer tissues was a predictor of poor patient survival. Thus, IL-22(+) cells promote colon cancer stemness via regulation of stemness genes that negatively affects patient outcome. Efforts to target this network might be a strategy in treating colorectal cancer patients.

Suarez-Carmona M, Hubert P, Gonzalez A, et al.
ΔNp63 isoform-mediated β-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma.
Oncotarget. 2014; 5(7):1856-68 [PubMed] Free Access to Full Article Related Publications
Beside a role in normal development/differentiation, high p63 immunoreactivity is also frequently observed in squamous cell carcinoma (SCC). Due to the complexity of the gene, the role of each p63 isotype in tumorigenesis is still confusing. Constitutively produced or induced in inflammatory conditions, human beta-defensins (HβDs) are cationic peptides involved in host defenses against bacteria, viruses and fungi. Here, we investigated both the role of p63 proteins in the regulation of HβDs and the implication of these antimicrobial peptides in tumor (lymph)angiogenesis. Thus, in contrast to TAp63 isotypes, we observed that ΔNp63 proteins (α, β, γ) induce HβD1, 2 and 4 expression. Similar results were observed in cancer tissues and cell lines. We next demonstrated that ΔNp63-overexpressing SCC are associated with both a poor prognosis and a high tumor vascularisation and lymphangiogenesis. Moreover, we showed that HβDs exert a chemotactic activity for (lymphatic) endothelial cells in a CCR6-dependent manner. The ability of HβDs to enhance (lymph)angiogenesis in vivo was also evaluated. We observed that HβDs increase the vessel number and induce a significant increase in relative vascular area compared to negative control. Taken together, the results of this study suggest that ΔNp63-regulated HβD could promote tumor (lymph)angiogenesis in SCC microenvironment.

Haruta M, Kamijo T, Nakagawara A, Kaneko Y
RASSF1A methylation may have two biological roles in neuroblastoma tumorigenesis depending on the ploidy status and age of patients.
Cancer Lett. 2014; 348(1-2):167-76 [PubMed] Related Publications
RASSF1A methylation was frequent in neuroblastomas found in infants by mass-screening or infants and children diagnosed clinically, whereas CASP8 and DCR2 methylation was only frequent in tumors in children. When classified according to the ploidy status, RASSF1A and PCDHB methylation was only associated with MYCN amplification and poor outcomes in infants with a clinically diagnosed diploid, not triploid tumor. RASSF1A and PCDHB methylation was associated with poor outcomes in children with triploid and diploid tumors, respectively, and with MYCN amplification in children with diploid tumor. RASSF1A methylation may have two biological roles based on the ploidy status and patient's age.

Mishra A, Garzon R
The (miR)e of CTCL.
Blood. 2014; 123(10):1438 [PubMed] Related Publications
In this issue of Blood, Ito et al demonstrate pathogenic implications of microRNA-150 (miR-150) repression in an aggressive form of cutaneous T-cell lymphoma (CTCL). Noncoding RNAs, such as microRNA, profoundly influence gene transcription and protein translation machinery to change hematopoietic cell fate in physiologic and pathologic conditions.

Takata K, Tanino M, Ennishi D, et al.
Duodenal follicular lymphoma: comprehensive gene expression analysis with insights into pathogenesis.
Cancer Sci. 2014; 105(5):608-15 [PubMed] Free Access to Full Article Related Publications
Follicular lymphoma (FL) of the gastrointestinal tract, particularly duodenal follicular lymphoma (DFL), is a rare variant of FL with indolent clinical behavior, and this disease is included in the 2008 World Health Organization classification system. In contrast to nodal follicular lymphoma (NFL), DFL occurs most frequently in the second part of the duodenum, lacks follicular dendritic cell meshworks and has memory B-cell characteristics. However, its molecular pathogenesis is still unclear. In the present study, we examined 10 DFL, 18 NFL and 10 gastric MALT lymphoma samples using gene expression analysis. Quantitative RT-PCR experiments and immunohistochemical analysis for 72 formalin-fixed, paraffin-embedded tissues from an independent series, including 32 DFL, 19 gastric MALT lymphoma and 27 NFL samples, were performed for validation of microarray data. Gene expression profiles of the three lymphoma types were compared using 2918 differentially expressed genes (DEG) and results suggested that DFL shares characteristics of MALT lymphoma. Among these DEG, CCL20 and MAdCAM-1 were upregulated in DFL and MALT but downregulated in NFL. In contrast, protocadherin gamma subfamily genes were upregulated in DFL and NFL. Quantitative RT-PCR and immunohistochemical studies demonstrated concordant results. Double immunofluorescence studies revealed that CCL20 and CCR6 were co-expressed in both DFL and MALT. We hypothesize that increased expression of CCL20 and MAdCAM-1 and co-expression of CCL20 and CCR6 may play an important role in tumorigenesis.

Stamatelli A, Vlachou C, Aroni K, et al.
Epigenetic alterations in sporadic basal cell carcinomas.
Arch Dermatol Res. 2014; 306(6):561-9 [PubMed] Related Publications
Basal cell carcinoma (BCC) is the most common malignant human neoplasm characterized by slow growth and virtual absence of metastases. Recently, it has become evident that along with genetic mutations epigenetic alterations play a key role in the pathogenesis of human cancer. We searched for promoter methylation of hMLH1, RASSF1A, DAPK, APC, DCR1 and DCR2 genes and BRAF mutations in BCCs in association with the clinicopathological parameters and the histological subtypes of the tumours. Fifty-two BCCs, 17 FFPE along with 35 fresh tissue samples with matching normal tissues for 26 cases were analyzed by methylation-specific PCR to assess the methylation status of hMLH1, RASSF1A, DAPK, APC, DCR1 and DCR2 genes after sodium bisulfite treatment of the tumour and normal DNA. hMLH1 and DCR1 gene expression was investigated by immunohistochemistry. BRAF mutations were studied by high resolution melting analysis. Methylation was detected at a variable frequency of 44, 33, 32.5, 32 and 14 % of DCR2, APC, DCR1, RASSF1 and DAPK promoters, respectively, whereas methylation of hMLH1 promoter was absent. No BRAF mutations were found. There was no correlation between the frequency of the promoter methylation of the above-mentioned genes and the clinicopathological features or the histological subtypes of the tumours. The relatively high frequency of RASSF1A, DCR1, DCR2 and APC promoter methylation may imply that methylation constitutes an important pathway in the tumourigenesis of BCC that could provide new opportunities in developing epigenetic therapies for BCC patients. Nevertheless, further studies are needed to establish the above-mentioned hypothesis.

Rubie C, Kruse B, Frick VO, et al.
Chemokine receptor CCR6 expression is regulated by miR-518a-5p in colorectal cancer cells.
J Transl Med. 2014; 12:48 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recently, involvement of the chemokine/receptor system CCL20/CCR6 in colorectal cancer (CRC) progression was shown. Here, we analyzed the functional interaction of miRNA-518-5p (miR-518a-5p) with CCR6 and its impact on CCR6 expression in CRC cells.
METHODS: MiR-518a-5p was identified by computer software to potentially interact with CCR6. Hence, functional implications of miR-518a-5p with the 3'UTR of CCR6 were analyzed using the Dual Luciferase Reporter assay system. Confirmation of the predicted target site for miR-518a-5p was achieved by site-directed mutagenesis of the seed sequence in the 3'UTR of CCR6 and subsequent application of the mutated seed sequence in a luciferase assay with miR-518a-5p mimics. Accordingly, two CRC cell lines (Caco-2 and HT-29) were transfected with miR-518a-5p miRNA mimics and gene and protein expression of CCR6 was monitored using qRT PCR and immunocytochemistry, respectively.
RESULTS: Addition of miR-518a-5p led to significant down-regulation of luciferase activity (P < 0.05), which was significantly reversed in a reporter test system containing the mutated seed sequences in the 3'UTR of CCR6. Following transfection of CRC cell lines with miR-518a-5p mimics and subsequent monitoring of CCR6 expression showed significant down-regulation of CCR6 mRNA and CCR6 protein expression in both CRC cell lines under investigation (P < 0.05).
CONCLUSIONS: We have shown that miR-518a-5p functionally interacts with CCR6 and that transfection of CRC cells with miR-518a-5p leads to significant CCR6 down-regulation. Consequently, CCR6 expression is regulated by miR-518a-5p in CRC cells indicating that regulation of CCR6 expression by miR-518a-5p might be a regulatory mechanism involved in CRC pathogenesis.

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