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Wang L, Qin H, Li L et al.Overexpression of CCL20 and its receptor CCR6 predicts poor clinical prognosis in human gliomas. Med Oncol 29:3491-3497

Department of Neurosurgery, Tangdu Hospital, No. 569, Xinsi Road, Baqiao District, Xi'an City, 710038, China.
Medical Oncology (Impact Factor: 2.63). 08/2012; 29(5). DOI: 10.1007/s12032-012-0314-9
Source: PubMed

ABSTRACT

Recent studies have demonstrated that the chemokine CCL20 and its receptor CCR6 may be involved in tumorigenesis, tumor progression and metastatic spread of various human malignancies. The aim of this study was to investigate the clinicopathological significance and prognostic value of CCL20 and CCR6 expression in human malignant glioma. CCL20 and CCR6 expression in human gliomas and nonneoplastic brain tissues was measured by immunohistochemistry. The association of CCL20 and CCR6 expression with clinicopathological factors or prognosis in glioma patients was statistically analyzed. The expression levels of CCL20 and CCR6 proteins were both up-regulated in glioma tissues. There was a significantly positive correlation between the expression of the two markers (r = 0.88; P < 0.001). In addition, the overexpressions of CCL20 and CCR6 were both detected in high-grade glioma tissues compared with those in low-grade tissues and increased with ascending tumor World Health Organization (WHO) grades (P = 0.006 and 0.008, respectively). The increased expressions of CCL20 and CCR6 proteins were also significantly correlated with low Karnofsky performance score (both P = 0.01). Moreover, univariate analysis found that CCL20 expression (P = 0.002), CCR6 expression (P = 0.002) and CCL20/CCR6 co-expression (P < 0.001) were all significantly associated with poor prognosis. In particular, glioma patients with CCL20/CCR6 co-expression have the shortest overall survival. Multivariate analysis further identified the expression levels of CCL20 and CCR6 to be independent prognostic factors. Our data suggest for the first time that CCL20 and CCR6 might play an important role in the regulation of aggressiveness in human gliomas. The up-regulation of CCL20 and CCR6 might be closely associated with poor clinical outcome of patients with gliomas.

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    • "Among these, the C-C chemokine CCL20, also known as macrophage infiltrating factor protein-3α (MIP-3α) or liver activation regulated chemokine (LARC), is the only known ligand for the receptor CCR6[3,4]. It has been reported that the expression levels of CCL20 and CCR6 are increased in many cancers such as gliomas, and colorectal and pancreatic cancers, and the increased expression of these molecules is closely associated with poor prognosis in cancer patients5678. Experimental data have shown that CCL20-CCR6 interaction increases the colony-forming www.impactjournals.com/oncotarget capacity of non-small cell lung cancer cells through upregulation of IL-17, and enhances hepatocellular carcinoma cell growth via activation of the ERK1/2 pathway[9,10]. "
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    ABSTRACT: We recently demonstrated that upregulation of a chemokine receptor CCR6 and its ligand CCL20 led to metastasis of advanced cutaneous T-cell lymphoma (CTCL) cells, suggesting the involvement of CCL20-CCR6 interaction in initiating CTCL cell metastasis. In this study, we determined whether this interaction is functional in metastatic CTCL cells. We first demonstrated increased STAT3 expression during the progression of primary CTCL. STAT3 was spontaneously activated and mediated the transcription of CCL20 in CTCL cell lines. Next, to determine whether the transient knockdown of STAT3, CCL20, or CCR6 or treatment with newtralizing antibody against CCL20 (neutralizing CCL20 antibody) could reduce the migration ability of CTCL cells, we conducted an in vitro migration assay. All treatments reduced the nutrition-dependent migration activity of CTCL cells. Notably, treatment with neutralizing CCL20 antibody reduced the migration ability of the cells without decreasing the expression of CCL20 and CCR6. This demonstrated that the CCL20-CCR6 interaction is actually functional in metastatic CTCL cells. Finally, to examine the in vivo effect of neutralizing CCL20 antibody, we used NOD/Shi-scid IL-2γnul mice inoculated with CTCL cells. These mice were expected to die due to metastasis of CTCL cells into multiple organs. However, administration of neutralizing CCL20 antibody significantly prolonged the survival of the xenografted mice. These findings suggested that automatic activation of the STAT3/CCL20/CCR6 cascade was involved in CTCL lymphomagenesis and that disruption of CCL20-CCR6 interaction could be a key therapeutic strategy against advanced CTCL.
    Full-text · Article · Jan 2016 · Oncotarget
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    • "Increased expression levels of CXCL8 may also contribute to the multidrug resistance seen in human breast cancer cells [50]. High expression of CCL20 is also closely associated with poor clinical outcome of patients with gliomas [51] and with a poorer prognosis in patients with hepatocellular carcinoma [52]. The CCL20/CCR6 axis has been shown to promote non-small cell lung cancer progression [53]. "
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    ABSTRACT: Ovarian cancer, an inflammation-associated cancer, is the fifth leading cause of cancer deaths in women. The malignancy produces a large amount of tumor necrosis factor (TNF) which promotes a proinflammatory tumor microenvironment. In addition, the epidermal growth factor receptor (EGFR) is frequently overexpressed in high-grade ovarian cancer, which likely aggravates cancer progression. Since ovarian cancer progression is closely associated with chemokine networks driven by inflammation or EGFR activation, we investigated the chemokine signatures elicited by EGF and TNF in ovarian cancer cells to determine their individual profiles and if there was in fact some kind of synergy between their actions on the chemokine network. We used a PCR array for the chemokine network to examine the signature of chemokines and their receptors elicited by EGF and TNF in four ovarian cancer cell lines (OVCAR-3, SKOV-3, CaOV-3 and TOV-21G). The chemokine network revealed that ovarian cancer cells commonly expressed high levels of proinflammatory chemokines such as CCL20, CXCL1-3 and CXCL8 in response to EGF or TNF. However, the responsiveness to EGF or TNF displayed a cell line specific pattern. Although OVCAR-3 and SKOV-3 cells were responsive to either EGF or TNF, their TNF responsiveness was dominant. On the other hand, CaOV-3 and TOV-21G cells were responsive to EGF but less to TNF, probably due to the high levels of non-canonical nuclear factor (NF)-kappaB components such as IKKalpha and p52 in these cell lines compared to OVCAR-3 and SKOV-3 cells. Among chemokine receptors, only CXCR5 was responsive to EGF or TNF in CaOV-3 cells. Finally, CCL20 and CXCL8 responded synergistically in response to EGF and TNF in OVCAR-3 and SKOV-3 cells. Our results indicate that CCL20, CXCL1-3 and CXCL8 are the primary chemokines induced by EGF or TNF and are elicited in these ovarian cancer cells via NF-kappaB, Akt and Erk signaling pathways. Of interest, there was a syngergistic response in terms of CCL20 and CXCL8 levels, when OVCAR-3 and SKOV-3 cells were exposed to EGF plus TNF. Targeting these proinflammatory chemokines may be a promising therapeutic strategy for ovarian cancer with abundant TNF and EGFR activation patterns.
    Full-text · Article · Jun 2013 · Journal of Inflammation
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    ABSTRACT: Originally, chemokines and their G-protein-coupled receptors were described to regulate multiple physiological functions, particularly tissue architecture and compartment-specific migration of white blood cells. Now, it is established that the chemokine/chemokine receptor system is also used by cancer cells for migration and metastatic spread. Here, we examined the relative levels of CC-chemokine CCL20 and its corresponding receptor CCR6 in resection specimens from patients with different malignant and non-malignant colorectal diseases as well as in colorectal liver metastases (CRLM). CCL20/CCR6 mRNA and protein expression profiles were assessed by quantitative real-time PCR (Q-RT-PCR), enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) in resection specimens from patients with ulcerative colitis (UC, n=15), colorectal adenoma (CRA, n=15), colorectal adenocarcinoma (CRC, n=61 and CRLM (n=16). Corresponding non-diseased tissues served as control. In contrast to UC tissues, the CCL20/CCR6 system showed a distinct up-regulation in CRA, CRC and CRLM related to corresponding non-affected tissues (p<0.05, respectively). Furthermore, CRA, CRC and CRLM tissue samples displayed significantly higher protein amounts of CCL20 in comparison to UC specimens (p<0.05, respectively). Our results strongly suggest an association between CCL20/CCR6 expression and the induction of CRA, CRC and the development of CRLM. Therefore, CCL20 and CCR6 may provide potential targets for novel treatment strategies of CRC. This article is protected by copyright. All rights reserved.
    Preview · Article · Jun 2013 · Scandinavian Journal of Immunology
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