Dataset Information

CCL17/TARC and CCR4 expression in Merkel cell carcinoma.

ABSTRACT: Merkel cell carcinoma (MCC) is a rare, highly aggressive neuroendocrine skin cancer. In more than 80% of the cases, Merkel cell polyomavirus (MCPyV) is a causal factor. The oncogenic potential of MCPyV is mediated through its viral oncoproteins, large T antigen (LT) and small t antigen (sT). To investigate the role of cytokines in MCC, a PCR array analysis for genes encoding inflammatory cytokines and receptors was performed on MCPyV-negative and MCPyV-positive MCC cell lines, respectively. We detected an increased expression of CCL17/TARC in the MCPyV-positive MKL2 cell line compared to the MCPyV-negative MCC13 cell line. Transfection studies in MCC13 cells with LT expression plasmid, and a luciferase reporter plasmid containing the CCL17/TARC promoter, exhibited stimulated promoter activity. Interestingly, the ectopic expression of CCL17/TARC upregulated MCPyV early and late promoter activities in MCC13 cells. Furthermore, recombinant CCL17/TARC activated both the mitogen-activated protein kinase and the NF-?B pathways. Finally, immunohistochemical staining on human MCC tissues showed a strong staining of CCL17/TARC and its receptor CCR4 in both LT-positive and -negative MCC. Taken together, CCL17/TARC and CCR4 may be a potential target in MCC therapy providing MCC patients with a better overall survival outcome.

SUBMITTER: Rasheed K

PROVIDER: S-EPMC6101144 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CCL17/TARC and CCR4 expression in Merkel cell carcinoma.

Rasheed Kashif K Abdulsalam Ibrahim I Fismen Silje S Grimstad Øystein Ø Sveinbjørnsson Baldur B Moens Ugo U

Oncotarget 20180731 59

Merkel cell carcinoma (MCC) is a rare, highly aggressive neuroendocrine skin cancer. In more than 80% of the cases, Merkel cell polyomavirus (MCPyV) is a causal factor. The oncogenic potential of MCPyV is mediated through its viral oncoproteins, large T antigen (LT) and small t antigen (sT). To investigate the role of cytokines in MCC, a PCR array analysis for genes encoding inflammatory cytokines and receptors was performed on MCPyV-negative and MCPyV-positive MCC cell lines, respectively. We d ...[more]

PMID: 30140381

Similar Datasets

Project description:BackgroundMacrophages (Mtheta) play a central role in the innate immune response and in the pathology of chronic inflammatory diseases. Macrophages treated with Th2-type cytokines such as Interleukin-4 (IL-4) and Interleukin-13 (IL-13) exhibit an altered phenotype and such alternatively activated macrophages are important in the pathology of diseases characterised by allergic inflammation including asthma and atopic dermatitis. The CC chemokine Thymus and Activation-Regulated Chemokine (TARC/CCL17) and its murine homologue (mTARC/ABCD-2) bind to the chemokine receptor CCR4, and direct T-cell and macrophage recruitment into areas of allergic inflammation. Delineating the molecular mechanisms responsible for the IL-4 induction of TARC expression will be important for a better understanding of the role of Th2 cytokines in allergic disease.ResultsWe demonstrate that mTARC mRNA and protein are potently induced by the Th2 cytokine, Interleukin-4 (IL-4), and inhibited by Interferon-gamma (IFN-gamma) in primary macrophages (Mtheta). IL-4 induction of mTARC occurs in the presence of PI3 kinase pathway and translation inhibitors, but not in the absence of STAT6 transcription factor, suggesting a direct-acting STAT6-mediated pathway of mTARC transcriptional activation. We have functionally characterised eleven putative STAT6 sites identified in the mTARC proximal promoter and determined that five of these contribute to the IL-4 induction of mTARC. By in vitro binding assays and transient transfection of isolated sites into the RAW 264.7 Mtheta cell-line, we demonstrate that these sites have widely different capacities for binding and activation by STAT6. Site-directed mutagenesis of these sites within the context of the mTARC proximal promoter revealed that the two most proximal sites, conserved between the human and mouse genes, are important mediators of the IL-4 response.ConclusionThe induction of mTARC by IL-4 results from cooperative interactions between STAT6 sites within the mTARC gene promoter. Significantly, we have shown that transfer of the nine most proximal mTARC STAT6 sites in their endogenous conformation confers potent (up to 130-fold) IL-4 inducibility on heterologous promoters. These promoter elements constitute important and sensitive IL-4-responsive transcriptional units that could be used to drive transgene expression in sites of Th2 inflammation in vivo.

Dataset Information

CCL17/TARC and CCR4 expression in Merkel cell carcinoma.

Publications

CCL17/TARC and CCR4 expression in Merkel cell carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets