Abstract |
In this study, we show that microRNA-150 (miR-150) is significantly downregulated in advanced cutaneous T-cell lymphoma (CTCL), and that this downregulation is strongly associated with tumor invasion/ metastasis. Inoculation of CTCL cell lines into nonobese diabetic/Shi-scid interleukin 2γ (IL-2γ) null mice led to CTCL cell migration to multiple organs; however, prior transfection of the cells with miR-150 substantially reduced the invasion/ metastasis by directly downregulating CCR6, a specific receptor for the chemokine CCL20. We also found that IL-22 and its specific receptor subunit, IL22RA1, were aberrantly overexpressed in advanced CTCL, and that production of IL-22 and CCL20 was increased in cultured CTCL cells. IL22RA1 knockdown specifically reduced CCL20 production in CTCL cells, suggesting that IL-22 upregulation may activate the production of CCL20 and its binding to CCR6, thereby enhancing the multidirectional migration potential of CTCL cells. CTCL cells also exhibited nutrition- and CCL20-dependent chemotaxis, which were inhibited by miR-150 transfection or CCR6 knockdown. From these findings, we conclude that, in the presence of continuous CCR6 upregulation accompanied by miR-150 downregulation, IL-22 activation leads to continuous CCL20-CCR6 interaction in CTCL cells and, in turn, autocrine metastasis to distal organs. This suggests miR-150, CCL20, and CCR6 could be key targets for the treatment of advanced CTCL.
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Authors | Mitsugu Ito, Kazuaki Teshima, Sho Ikeda, Akihiro Kitadate, Atsushi Watanabe, Miho Nara, Junsuke Yamashita, Koichi Ohshima, Kenichi Sawada, Hiroyuki Tagawa |
Journal | Blood
(Blood)
Vol. 123
Issue 10
Pg. 1499-511
(Mar 06 2014)
ISSN: 1528-0020 [Electronic] United States |
PMID | 24385540
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Chemokine CCL20
- Interleukins
- MIRN150 microRNA, human
- MicroRNAs
- Receptors, CCR6
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Topics |
- Animals
- Autocrine Communication
- Cell Line, Tumor
- Chemokine CCL20
(genetics, metabolism)
- Chemotaxis
(genetics)
- Cluster Analysis
- Disease Models, Animal
- Gene Expression
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Genes, Tumor Suppressor
- Humans
- Interleukins
(genetics, metabolism)
- Lymphoma, T-Cell, Cutaneous
(genetics, mortality, pathology)
- Mice
- MicroRNAs
(genetics)
- Neoplasm Invasiveness
(genetics)
- Neoplasm Metastasis
(genetics)
- Neoplasm Staging
- RNA Interference
- Receptors, CCR6
(genetics)
- Transfection
- Xenograft Model Antitumor Assays
- Interleukin-22
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