title: MicroRNA-150 inhibits tumor invasion and metastasis by targeting the chemokine receptor CCR6, in advanced cutaneous T-cell lymphoma.
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.
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan;
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Ito
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Teshima
authors.forename: Sho
authors.initials: S
authors.lastname: Ikeda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kitadate
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.forename: Miho
authors.initials: M
authors.lastname: Nara
authors.forename: Junsuke
authors.initials: J
authors.lastname: Yamashita
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sawada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tagawa
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics; D016000:Cluster Analysis; D004195:Disease Models, Animal; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009367:Neoplasm Staging; D034622:RNA Interference; D054399:Receptors, CCR6 / Q000235:genetics*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000097043:Interleukin-22
chemical_list: D054418:Chemokine CCL20; D007378:Interleukins; D035683:MicroRNAs; D054399:Receptors, CCR6; D000097043:Interleukin-22; C533097:MIR150, human