Abstract 4019: MicroRNA-150 inhibits tumor invasion and metastasis by targeting IL-22-CC20-CCR6 autocrine signaling in advanced T-cell lymphoma

Abstract

Abstract MicroRNA(miRNA)s are involved in regulating diverse cellular pathways. Here we provide the first evidence of the relationship between a chemokine and a miRNA affecting tumor invasion and metastasis in malignant lymphoma. In this study, we examined expression of a tumor suppressive miRNA, microRNA-150 (miR-150), in a panel of 49 CD4+ T-cell lymphomas with lymphnode or peripheral blood involvement [37 peripheral T-cell lymphomas and 12 metastatic cutaneous T-cell lymphomas (CTCL)] and found that it is significantly downregulated, as compared to its level in normal CD4+ T cells. Inoculation of CTCL cell lines into NOD/Shi-scid IL-2γnul 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 IL-22 upregulation may activate 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. CD4+ T helper cells are divided into TH1, TH2, TH17, and TH22 subsets. Among these, the TH22 subset produces only IL-22, while TH17 cells produce both IL-17 and IL-22. Normally, IL-22 activates CCL20 transcription by binding to the IL-22RA1/IL-10RB receptor, which is not expressed in lymphoid organs or lymphocytes. In the present study, we found that both IL-22 and its receptor subunit, IL-22RA1, are aberrantly overexpressed in advanced CTCL, but IL-17 is not expressed, suggesting CTCL is derived from the TH22 subset. 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. For molecular targeting therapy, we used anti-CCL20 antibody for CTCL cells and in vitro and in vivo analyses could demonstrate that anti-CCL20 was effective to reduce tumor invasion and migration. This is the first report demonstrating an invasion/metastasis mechanism in advanced lymphoma. Citation Format: Hiroyuki Tagawa, Mitsugu Ito, Sho Ikeda, Akihiko Kitadate, Kenichi Sawada. MicroRNA-150 inhibits tumor invasion and metastasis by targeting IL-22-CC20-CCR6 autocrine signaling in advanced T-cell lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4019. doi:10.1158/1538-7445.AM2014-4019