MicroRNA-150 inhibits tumor invasion and metastasis by targeting the chemokine receptor CCR6, in advanced cutaneous T-cell lymphoma
MicroRNA-150 inhibits tumor invasion and metastasis by targeting the chemokine receptor CCR6, in advanced cutaneous T-cell lymphoma
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DOI：
10.1182/blood-2013-09-527739
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发表时间：
2014-03-06
期刊：
影响因子：
20.3
通讯作者：
Tagawa, Hiroyuki
中科院分区：
文献类型：
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作者：
Ito, Mitsugu;Teshima, Kazuaki;Tagawa, Hiroyuki
在这项研究中，我们发现microRNA-150（miR-150）在晚期皮肤T细胞淋巴瘤（CTCL）中显著下调，并且这种下调与肿瘤侵袭/转移密切相关。将CTCL细胞系接种到非肥胖糖尿病/Shi-scid白细胞介素2 γ（IL-2 γ）缺失小鼠中导致CTCL细胞迁移到多个器官;然而，先前用miR-150转染细胞通过直接下调CCR 6（趋化因子CCL 20的特异性受体）显著降低了侵袭/转移。我们还发现IL-22及其特异性受体亚基IL-22 RA 1在晚期CTCL中异常过表达，并且在培养的CTCL细胞中IL-22和CCL 20的产生增加。IL 22 RA 1敲低特异性地减少CTCL细胞中CCL 20的产生，表明IL-22上调可以激活CCL 20的产生及其与CCR 6的结合，从而增强CTCL细胞的多向迁移潜力。CTCL细胞还表现出营养和CCL 20依赖的趋化性，这被miR-150转染或CCR 6敲低抑制。从这些发现中，我们得出结论，在连续CCR 6上调伴随miR-150下调的情况下，IL-22激活导致CTCL细胞中连续的CCL 20-CCR 6相互作用，进而导致向远端器官的自分泌转移。这表明miR-150、CCL 20和CCR 6可能是治疗晚期CTCL的关键靶点。
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 2 gamma (IL-2 gamma) 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.