Microrna-150 Inhibits Tumor Invasion and Metastasis By Targeting The Chemokine Receptor CCR6 In Advanced Cutaneous T-Cell Lymphoma

MicroRNA (miRNA)s are a class of small regulatory RNA molecules that play important roles in tumor development by pairing with the 3' untranslated region (UTR) of target messenger RNAs to repress their productive translation. Thus although the genes responsible for T-cell lymphomas remain largely unknown, in some lymphoma subtypes, miRNA dysregulation may contribute to tumorigenesis. For example, altered expression of various oncRogenic or tumor suppressive miRNAs has been identified in lymphomas/leukemias and solid tumors We show here that a tumor suppressive miRNA, miR-150, is significantly downregulated in advanced cutaneous T-cell lymphoma (CTCL), and that the downregulation is strongly associated with tumor invasion and metastasis. Inoculation of cutaneous T-cell lymphoma cell lines into NOD/Shi-scid IL-2γnul mice led to CTCL cell migration to multiple organs, but this invasion/metastasis was substantially reduced in miR-150-transfected CTCL cells due to direct downregulation of CCR6, a specific receptor for the chemokine CCL20. MiR-150 thus appears to negatively regulate the interaction between CCL20 and CCR6 in CTCL cells, thereby inhibiting autocrine CTCL cell metastasis. CD4⁺ T helper cells are divided into T_H1, T_H2, T_H17, and T_H22 subsets. Among these, the T_H22 subset produces only IL-22, while T_H17 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 further 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 T_H22 subset. In the presence of continuous upregulation of CCR6 accompanied by downregulation of miR-150, IL-22 activation could lead to continuous CCL20-CCR6 interaction in CTCL cells and, in turn, autocrine metastasis to distal organs. This is the first report demonstrating an invasion/metastasis mechanism in advanced CTCL.