MicroRNA-150 inhibits tumor invasion and metastasis by targeting the chemokine receptor CCR6, in advanced cutaneous T-cell lymphoma

Abstract

Key Points• Aberrantly diminished expression of miR-150 allows advanced CTCL to invade multiple organs with upregulation of CCR6.• MiR-150 inhibits IL-22-CCL20-CCR6 autocrine signaling in advanced CTCL.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 2g (IL-2g) 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.

Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia

“…MicroRNA-150 deregulation has been reported in various cancers, including cutaneous T-cell lymphoma (28) and Burkitt lymphoma (29), as well as in solid cancers, such as in esophagi squamous carcinoma (30), non-small-cell lung carcinoma (31) and colorectal cancer (32). Surprisingly, cellular miR-150 upregulation was not always observed in tumoral tissue when compared with normal tissue; indeed, a lower level of cellular miR-150 is observed in esophagi (30), lung (31) and colorectal cancer (32) and T-cell lymphoma (28). However, when only the tumoral tissue is taken into consideration, low cellular miR-150 expression is always associated with a greater tumoral potential and a poorer prognosis, as confirmed in the present study.…”

Role of microRNA-150 in solid tumors

“…The expression signature of miR-150 in the plasma indicated that it may serve as a valuable diagnostic and potentially prognostic biomarker for human AML (19). Furthermore, in cutaneous T-cell lymphoma, upregulation of miR-150 inhibited tumor invasion and metastasis by targeting the chemokine CCL20 receptor, CCR6 (20). These results have provided a novel insight into the function of miR-150 as a tumor suppressor in the pathogenesis of hematological malignancies, as well as a basis for novel therapies targeting miR-150 for the treatment of these hematological malignancies discussed above.…”

Amplification of Long Noncoding RNA ZFAS1 Promotes Metastasis in Hepatocellular Carcinoma

“…miR-150, frequently downregulated in HCC (Supplementary Fig. S4), acts as a tumor suppressor (29,30). To validate the direct binding between ZFAS1 and miR-150 at endogenous levels, we carried out an RIP with MS2-binding protein (MS2bp), which specifically binds RNA containing MS2-binding sequences (MS2bs).…”