Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma.
Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma.
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DOI：
10.18632/oncotarget.13810
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发表时间：
2017-01-31
期刊：
影响因子：
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通讯作者：
Tagawa H
中科院分区：
文献类型：
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作者：
Abe F;Kitadate A;Ikeda S;Yamashita J;Nakanishi H;Takahashi N;Asaka C;Teshima K;Miyagaki T;Sugaya M;Tagawa H
肿瘤抑制性microRNA（miR）-150通过与C-C趋化因子受体6（CCR 6）3′-非翻译区（3′-UTR）“种子序列”mRNA结合抑制晚期皮肤T细胞淋巴瘤（CTCL）转移。由于组蛋白去乙酰化酶抑制剂（HDACI）伏立诺他显示出治疗晚期CTCL的优异结果，HDACI可以通过靶向miR-150和/或CCR 6来减少CTCL的转移。为了检查这些候选分子是否是晚期CTCL中的必需HDACI靶标，我们使用My-La、HH和HUT 78 CTCL细胞系进行功能分析，因为我们先前证明它们在NOD/Shi-scid IL-2γnul小鼠（CTCL小鼠）中的异种移植物诱导了多种转移。我们发现泛HDACI（伏立诺他和帕比司他）抑制CTCL细胞的迁移并下调CCR 6。针对CTCL细胞系的miRNA微阵列分析表明，这些泛HDACIs通常上调161种miRNA，包括34种已知的肿瘤抑制性miRNA，如miR-150。尽管在这161个miRNA中包括35个具有CCR 6“种子序列”的miRNA，但与正常CD 4 + T细胞相比，miR-150和miR-185- 5 p在CTCL细胞中下调。针对CTCL细胞的12种候选miRNAs的转导揭示了miR-150最有效地抑制其迁移能力并下调CCR 6。定量逆转录-聚合酶链反应显示，miR-150在晚期而非早期CTCL原发病例中下调。最后，我们将miR-150或siCCR 6注射到CTCL小鼠中，发现小鼠存活时间显著延长。这些结果表明，miR-150及其靶点CCR 6是具有转移潜能的晚期CTCL中泛HDACI的重要治疗靶点。
Tumor suppressive microRNA (miR)-150 inhibits metastasis by combining with the C-C chemokine receptor 6 (CCR6) “seed sequence” mRNA of the 3′-untranslated region (3′-UTR) in advanced cutaneous T-cell lymphoma (CTCL). Because the histone deacetylase inhibitor (HDACI) vorinostat showed excellent outcomes for treating advanced CTCL, HDACIs may reduce the metastasis of CTCL by targeting miR-150 and/ or CCR6. To examine whether these candidate molecules are essential HDACI targets in advanced CTCL, we used the My-La, HH, and HUT78 CTCL cell lines for functional analysis because we previously demonstrated that their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) induced multiple metastases. We found that pan- HDACIs (vorinostat and panobinostat) inhibited the migration of CTCL cells and downregulated CCR6. The miRNA microarray analysis against CTCL cell lines demonstrated that these pan-HDACIs commonly upregulated 161 miRNAs, including 34 known tumor suppressive miRNAs such as miR-150. Although 35 miRNAs possessing the CCR6 “seed sequence” were included in these 161 miRNAs, miR-150 and miR-185-5p were downregulated in CTCL cells compared to in normal CD4+ T-cells. The transduction of 12 candidate miRNAs against CTCL cells revealed that miR-150 most efficiently inhibited their migration capabilities and downregulated CCR6. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that miR-150 was downregulated in advanced but not early CTCL primary cases. Finally, we injected miR-150 or siCCR6 into CTCL mice and found that mouse survival was significantly prolonged. These results indicate that miR-150 and its target, CCR6, are essential therapeutic targets of pan-HDACIs in advanced CTCL with metastatic potential.