Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma.
Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma.
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DOI：
10.18632/oncotarget.4111
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发表时间：
2015-08-21
期刊：
影响因子：
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通讯作者：
Odum N
中科院分区：
文献类型：
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作者：
Sibbesen NA;Kopp KL;Litvinov IV;Jønson L;Willerslev-Olsen A;Fredholm S;Petersen DL;Nastasi C;Krejsgaard T;Lindahl LM;Gniadecki R;Mongan NP;Sasseville D;Wasik MA;Iversen L;Bonefeld CM;Geisler C;Woetmann A;Odum N
Janus激酶-3（Jak 3）及其关键下游效应物信号转导和转录激活因子-3（STAT 3）和STAT 5的异常激活是皮肤T细胞淋巴瘤（CTCL）恶性转化的关键特征。然而，它仍然只是部分了解Jak 3/STAT激活如何促进淋巴瘤发生。最近，非编码microRNAs（miRNAs）已被牵连在这种恶性肿瘤的发病机制。在这里，我们表明：（i）与非恶性T细胞相比，恶性T细胞显示肿瘤抑制miRNA miR-22的表达降低，（ii）STAT 5结合miR-22宿主基因的启动子，（iii）抑制Jak 3，STAT 3和STAT 5触发pri-miR-22和miR-22的表达增加。姜黄素，一种具有抗Jak 3活性的营养素和组蛋白脱乙酰酶抑制剂（HDACi）也触发pri-miR-22和miR-22的表达增加。用重组miR-22转染恶性T细胞可抑制经验证的miR-22靶标的表达，包括NCoA 1（其他癌症中的转录共激活因子）以及HDAC 6、MAX、MYCBP、PTEN和CDK 2，这些靶标均与CTCL发病机制有关。总之，我们提供了第一个证据，证明CTCL细胞中Jak 3/STAT 3/STAT 5信号转导失调抑制了编码miR-22（一种新型肿瘤抑制miRNA）的基因的表达。
Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA.