STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma
STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma
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DOI：
10.4161/cc.24987
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发表时间：
2013-06-15
期刊：
影响因子：
4.3
通讯作者：
Woetmann, Anders
中科院分区：
文献类型：
--
作者：
Kopp, Katharina L.;Ralfkiaer, Ulrik;Woetmann, Anders
皮肤T细胞淋巴瘤（CTCL）的发病机制仍然是一个谜。最近的发现表明，致癌microRNA miR-155在CTCL患者的受影响皮肤中过表达。在这里，我们解决了驱动miR-155表达的因素，并研究了其在CTCL发病机制中的作用。我们发现恶性T细胞组成型表达高水平的miR-155及其宿主基因BIC（B细胞整合簇）。使用ChIP-seq，我们将BIC鉴定为转录因子STAT 5的靶标，其在恶性T细胞中被异常激活，并在非恶性T细胞中被IL-2/IL-15诱导。用JAK抑制剂或siRNA介导的STAT 5敲低孵育降低BIC/miR-155表达，而IL-2和IL-15增加它们在细胞系和原代细胞中的表达。相比之下，STAT 3的敲低没有影响，并且BIC不是STAT 3的转录靶点，表明STAT 5对BIC/miR-155表达的调节是高度特异性的。反义miR-155以及STAT 5和BIC的敲低均显著抑制恶性增殖。总之，我们首次提供了STAT 5驱动癌基因BIC/miR-155在癌症中表达的证据。此外，我们的数据表明，STAT 5/BIC/miR-155途径促进恶性T细胞的增殖，因此是CTCL治疗的假定靶点。
The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains elusive. Recent discoveries indicate that the oncogenic microRNA miR-155 is overexpressed in affected skin from CTCL patients. Here, we address what drives the expression of miR-155 and investigate its role in the pathogenesis of CTCL. We show that malignant T cells constitutively express high levels of miR-155 and its host gene BIC (B cell integration cluster). Using ChIP-seq, we identify BIC as a target of transcription factor STAT5, which is aberrantly activated in malignant T cells and induced by IL-2/IL-15 in non-malignant T cells. Incubation with JAK inhibitor or siRNA-mediated knockdown of STAT5 decreases BIC/miR-155 expression, whereas IL-2 and IL-15 increase their expression in cell lines and primary cells. In contrast, knockdown of STAT3 has no effect, and BIC is not a transcriptional target of STAT3, indicating that regulation of BIC/miR-155 expression by STAT5 is highly specific. Malignant proliferation is significantly inhibited by an antisense-miR-155 as well as by knockdown of STAT5 and BIC.In conclusion, we provide the first evidence that STAT5 drives expression of oncogenic BIC/miR-155 in cancer. Moreover, our data indicate that the STAT5/BIC/miR-155 pathway promotes proliferation of malignant T cells, and therefore is a putative target for therapy in CTCL.