Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas.
Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas.
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DOI：
10.1002/emmm.200900028
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发表时间：
2009-08
影响因子：
11.1
通讯作者：
David, Michael
中科院分区：
文献类型：
--
作者：
Pedersen, Irene M.;Otero, Dennis;Kao, Elaine;Miletic, Ana V.;Hother, Christoffer;Ralfkiaer, Elisabeth;Rickert, Robert C.;Gronbaek, Kirsten;David, Michael
非编码microRNAs(MiRs)是蛋白质表达转录后调控的重要组成部分，与编码mRNAs一样具有致癌特性。然而，调控miR表达的机制和受影响转录本的身份仍然知之甚少。在这里，我们确定肌醇磷酸酶SHIP1是致癌miR-155的真正靶点。我们证明，在弥漫性大B细胞淋巴瘤中，miR155水平的升高以及随之而来的SHIP1表达的降低是促炎细胞因子肿瘤坏死因子α(肿瘤坏死因子α)自分泌刺激的结果。抗肿瘤坏死因子α方案，如依替那普或英夫利昔单抗，足以降低miR155水平，恢复SHIP1的表达，并伴随着细胞增殖的抑制。此外，我们观察到对Eternacept的反应，DLBCL异种移植的肿瘤负荷显著降低。这些发现有力地支持了细胞因子调节的miRs可以作为炎症和癌症之间的关键联系的概念，并说明了抗肿瘤坏死因子α治疗作为一种新的、可立即获得的(Co)治疗DLBCL的可行性。
Non-coding microRNAs (miRs) are a vital component of post-transcriptional modulation of protein expression and, like coding mRNAs harbour oncogenic properties. However, the mechanisms governing miR expression and the identity of the affected transcripts remain poorly understood. Here we identify the inositol phosphatase SHIP1 as a bonafide target of the oncogenic miR-155. We demonstrate that in diffuse large B cell lymphoma (DLBCL) elevated levels of miR-155, and consequent diminished SHIP1 expression are the result of autocrine stimulation by the pro-inflammatory cytokine tumour necrosis factor α (TNFα). Anti-TNFα regimen such as eternacept or infliximab were sufficient to reduce miR-155 levels and restored SHIP1 expression in DLBCL cells with an accompanying reduction in cell proliferation. Furthermore, we observed a substantial decrease in tumour burden in DLBCL xenografts in response to eternacept. These findings strongly support the concept that cytokine-regulated miRs can function as a crucial link between inflammation and cancer, and illustrate the feasibility of anti-TNFα therapy as a novel and immediately accessible (co)treatment for DLBCL.
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影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
20.3
作者：
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作者：
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通讯作者：
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64.8
作者：
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通讯作者：
Staudt, LM