期刊
EMBO MOLECULAR MEDICINE
卷 1, 期 5, 页码 288-295出版社
WILEY
DOI: 10.1002/emmm.200900028
关键词
inflammation; lymphoma; microRNA; phosphatase; TNF alpha
资金
- NIH [T32 CA09523, K01 CA122192, R01 HL088686, R01CA135531]
- Novo Nordisk Foundation
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 alpha (TNF alpha). Anti-TNF alpha 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-TNF alpha therapy as a novel and immediately accessible (co)treatment for DLBCL.
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