Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas.
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 a (TNFalpha). Anti-TNFalpha 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-TNFalpha therapy as a novel and immediately accessible (co)treatment for DLBCL.
Pedersen
Irene M
IM
Section of Molecular Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
Otero
Dennis
D
Kao
Elaine
E
Miletic
Ana V
AV
Hother
Christoffer
C
Ralfkiaer
Elisabeth
E
Rickert
Robert C
RC
Gronbaek
Kirsten
K
David
Michael
M
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases