Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas

TY - JOUR

T1 - Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas

AU - Pedersen, Irene M

AU - Otero, Dennis

AU - Kao, Elaine

AU - Miletic, Ana V

AU - Hother, Christoffer

AU - Ralfkiaer, Elisabeth

AU - Rickert, Robert C

AU - Gronbaek, Kirsten

AU - David, Michael

N1 - Keywords: Animals; Cell Line, Tumor; Cell Proliferation; Gene Expression; Humans; Lymphoma, B-Cell; Mice; Mice, SCID; MicroRNAs; Neoplasm Transplantation; Phosphoric Monoester Hydrolases; Protein Transport; Tumor Necrosis Factor-alpha

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1002/emmm.200900028

DO - 10.1002/emmm.200900028

M3 - Journal article

C2 - 19890474

SN - 1757-4676

VL - 1

SP - 288

EP - 295

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 5

ER -