Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo.
MicroRNAs are important regulators of gene expression in normal development and disease. miR-9 is overexpressed in several cancer forms, including brain tumours, hepatocellular carcinomas, breast cancer and Hodgkin lymphoma (HL). Here we demonstrated a relevance for miR-9 in HL pathogenesis and identified two new targets Dicer1 and HuR. HL is characterized by a massive infiltration of immune cells and fibroblasts in the tumour, whereas malignant cells represent only 1% of the tumour mass. These infiltrates provide important survival and growth signals to the tumour cells, and several lines of evidence indicate that they are essential for the persistence of HL. We show that inhibition of miR-9 leads to derepression of DICER and HuR, which in turn results in a decrease in cytokine production by HL cells followed by an impaired ability to attract normal inflammatory cells. Finally, inhibition of miR-9 by a systemically delivered antimiR-9 in a xenograft model of HL increases the protein levels of HuR and DICER1 and results in decreased tumour outgrowth, confirming that miR-9 actively participates in HL pathogenesis and points to miR-9 as a potential therapeutic target.
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
E
E
Leucci
A
A
Zriwil
L H
LH
Gregersen
K T
KT
Jensen
S
S
Obad
C
C
Bellan
L
L
Leoncini
S
S
Kauppinen
A H
AH
Lund
D020413:3' Untranslated Regions; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020413:3' Untranslated Regions; D016207:Cytokines; D051959:ELAV Proteins; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases