miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth

Abstract

The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 3′ untranslated region (UTR) analysis upon miR-17-19b overexpression. We identify over one hundred miR-17-19b targets, of which 40% are co-regulated by c-MYC. Downregulation of a new miR-17/20 target, checkpoint kinase 2 (Chek2), increases the recruitment of HuR to c-MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 3′ UTR shortening at different stages of tumorigenesis.

miR-28 regulates the germinal center reaction and blocks tumor growth in preclinical models of non-Hodgkin lymphoma

“…25 In our study, we believed that the combination of transcriptome and proteome approaches was the preferable choice for miRNA target identification, to allow the detection of miR-28 activity both at the level of mRNA stability reduction and at the level of translation inhibition. 32,33 Importantly, this strategy has led to the finding that miR-28 significantly alters the BCR signaling network, the key signaling pathway regulating B-cell proliferation and cell death. Dampened BCR signaling in miR-28-expressing B cells is confirmed by reduced phosphorylation of key mediators of BCR signaling such as AKT and ERK and by reduced expression of the NF-kB mediators NF-kB2 and IKKb and the antiapoptotic effector Bcl-2.…”

MYC/miR-17-92 interplay maintains B-lymphoma cell homeostasis

“…5 At this stage of tumor progression, the transcriptome has been pervasively shaped by high levels of MYC: in particular, we observed that, in addition to different transcriptional programs being active, extensive 3 0 UTR (untranslated region) shortening contributes to change the mRNA landscape. This observation, combined with the fact that miRNAs bind to the 3 0 UTRs of their target genes, led us to hypothesize that the transcriptome plasticity, occurring in the transition from early-to late-tumor stage, can lead to a substantial modification of the pool of targets for any given miRNA, and thus modify the MYC/miR-17-92 functional interplay.…”

The Role of miRNAs in Diagnosis, Prognosis and Treatment Prediction in Cervical Cancer

“…Although the mechanism of the oncogenic effect has not been fully elucidated, the authors suggested a decrease of apoptosis in these cells. The mechanisms that underlie the synergy between c-myc and miR-17-19b overexpression in B-cell lymphomas were demonstrated 10 years later by Mihailovich et al [28] based on a comprehensive analysis integrating proteomics, transcriptomics and miRNAs prediction analysis. The third landmark study performed by O'Donnell et al [29] demonstrated that the activity of E2F1 transcriptional factor can be controlled by two clusters of miRNAs (mir-17 and mir-106a) whose expression is activated by c-myc oncogene.…”