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

被引：0

作者：

Marija Mihailovich

Michael Bremang

Valeria Spadotto

Daniele Musiani

Elena Vitale

Gabriele Varano

Federico Zambelli

Francesco M. Mancuso

David A. Cairns

Giulio Pavesi

Stefano Casola

Tiziana Bonaldi

机构：

[1] European Institute of Oncology,Department of Experimental Oncology

[2] Via Adamello 16,Department of Biosciences

[3] Milan 20139,undefined

[4] Italy,undefined

[5] Units of Genetics of B cells and lymphomas,undefined

[6] IFOM,undefined

[7] FIRC Institute of Molecular Oncology Foundation,undefined

[8] Milan University,undefined

[9] Present address: Department of Oncological Sciences Icahn School of Medicine at Mount Sinai One Gustave L. Levy,undefined

[10] Box 1075,undefined

[11] New York,undefined

[12] New York 10029,undefined

[13] USA,undefined

[14] Present address: Cancer Genomics Group,undefined

[15] Vall d'Hebron Institute of Oncology (VHIO),undefined

[16] 08035 Barcelona,undefined

[17] Spain,undefined

[18] Present address: Leeds Institute of Cancer and Pathology,undefined

[19] University of Leeds,undefined

[20] Leeds LS9 7TF,undefined

[21] UK,undefined

来源：

Nature Communications | / 6卷

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摘要：

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.

引用

共 145 条

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