MicroRNA-155 contributes to plexiform neurofibroma growth downstream of MEK

Youjin Na, Ashley Hall, Kwangmin Choi, Liang Hu, Jonathan Rose, Robert A. Coover, Adam Miller, Robert F. Hennigan, Eva Dombi, Mi Ok Kim, Subbaya Subramanian, Nancy Ratner, Jianqiang Wu

Research output: Contribution to journalArticlepeer-review

Abstract

MicroRNAs (miRs) are small non-coding RNAs that can have large impacts on oncogenic pathways. Possible functions of dysregulated miRs have not been studied in neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNFs). In PNFs, Schwann cells (SCs) have biallelic NF1 mutations necessary for tumorigenesis. We analyzed a miR microarray comparing with normal and PNF SCs and identified differences in miR expression, and we validated in mouse PNFs versus normal mouse SCs by qRT-PCR. Among these, miR-155 was a top overexpressed miR, and its expression was regulated by RAS/MAPK signaling. Overexpression of miR-155 increased mature Nf1−/− mouse SC proliferation. In SC precursors, which model tumor-initiating cells, pharmacological and genetic inhibition of miR-155 decreased PNF-derived sphere numbers in vitro, and we identified Maf as a miR-155 target. In vivo, global deletion of miR-155 significantly decreased tumor number and volume, increasing mouse survival. Fluorescent nanoparticles entered PNFs, suggesting that an anti-miR might have therapeutic potential. However, treatment of established PNFs using anti-miR-155 peptide nucleic acid-loaded nanoparticles marginally decreased tumor numbers and did not reduce tumor growth. These results suggest that miR-155 plays a functional role in PNF growth and/or SC proliferation, and that targeting neurofibroma miRs is feasible, and might provide novel therapeutic opportunities.

Original languageEnglish (US)
Pages (from-to)951-963
Number of pages13
JournalOncogene
Volume40
Issue number5
DOIs
StatePublished - Feb 4 2021

Bibliographical note

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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