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MicroRNA-155 contributes to plexiform neurofibroma growth downstream of MEK

Oncogene volume 40, pages 951–963 (2021)Cite this article

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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.

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Fig. 1: MiR-155 is overexpressed in both mouse and human plexiform neurofibromas.
Fig. 2: MiR-155 regulates neurofibroma sphere numbers.
Fig. 3: Global deletion of miR-155 prolongs survival and decreases tumor number and size in the Nf1fl/fl;DhhCre neurofibroma mouse model.
Fig. 4: MEK regulates miR-155 expression through AP-1 binding to miR-155.
Fig. 5: Maf is a direct target of miR-155.
Fig. 6: Administration of anti-miR-155-PNAs-NPs in vivo marginally reduces tumor numbers.
Fig. 7: Anti-miR-155-PNAs effectively inhibits cell proliferation and increases target protein expression.

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Acknowledgements

We thank Drs. Mark Saltzman and Christopher J. Cheng (Yale School of Engineering and Applied Science) for providing fluorescence-conjugated nanoparticles to fulfill part of the in vivo experiments. This work was supported by NIH R01 NS097233 to J.W. NIH R0 NS28840 and R37 NS096356 to N.R.

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  1. Robert A. Coover

    Present address: Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, One University Parkway, High Point, NC, 27268, USA

Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA

    Youjin Na, Ashley Hall, Kwangmin Choi, Liang Hu, Jonathan Rose, Robert A. Coover, Adam Miller, Robert F. Hennigan, Nancy Ratner & Jianqiang Wu

  2. Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, 20892, USA

    Eva Dombi

  3. Department of Epidemiology and Biostatistics, UCSF, Box 0128, 1450 3rd St. Suite 285, San Francisco, CA, 94143, USA

    Mi-Ok Kim

  4. Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA

    Subbaya Subramanian

  5. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA

    Nancy Ratner & Jianqiang Wu

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Na, Y., Hall, A., Choi, K. et al. MicroRNA-155 contributes to plexiform neurofibroma growth downstream of MEK. Oncogene 40, 951–963 (2021). https://doi.org/10.1038/s41388-020-01581-9

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