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MicroRNA-155 contributes to plexiform neurofibroma growth downstream of MEK

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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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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