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EphrinA1 inhibits malignant mesothelioma tumor growth via let-7 microRNA-mediated repression of the RAS oncogene

Cancer Gene Therapy volume 18, pages 806–816 (2011)Cite this article

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Abstract

EphrinA1 binding with receptor EphA2 suppresses malignant mesothelioma (MM) growth. The mechanisms whereby EphrinA1 attenuates the MM cell (MMC) growth are not clear. In this study, we report that the activation of MMCs with EphrinA1 leads to an induction of let-7 microRNA (miRNA) expression, repression of RAS proto-oncogene and the attenuation of MM tumor growth. The expression of miRNAs was determined by reverse transcription-quantitative polymerase chain reaction and in situ hybridization. RAS expression was determined by q-PCR, western blotting and immunofluorescence. MMC proliferation and tumor growth were determined by WST-1 and Matrigel assay, respectively. EphrinA1 activation induced several fold increases in let-7a1, let-7a3, let-7f1 and let-7f2 miRNA expression in MMCs. In contrast, EphrinA1 activation significantly downregulated H-RAS, K-RAS and N-RAS expression and inhibited MMC proliferation and tumor growth. In MMCs transfected with 2′-O-methyl antisense oligonucleotides to let-7 miRNA, EphrinA1 activation failed to inhibit the proliferative response and tumor growth. In mismatch antisense oligonucleotide-treated MMCs, the proliferation and tumor growth were comparable to untreated proliferating cells. Furthermore, the transfection of MMCs with let-7a miRNA precursor inhibited RAS expression and attenuated MMC tumor growth. Our data revealed that EphrinA1 signaling induces let-7 miRNA expression and attenuates MM tumor growth by targeting RAS proto-oncogene in MMCs.

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Acknowledgements

This work was supported by NIR Grant no. 00079054; RC1 (no. 00083831) from Florida Department of Health (NN); and VA Merit Review (KAM). The technical assistance of Zita Burkhalter was greatly acknowledged.

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Authors and Affiliations

  1. Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Florida, Gainesville, FL, USA

    N Khodayari, K A Mohammed & N Nasreen

  2. NF/SG Veterans Health System, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL, USA

    K A Mohammed & N Nasreen

  3. Biomaterial Science and Engineering, University of Florida, Gainesville, FL, USA

    E P Goldberg

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  1. N Khodayari
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Correspondence to N Nasreen.

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Khodayari, N., Mohammed, K., Goldberg, E. et al. EphrinA1 inhibits malignant mesothelioma tumor growth via let-7 microRNA-mediated repression of the RAS oncogene. Cancer Gene Ther 18, 806–816 (2011). https://doi.org/10.1038/cgt.2011.50

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