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Upregulation of miR-21 by Ras in vivo and its role in tumor growth

Oncogene volume 30, pages 275–286 (2011)Cite this article

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Abstract

miR-21 is a microRNA (miRNA) frequently overexpressed in human cancers. Here we show that miR-21 is upregulated both in vitro and in vivo by oncogenic Ras, thus linking this miRNA to one of the most frequently activated oncogenes in human cancers. Ras regulation of miR-21 occurs with a delayed kinetic and requires at least two Ras downstream pathways. A screen of human thyroid cancers and non-small-cell lung cancers for the expression of miR-21 reveals that it is overexpressed mainly in anaplastic thyroid carcinomas, the most aggressive form of thyroid cancer, whereas in lung its overexpression appears to be inversely correlated with tumor progression. We also show that a LNA directed against miR-21 slows down tumor growth in mice. Consistently, a search for mRNAs downregulated by miR-21 shows an enrichment for mRNAs encoding cell cycle checkpoints regulators, suggesting an important role for miR-21 in oncogenic Ras-induced cell proliferation.

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References

  • Abulaiti A, Fikaris AJ, Tsygankova OM, Meinkoth JL . (2006). Ras induces chromosome instability and abrogation of the DNA damage response. Cancer Res 66: 10505–10512.

    Article  CAS  Google Scholar 

  • Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP . (2008). The impact of microRNAs on protein output. Nature 455: 64–71.

    Article  CAS  Google Scholar 

  • Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S et al. (2004). Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 101: 2999–3004.

    Article  CAS  Google Scholar 

  • Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM et al. (2008). Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 40: 43–50.

    Article  CAS  Google Scholar 

  • De Vita G, Bauer L, da Costa VM, De Felice M, Baratta MG, De Menna M et al. (2005). Dose-dependent inhibition of thyroid differentiation by RAS oncogenes. Mol Endocrinol 19: 76–89.

    Article  CAS  Google Scholar 

  • Esquela-Kerscher A, Slack FJ . (2006). Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 6: 259–269.

    Article  CAS  Google Scholar 

  • Fujita S, Ito T, Mizutani T, Minoguchi S, Yamamichi N, Sakurai K et al. (2008). miR-21 Gene expression triggered by AP-1 is sustained through a double-negative feedback mechanism. J Mol Biol 378: 492–504.

    Article  CAS  Google Scholar 

  • Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP . (2007). MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27: 91–105.

    Article  CAS  Google Scholar 

  • Guerra C, Mijimolle N, Dhawahir A, Dubus P, Barradas M, Serrano M et al. (2003). Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4: 111–120.

    Article  CAS  Google Scholar 

  • He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S et al. (2005). The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA 102: 19075–19080.

    Article  CAS  Google Scholar 

  • He X, He L, Hannon GJ . (2007). The guardian's little helper: microRNAs in the p53 tumor suppressor network. Cancer Res 67: 11099–11101.

    Article  CAS  Google Scholar 

  • John B, Enright AJ, Aravin A et al. (2004). Human MicroRNA targets. PLoS Biol 2: e363.

    Article  Google Scholar 

  • Kertesz M, Iovino N, Unnerstall U, Gaul U, Segal E . (2007). The role of site accessibility in microRNA target recognition. Nat Genet 39: 1278–1284.

    Article  CAS  Google Scholar 

  • Knauf JA, Ouyang B, Knudsen ES, Fukasawa K, Babcock G, Fagin JA . (2006). Oncogenic RAS induces accelerated transition through G2/M and promotes defects in the G2 DNA damage and mitotic spindle checkpoints. J Biol Chem 281: 3800–3809.

    Article  CAS  Google Scholar 

  • Krichevsky AM, Gabriely G . (2009). miR-21: a small multi-faceted RNA. J Cell Mol Med 13: 39–53.

    Article  CAS  Google Scholar 

  • Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A et al. (2007). A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129: 1401–1414.

    Article  CAS  Google Scholar 

  • Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K et al. (2008). Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab 93: 3106–3116.

    Article  CAS  Google Scholar 

  • Löffler D, Brocke-Heidrich K, Pfeifer G, Stocsits C, Hackermüller J, Kretzschmar AK et al. (2007). Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood 110: 1330–1333.

    Article  Google Scholar 

  • Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. (2005). MicroRNA expression profiles classify human cancers. Nature 435: 834–838.

    Article  CAS  Google Scholar 

  • Markou A, Tsaroucha EG, Kaklamanis L, Fotinou M, Georgoulias V, Lianidou ES . (2008). Prognostic value of mature microRNA-21 and microRNA-205 overexpression in non-small cell lung cancer by quantitative real-time RT-PCR. Clin Chem 54: 1696–1704.

    Article  CAS  Google Scholar 

  • Martinsson-Ahlzen HS, Liberal V, Grunenfelder B, Chaves SR, Spruck CH, Reed SI . (2008). Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells. Mol Cell Biol 28: 5698–5709.

    Article  CAS  Google Scholar 

  • Miller KA YN, Baker K, Liao XH, Refetoff S, Di Cristofano A . (2009). Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo. Cancer Res 69: 3689–3694.

    Article  Google Scholar 

  • O′Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT . (2005). c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435: 839–843.

    Article  Google Scholar 

  • Pines J, Hunter T . (1989). Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell 58: 833–846.

    Article  CAS  Google Scholar 

  • Seike M, Goto A, Okano T, Bowman ED, Schetter AJ, Horikawa I et al. (2009). MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. Proc Natl Acad Sci USA 106: 12085–12090.

    Article  CAS  Google Scholar 

  • Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY . (2007). miR-21-mediated tumor growth. Oncogene 26: 2799–2803.

    Article  CAS  Google Scholar 

  • Talotta F, Cimmino A, Matarazzo MR, Casalino L, De Vita G, D′Esposito M et al. (2009). An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation. Oncogene 28: 73–84.

    Article  CAS  Google Scholar 

  • Visone R, Pallante P, Vecchione A, Cirombella R, Ferracin M, Ferraro A et al. (2007). Specific microRNAs are downregulated in human thyroid anaplastic carcinomas. Oncogene 26: 7590–7595.

    Article  CAS  Google Scholar 

  • Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F et al. (2006). A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103: 2257–2261.

    Article  CAS  Google Scholar 

  • Xiao F, Zuo Z, Cai G, Kang S, Gao X, Li T . (2009). miRecords: an integrated resource for microRNA-target interactions. Nucleic Acids Res 37: D105–D110.

    Article  CAS  Google Scholar 

  • Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M et al. (2006). Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9: 189–198.

    Article  CAS  Google Scholar 

  • Zhang B, Pan X, Cobb GP, Anderson TA . (2007). microRNAs as oncogenes and tumor suppressors. Dev Biol 302: 1–12.

    Article  CAS  Google Scholar 

  • Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A et al. (2006). microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA 103: 9136–9141.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Pietro Carotenuto (CROM, Centro Ricerche Oncologiche Mercogliano, Italy), Ilaria Pedicelli (Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Monaldi Hospital, Naples, Italy) and Nicolina De Rosa (Department of Pathology, Monaldi Hospital, Naples, Italy) for collection and technical help in the analysis of lung cancer samples. This work was supported by EU-Project-SIROCCO (Grant LSHG-CT-2006-037900), Associazione Italiana per la Ricerca sul Cancro (AIRC) to RDL and AIRC, EUFP7 Tumic to MZ.

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Authors and Affiliations

  1. IRGS Biogem s.c.ar.l., Ariano Irpino, Italy

    D Frezzetti, P Zoppoli, P De Luca & M Ceccarelli

  2. Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università degli Studi di Napoli ′Federico II′, Naples, Italy

    D Frezzetti, A Fusco, R Di Lauro & G De Vita

  3. SEMM, European School of Molecular Medicine, Naples Site, Naples, Italy

    M De Menna

  4. CEINGE, Centro di Ingegneria Genetica e Biotecnologie Avanzate, Naples, Italy

    M De Menna, A Ferraro, A M Bello & M Zollo

  5. Department of Biological and Environmental Studies, University of Sannio, Benevento, Italy

    P Zoppoli & M Ceccarelli

  6. Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

    C Guerra & M Barbacid

  7. NOGEC, Naples Oncogenomic Center, Naples, Italy

    A Ferraro & A Fusco

  8. Stazione Zoologica Anton Dohrn, Naples, Italy

    P De Luca

  9. Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Monaldi Hospital, Naples, Italy

    C Calabrese

  10. Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy

    A Fusco

  11. Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli, Naples, Italy

    M Zollo

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  1. D Frezzetti
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  2. M De Menna
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Correspondence to R Di Lauro or G De Vita.

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Supplementary information accompanies the paper on the Oncogene website

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Frezzetti, D., Menna, M., Zoppoli, P. et al. Upregulation of miR-21 by Ras in vivo and its role in tumor growth. Oncogene 30, 275–286 (2011). https://doi.org/10.1038/onc.2010.416

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  • DOI: https://doi.org/10.1038/onc.2010.416

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