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Overexpression of genes involved in miRNA biogenesis in medullary thyroid carcinomas with RET mutation

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Abstract

Abnormal expression of non-coding micro RNA (miRNA) has been described in medullary thyroid carcinoma (MTC). Expression of genes encoding factors involved in miRNA biogenesis results often deregulated in human cancer and correlates with aggressive clinical behavior. In this study, expression of four genes involved in miRNA biogenesis (DICER, DROSHA, DCGR8, and XPO5) was investigated in 54 specimens of MTC. Among them, 33 and 13 harbored RET and RAS mutations, respectively. DICER, DGCR8, and XPO5 mRNA levels were significantly overexpressed in MTC harboring RET mutations, in particular, in the presence of RET634 mutation. When MTCs with RET and RAS mutations were compared, only DGCR8 displayed a significant difference, while MTCs with RAS mutations did not show significant differences with respect to non-mutated tumors. We then attempted to correlate expression of miRNA biogenesis genes with tumor aggressiveness. According to the TNM status, MTCs were divided in two groups and compared (N0 M0 vs. N1 and/or M1): for all four genes no significant difference was detected. Cell line experiments, in which expression of a RET mutation is silenced by siRNA, suggest the existence of a causal relationship between RET mutation and overexpression of DICER, DGCR8, and XPO5 genes. These findings demonstrate that RET- but not RAS-driven tumorigenic alterations include abnormalities in the expression of some important genes involved in miRNA biogenesis that could represent new potential markers for targeted therapies in the treatment of RET-mutated MTCs aimed to restore the normal miRNA expression profile.

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Acknowledgments

The study was supported by research Grants from The Umberto Di Mario Foundation and from the Banca d’Italia. It was also supported by Grants to GD from the Associazione Italiana per la Ricerca sul Cancro (AIRC) (Grant No. IG 10296) and the Italian Government MIUR (Grant No. 20093WAPYK_003), and to AFC from the Italian Government MIUR (Grant No. 200937N3ME_005).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Dipartimento di Scienze Mediche e Biologiche, Università di Udine, Piazzale Kolbe 4, 33100, Udine, Italy

    Cinzia Puppin, Elisa Lavarone, Federica Baldan & Giuseppe Damante

  2. Dipartimento di Medicina Interna e “Specialità” Mediche, Università di Roma Sapienza, Rome, Italy

    Cosimo Durante, Marialuisa Sponziello, Antonella Verrienti, Valeria Pecce & Sebastiano Filetti

  3. Dipartimento di Medicina Molecolare, Università di Roma “Sapienza”, Rome, Italy

    Antonio Francesco Campese

  4. Institut Gustave Roussy, Université Paris Sud, Villejuif, France

    Amelie Boichard & Ludovic Lacroix

  5. Dipartimento di Scienze della Salute, Università di Catanzaro, Catanzaro, Italy

    Diego Russo

  6. Azienda Ospedaliero-universitaria S. Maria della Misericordia, Udine, Italy

    Giuseppe Damante

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  1. Cinzia Puppin
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Puppin, C., Durante, C., Sponziello, M. et al. Overexpression of genes involved in miRNA biogenesis in medullary thyroid carcinomas with RET mutation. Endocrine 47, 528–536 (2014). https://doi.org/10.1007/s12020-014-0204-3

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