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Thyroid targeting of the N-ras(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas

Abstract

Ras oncogenes are frequently mutated in thyroid carcinomas. To verify the role played by N-ras in thyroid carcinogenesis, we generated transgenic mice in which a human N-ras(Gln61Lys) oncogene (Tg-N-ras) was expressed in the thyroid follicular cells. Tg-N-ras mice developed thyroid follicular neoplasms; 11% developed follicular adenomas and 40% developed invasive follicular carcinomas, in some cases with a mixed papillary/follicular morphology. About 25% of the Tg-N-ras carcinomas displayed large, poorly differentiated areas, featuring vascular invasion and forming lung, bone or liver distant metastases. N-ras(Gln61Lys) expression in cultured PC Cl 3 thyrocytes induced thyroid-stimulating hormone-independent proliferation and genomic instability with micronuclei formation and centrosome amplification. These findings support the notion that mutated ras oncogenes could be able to drive the formation of thyroid tumors that can progress to poorly differentiated, metastatic carcinomas.

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Acknowledgements

We are grateful to JE Dumont for the Tg promoter, A Greco for the TRK-T1 cDNA, M De Felice and R Di Lauro for thyroid-specific antibodies. We thank S Sequino for animal care and Jean Gilder for text editing. This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Progetto Strategico Oncologia of the CNR/MIUR, the Italian Ministero della Salute and the NOGEC (Naples OncoGEnomic Center).

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Correspondence to M Santoro.

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Vitagliano, D., Portella, G., Troncone, G. et al. Thyroid targeting of the N-ras(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas. Oncogene 25, 5467–5474 (2006). https://doi.org/10.1038/sj.onc.1209527

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