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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References
Carcangiu ML, Zampi G, Rosai J . (1984). Am J Surg Pathol 8: 655–668.
DeLellis RA, Williams ED . (2004). In: DeLellis LA, Lloyd RV, Heitz PU, Eng C (eds). Tumours of Endocrine Organs. World Health Organization Classification of Tumors: Lyon, pp 51–56.
Downward J . (2003). Nat Rev Cancer 3: 11–22.
Doxsey S, Zimmerman W, Mikule K . (2005). Trends Cell Biol 15: 303–311.
Ellis CA, Clark G . (2000). Cell Signal 12: 425–434.
Fagin JA . (2002). Mol Endocrinol 16: 903–911.
Fagin JA . (2004). J Endocrinol 183: 249–256.
Garcia-Rostan G, Zhao H, Camp RL, Pollan M, Herrero A, Pardo J et al. (2003). J Clin Oncol 21: 3226–3235.
Gisselsson D, Bjork J, Hoglund M, Mertens F, Dal Cin P, Akerman M et al. (2001). Am J Pathol 158: 199–206.
Greco A, Pierotti MA, Bongarzone I, Pagliardini S, Lanzi C, Della Porta G . (1992). Oncogene 7: 237–242.
Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho JY et al. (1996). Endocrinology 137: 375–378.
Jokinen MP, Botts S . (1994). In: Turusob V, Mohr U (eds). Pathology of Tumours in Laboratory Animals. Volume 2 Tumours of the Mouse. WHO International Agency for Research on Cancer: Lyon, pp 565–594.
Knauf JA, Ma X, Smith EP, Zhang L, Mitsutake N, Liao XH et al. (2005). Cancer Res 65: 4238–4245.
Knauf JA, Ouyang B, Knudsen ES, Fukasawa K, Babcock G, Fagin JA . (2006). J Biol Chem 281: 3800–3809.
Ledent C, Coppee F, Dumont JE, Vassart G, Parmentier M . (1996). Exp Clin Endocrinol Diabetes 104: 43–46.
Ledent C, Dumont J, Vassart G, Parmentier M . (1991). Endocrinology 129: 1391–1401.
Ledent C, Dumont JE, Vassart G, Parmentier M . (1992). EMBO J 11: 537–542.
Malumbres M, Barbacid M . (2003). Nat Rev Cancer 3: 459–465.
Melillo RM, Castellone MD, Guarino V, De Falco V, Cirafici AM, Salvatore G et al. (2005). J Clin Invest 115: 1068–1081.
Motoi N, Sakamoto A, Yamochi T, Horiuchi H, Motoi T, Machinami R . (2000). Pathol Res Pract 196: 1–7.
Mitsutake N, Knauf JA, Mitsutake S, Mesa Jr C, Zhang L, Fagin JA . (2005). Cancer Res 65: 2465–2473.
Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F et al. (2003a). J Clin Endocrinol Metab 88: 5399–5404.
Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn II GW, Tallini G et al. (2003b). J Clin Endocrinol Metab 88: 2318–2326.
Powell Jr DJ, Russell J, Nibu K, Li G, Rhee E, Liao M et al. (1998). Cancer Res 58: 5523–5528.
Postiglione MP, Parlato R, Rodriguez-Mallon A, Rosica A, Mithbaokar P, Maresca M et al. (2002). Proc Natl Acad Sci USA 99: 15462–15467.
Rochefort P, Caillou B, Michiels FM, Ledent C, Talbot M, Schlumberger M et al. (1996). Oncogene 12: 111–118.
Russell JP, Powell DJ, Cunnane M, Greco A, Portella G, Santoro M et al. (2000). Oncogene 19: 5729–5735.
Saavedra HI, Knauf JA, Shirokawa JM, Wang J, Ouyang B, Elisei R et al. (2000). Oncogene 19: 3948–3954.
Santelli G, de Franciscis V, Portella G, Chiappetta G, D’Alessio A, Califano D et al. (1993). Cancer Res 53: 5523–5527.
Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G et al. (1996). Oncogene 12: 1821–1826.
Sherman SI . (2003). Lancet 361: 501–511.
Tallini G . (2002). Endocr Pathol 13: 271–288.
Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C . (2003). J Clin Endocrinol Metab 88: 2745–2752.
Xing M . (2005). Endocr Relat Cancer 12: 245–262.
Zhu Z, Gandhi M, Nikiforova MN, Fisher AH, Nikiforov YE . (2003). Am J Clin Pathol 120: 71–77.
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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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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DOI: https://doi.org/10.1038/sj.onc.1209527
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