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

• Published in: Oncogene Vol. 25; no. 39; pp. 5467 - 5474
• Main Authors: VITAGLIANO, D, PORTELLA, G, PASQUINELLI, R, CHIAPPETTA, G, TERRACCIANO, D, MACCHIA, V, MELILLO, R. M, FUSCO, A, SANTORO, M, TRONCONE, G, FRANCIONE, A, ROSSI, C, BRUNO, A, GIORGINI, A, COLUZZI, S, NAPPI, T. C, ROTHSTEIN, J. L
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 31-08-2006; Nature Publishing Group
• Subjects: Adenocarcinoma, Follicular - genetics; Adenocarcinoma, Follicular - pathology; Adenoma - genetics; Adenoma - pathology; Amino Acid Substitution; Animals; Biological and medical sciences; Cancer; Carcinogenesis; Cell Differentiation; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Fundamental and applied biological sciences. Psychology; Gene expression; Genes, ras; Genetics; Genomic instability; Hormones; Humans; Metastases; Mice; Mice, Transgenic; Micronuclei; Molecular and cellular biology; Mutation; Neoplasm Invasiveness; Oncogenes; Rodents; Thyrocytes; Thyroid cancer; Thyroid carcinoma; Thyroid gland; Thyroid Gland - pathology; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Thyroid-stimulating hormone; Transgenic animals; Transgenic mice; Tumors; Carcinoma; Targeting; Enzyme; ras; Transferases; Rodentia; progression; Malignant tumor; Carcinogenesis; Vertebrata; Mammalia; Mouse; thyroid; Kinase; C-Onc gene; Differentiation; Onc gene; Protooncogene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209527

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 approximately 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.