Journal Article

RAS oncogene activation induces proliferation in normal human thyroid epithelial cells without loss of differentiation

Gire, Véronique, Wynford-Thomas, David

2000

Overview

Neoplastic transformation of rodent thyroid epithelial cell lines by mutant RAS genes has been widely studied as an experimental model of oncogene-induced loss of tissue-specific differentiation. However, separate evidence strongly implicates RAS mutation as an early event in human thyroid tumour development at a stage prior to loss of differentiation. To resolve this controversy we examined the short- and long-term responses of normal human thyroid epithelial cells to mutant RAS introduced by micro-injection and retroviral transduction respectively. In both cases, expression of RAS at a level sufficient to induce rapid proliferation did not lead to loss of differentiation as shown by expression of cytokeratin 18, E-cadherin, thyroglobulin, TTF-1 and Pax-8 proteins. Indeed, RAS was able to prevent, and to reverse, the loss of thyroglobulin expression which occurs normally in TSH-deficient culture medium. These responses were partially mimicked by activation of RAF, a major RAS effector, indicating involvement of the MAP Kinase signal pathway. The striking contrast between the effect of mutant RAS on differentiation in primary human, compared to immortalized rodent, epithelial cultures is most likely explained by the influence of additional co-operating abnormalities in the latter, and highlights the need for caution in extrapolating from cell line data.

• Publisher: Nature Publishing,Nature Publishing Group
• Subject: Biological and medical sciences / Cadherins - biosynthesis / Cadherins - genetics / Cell culture / Cell differentiation / Cell Differentiation - genetics / Cell Division - genetics / Cell physiology / Cell proliferation / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cells, Cultured / Cellular signal transduction / Colony-Forming Units Assay / Cyclic AMP - physiology / Cytokeratin / cytokeratin 18 / DNA-Binding Proteins - biosynthesis / DNA-Binding Proteins - genetics / E-cadherin / Epithelial cells / Epithelial Cells - cytology / Epithelial Cells - metabolism / Fundamental and applied biological sciences. Psychology / Gene Expression Regulation / Genes, ras / Genetic aspects / Humans / Keratins - biosynthesis / Keratins - genetics / MAP kinase / MAP Kinase Signaling System / Microinjections / Molecular and cellular biology / Mutants / Nuclear Proteins - biosynthesis / Nuclear Proteins - genetics / Oncogene Protein p21(ras) - chemistry / Oncogene Protein p21(ras) - physiology / Oncogenes / Paired Box Transcription Factors / PAX8 Transcription Factor / Physiological aspects / Raf protein / Ras genes / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - physiology / Risk factors / Thyrocytes / Thyroglobulin / Thyroglobulin - biosynthesis / Thyroglobulin - genetics / Thyroid / Thyroid cancer / Thyroid gland / Thyroid Gland - cytology / Thyroid Gland - metabolism / Thyroid Nuclear Factor 1 / Thyroid-stimulating hormone / Trans-Activators - biosynthesis / Trans-Activators - genetics / Transcription Factors - biosynthesis / Transcription Factors - genetics / Transfection / Tumors