title: RAS oncogene activation induces proliferation in normal human thyroid epithelial cells without loss of differentiation.
abstract: 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.
authors.affiliation: Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, UK.
authors.forename: V
authors.initials: V
authors.lastname: Gire
authors.forename: D
authors.initials: D
authors.lastname: Wynford-Thomas
mesh_terms: D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D000242:Cyclic AMP / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D011905:Genes, ras; D006801:Humans; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics; D020935:MAP Kinase Signaling System; D008845:Microinjections; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D015689:Oncogene Protein p21(ras) / Q000737:chemistry / Q000502:physiology*; D009857:Oncogenes; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D013954:Thyroglobulin / Q000096:biosynthesis / Q000235:genetics; D013961:Thyroid Gland / Q000166:cytology* / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection
chemical_list: D015820:Cadherins; D004268:DNA-Binding Proteins; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D011993:Recombinant Fusion Proteins; D000074482:Thyroid Nuclear Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D007633:Keratins; D013954:Thyroglobulin; D000242:Cyclic AMP; D015689:Oncogene Protein p21(ras)