TPA induces a block of differentiation and increases the susceptibility to neoplastic transformation of a rat thyroid epithelial cell line.
The PC Cl 3 cell line is a well-characterized epithelial cell line of rat thyroid origin. This cell line retains in vitro the typical markers of thyroid differentiation: thyroglobulin (TG) synthesis and secretion, iodide uptake, thyroperoxidase (TPO) expression, and dependency on TSH for growth. Although the differentiated phenotype of thyroid cells has been relatively well described, the molecular mechanisms that regulate both differentiation and neoplastic transformation of thyroid cells still need to be investigated in detail. Protein kinase C (PKC), the target of tetradecanoylphorbol acetate (TPA), regulates growth and differentiation of several cell types. Here we show that treatment of PC Cl 3 cells with TPA induces an acute block of thyroid differentiation. TPA-treated PC Cl 3 cells are unable to trap iodide and the expression levels of thyroglobulin, TSH receptor, and TPO genes are drastically reduced by TPA treatment. This differentiation block is not caused by a reduced expression of one of the master genes of thyroid differentiation, the thyroid transcription factor 1 (TTF-1). TPA-treated PC Cl 3 cells display an increased growth rate indicating that, in addition to the differentiation block, TPA also significantly affects the growth regulation of thyroid cells. Finally, TPA treatment dramatically increases the number of transformation foci induced in PC Cl 3 cells by retroviruses carrying v-Ki-ras, v-Ha-ras, and v-mos oncogenes. These findings support the notion that the PKC pathway can influence proliferation, differentiation, and neoplastic transformation of thyroid cells in culture.
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Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Università di Napoli Federico II/Centro di Endocrinologia e Oncologia Sperimentale del C.N.R., Italy.
Vitagliano
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Li
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Sferratore
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D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D002273:Carcinogens / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016258:Genes, mos; D011905:Genes, ras; D016391:Genes, src; D007453:Iodide Peroxidase / Q000187:drug effects / Q000235:genetics; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C; D051381:Rats; D011919:Rats, Inbred Strains; D011989:Receptors, Thyrotropin / Q000187:drug effects / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D013954:Thyroglobulin / Q000187:drug effects / Q000235:genetics; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D002273:Carcinogens; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D011989:Receptors, Thyrotropin; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D013954:Thyroglobulin; D007453:Iodide Peroxidase; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate