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Int. J. Environ. Res. Public Health 2019, 16(1), 122;

A Toxicogenomic Approach Reveals a Novel Gene Regulatory Network Active in In Vitro and In Vivo Models of Thyroid Carcinogenesis

IRGS, Biogem, Via Camporeale, 83031 Ariano Irpino, Avellino, Italy
Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, 80131 Naples, Italy
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX 77843, USA
Department of Science and Technology, University of Sannio, via Port’Arsa 11, 82100 Benevento, Italy
Department of Public Health, University of Naples “Federico II”, 80131 Naples, Italy
Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
IEOS-CNR, Via Pansini 6, 80131 Naples, Italy
These authors contributed equally to this work and are corresponding authors.
Authors to whom correspondence should be addressed.
Received: 26 November 2018 / Revised: 21 December 2018 / Accepted: 27 December 2018 / Published: 4 January 2019
(This article belongs to the Special Issue Environmental Carcinogens)
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Epidemiological and experimental studies emphasize the link between environmental chemicals exposure and thyroid cancer. However, this association is strongly debated and the mechanisms of action of environmental thyroid carcinogens still need to be identified. The analysis of in vitro transcriptomic data developed to investigate the effects of chlorpyrifos on immortalized thyrocytes highlighted the impaired expression of genes involved in endodermal carcinogenesis. This endodermal carcinogenic gene-network (ECGN, including Zfp36l2, Dmbt1, Ddit4), was validated in cellular and mouse models of thyroid carcinogenesis, characterized by the constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and in immortalized thyrocytes exposed to tetrachlorodibenzo-p-dioxin (TCDD) and chlorpyrifos (CPF). The mRNA levels of Zfp36l2, Dmbt1 and Ddit4 were increased in models characterized by MAPK activation or following TCDD exposure, whereas they were inhibited by CPF exposure. Overall, the ECGN transcripts identify a novel gene-regulatory network associated with thyroid carcinogenesis promoted by genetic mutation or by environmental carcinogens. The latter have opposite effects on the modulation of the ECGN transcripts according to their mechanisms of action in promoting carcinogenesis. Therefore, the analyses of ECGN might be helpful in discriminating compounds that promote cellular survival associated or not to proliferation of thyrocytes. View Full-Text
Keywords: pesticides; TCDD; gene expression; thyroid cancer; cell survival pesticides; TCDD; gene expression; thyroid cancer; cell survival

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Reale, C.; Russo, F.; Credendino, S.C.; Cuomo, D.; De Vita, G.; Mallardo, M.; Pennino, F.; Porreca, I.; Triassi, M.; De Felice, M.; Ambrosino, C. A Toxicogenomic Approach Reveals a Novel Gene Regulatory Network Active in In Vitro and In Vivo Models of Thyroid Carcinogenesis. Int. J. Environ. Res. Public Health 2019, 16, 122.

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