Oncotarget

Research Papers:

A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC

Gianluca Occhi _, Susi Barollo, Daniela Regazzo, Loris Bertazza, Francesca Galuppini, Vincenza Guzzardo, Marie Lise Jaffrain-Rea, Federica Vianello, Denis Ciato, Filippo Ceccato, Sara Watutantrige-Fernando, Andrea Bisognin, Stefania Bortoluzzi, Gianmaria Pennelli, Marco Boscaro, Carla Scaroni and Caterina Mian

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Oncotarget. 2015; 6:32104-32114. https://doi.org/10.18632/oncotarget.5194

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Abstract

Gianluca Occhi1,*, Susi Barollo2,*, Daniela Regazzo2, Loris Bertazza2, Francesca Galuppini3, Vincenza Guzzardo3, Marie Lise Jaffrain-Rea4,5, Federica Vianello6, Denis Ciato2, Filippo Ceccato2, Sara Watutantrige-Fernando2, Andrea Bisognin1, Stefania Bortoluzzi7, Gianmaria Pennelli3, Marco Boscaro2, Carla Scaroni2, Caterina Mian2

1Department of Biology, University of Padova, Padova, Italy

2Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy

3Surgical Pathology & Cytopathology Unit, Department of Medicine, Hospital/University of Padova, Padova, Italy

4Department of Clinical and Biotechnological Sciences, University of L’Aquila, L’Aquila, Italy

5Neuromed Institute, Department of Neurological Sciences, University of L’Aquila, L’Aquila, Italy

6Department of Radiotherapy, Istituto Oncologico del Veneto, IOV-IRCCS, Padova, Italy

7Department of Molecular Medicine, University of Padova, Padova, Italy

*These authors have contributed equally to this work

Correspondence to:

Gianluca Occhi, e-mail: [email protected]

Keywords: papillary thyroid cancer, aryl hydrocarbon receptor, BRAF, gene expression, meta-analysis

Received: April 30, 2015     Accepted: September 03, 2015     Published: September 16, 2015

ABSTRACT

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAFV600E may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice.


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