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Oncotarget. 2015 Oct 13;6(31):32104-14. doi: 10.18632/oncotarget.5194.

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

Author information

1
Department of Biology, University of Padova, Padova, Italy.
2
Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.
3
Surgical Pathology & Cytopathology Unit, Department of Medicine, Hospital/University of Padova, Padova, Italy.
4
Department of Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila, Italy.
5
Neuromed Institute, Department of Neurological Sciences, University of L'Aquila, L'Aquila, Italy.
6
Department of Radiotherapy, Istituto Oncologico del Veneto, IOV-IRCCS, Padova, Italy.
7
Department of Molecular Medicine, University of Padova, Padova, Italy.

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.

KEYWORDS:

BRAF; aryl hydrocarbon receptor; gene expression; meta-analysis; papillary thyroid cancer

PMID:
26392334
PMCID:
PMC4741662
DOI:
10.18632/oncotarget.5194
[Indexed for MEDLINE]
Free PMC Article

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