title: A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC.
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.
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Occhi
authors.affiliation: Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Susi
authors.initials: S
authors.lastname: Barollo
authors.affiliation: Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Regazzo
authors.affiliation: Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: Bertazza
authors.affiliation: Surgical Pathology & Cytopathology Unit, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Galuppini
authors.affiliation: Surgical Pathology & Cytopathology Unit, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Guzzardo
authors.affiliation: Department of Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila, Italy.|Neuromed Institute, Department of Neurological Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Marie Lise
authors.initials: ML
authors.lastname: Jaffrain-Rea
authors.affiliation: Department of Radiotherapy, Istituto Oncologico del Veneto, IOV-IRCCS, Padova, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Vianello
authors.affiliation: Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Denis
authors.initials: D
authors.lastname: Ciato
authors.affiliation: Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Ceccato
authors.affiliation: Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Watutantrige-Fernando
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bisognin
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bortoluzzi
authors.affiliation: Surgical Pathology & Cytopathology Unit, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Pennelli
authors.affiliation: Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Boscaro
authors.affiliation: Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Scaroni
authors.affiliation: Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: BRAF; aryl hydrocarbon receptor; gene expression; meta-analysis; papillary thyroid cancer