title: BRAFV600E mutation, TIMP-1 upregulation, and NF-κB activation: closing the loop on the papillary thyroid cancer trilogy.
abstract: BRAF(V600E) is the most common mutation found in papillary thyroid carcinoma (PTC). Tissue inhibitor of metalloproteinases (TIMP-1) and nuclear factor (NF)-κB have been shown to play an important role in thyroid cancer. In particular, TIMP-1 binds its receptor CD63 on cell surface membrane and activates Akt signaling pathway, which is eventually responsible for its anti-apoptotic activity. The aim of our study was to evaluate whether interplay among these three factors exists and exerts a functional role in PTCs. To this purpose, 56 PTC specimens were analyzed for BRAF(V600E) mutation, TIMP-1 expression, and NF-κB activation. We found that BRAF(V600E) mutation occurs selectively in PTC nodules and is associated with hyperactivation of NF-κB and upregulation of both TIMP-1 and its receptor CD63. To assess the functional relationship among these factors, we first silenced BRAF gene in BCPAP cells, harboring BRAF(V600E) mutation. We found that silencing causes a marked decrease in TIMP-1 expression and NF-κB binding activity, as well as decreased invasiveness. After treatment with specific inhibitors of MAPK pathway, we found that only sorafenib was able to increase IκB-α and reduce both TIMP-1 expression and Akt phosphorylation in BCPAP cells, indicating that BRAF(V600E) activates NF-κB and this pathway is MEK-independent. Taken together, our findings demonstrate that BRAF(V600E) causes upregulation of TIMP-1 via NF-κB. TIMP-1 binds then its surface receptor CD63, leading eventually to Akt activation, which in turn confers antiapoptotic behavior and promotion of cell invasion. The recognition of this functional trilogy provides insight on how BRAF(V600E) determines cancer initiation, progression, and invasiveness in PTC, also identifying new therapeutic targets for the treatment of highly aggressive forms.
authors: Sezione di Endocrinologia, Laboratorio di Endocrinologia Molecolare, Dipartimento di Biomedico di Medicina Interna e Specialistica (DIBIMIS), University of Palermo, Italy.
authors: Alessandra
authors: A
authors: Bommarito
authors: Pierina
authors: P
authors: Richiusa
authors: Elvira
authors: E
authors: Carissimi
authors: Giuseppe
authors: G
authors: Pizzolanti
authors: Vito
authors: V
authors: Rodolico
authors: Giovanni
authors: G
authors: Zito
authors: Angela
authors: A
authors: Criscimanna
authors: Francesco
authors: F
authors: Di Blasi
authors: Maria
authors: M
authors: Pitrone
authors: Monica
authors: M
authors: Zerilli
authors: Marco C
authors: MC
authors: Amato
authors: Gaetano
authors: G
authors: Spinelli
authors: Valeria
authors: V
authors: Carina
authors: Giuseppe
authors: G
authors: Modica
authors: M Adelfio
authors: MA
authors: Latteri
authors: Aldo
authors: A
authors: Galluzzo
authors: Carla
authors: C
authors: Giordano
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000502:physiology; D002277:Carcinoma; D002291:Carcinoma, Papillary; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000502:physiology; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics; D014633:Valine / Q000235:genetics
chemical_list: D016328:NF-kappa B; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D018698:Glutamic Acid; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D014633:Valine