BRAFV600E mutation, TIMP-1 up-regulation and NF-{kappa}B activation: closing the loop on the papillary thyroid cancer trilogy.

Vito Rodolico, Giuseppe Pizzolanti, Marco Calogero Amato, Aldo Galluzzo, Giovanni Zito, Monica Zerilli, Carla Giordano, Giuseppe Modica, Maria Pitrone, Mario Latteri, Carla Giordano, Gaetano Spinelli, Francesco Di Blasi, Alessandra Bommarito, Angela Criscimanna, Elvira Carissimi, Gabriele Spinelli, Valeria Carina

Risultato della ricerca: Article

41 Citazioni (Scopus)

Abstract

BRAFV600E is the most common mutation found in papillary thyroid carcinoma (PTC). Tissue inhibitor of metalloproteinases (TIMP-1) and nuclear factor (NF)-kB 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 esponsible for its antiapoptotic 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 BRAFV600E mutation, TIMP-1 expression, and NF-kB activation. We found that BRAFV600E mutation occurs selectively in PTC nodules and is associated with hyperactivation of NF-kB 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 BRAFV600E mutation. We found that silencing causes a marked decrease in TIMP-1 expression and NF-kB binding activity, as well as decreased invasiveness. After treatment with specific inhibitors of MAPK pathway, we found that only sorafenib was able to increase IkB-a and reduce both TIMP-1 expression and Akt phosphorylation in BCPAP cells, indicating that BRAFV600E activates NF-kB and this pathway is MEK-independent. Taken together, our findings demonstrate that BRAFV600E causes upregulation of TIMP-1 via NF-kB. 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 BRAFV600E determines cancer initiation, progression, and invasiveness in PTC, also identifying new therapeutic targets for the treatment of highly aggressive forms.
Lingua originaleEnglish
pagine (da-a)669-685
Numero di pagine17
RivistaDefault journal
Volume18
Stato di pubblicazionePublished - 2011

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Tissue Inhibitor of Metalloproteinase-1
NF-kappa B
Up-Regulation
Mutation
Papillary Thyroid cancer
Thyroid Nodule
Factor IX
Mitogen-Activated Protein Kinase Kinases
Thyroid Neoplasms
Phosphorylation
Cell Membrane

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

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BRAFV600E mutation, TIMP-1 up-regulation and NF-{kappa}B activation: closing the loop on the papillary thyroid cancer trilogy. / Rodolico, Vito; Pizzolanti, Giuseppe; Amato, Marco Calogero; Galluzzo, Aldo; Zito, Giovanni; Zerilli, Monica; Giordano, Carla; Modica, Giuseppe; Pitrone, Maria; Latteri, Mario; Giordano, Carla; Spinelli, Gaetano; Di Blasi, Francesco; Bommarito, Alessandra; Criscimanna, Angela; Carissimi, Elvira; Spinelli, Gabriele; Carina, Valeria.

In: Default journal, Vol. 18, 2011, pag. 669-685.

Risultato della ricerca: Article

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title = "BRAFV600E mutation, TIMP-1 up-regulation and NF-{kappa}B activation: closing the loop on the papillary thyroid cancer trilogy.",
abstract = "BRAFV600E is the most common mutation found in papillary thyroid carcinoma (PTC). Tissue inhibitor of metalloproteinases (TIMP-1) and nuclear factor (NF)-kB 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 esponsible for its antiapoptotic 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 BRAFV600E mutation, TIMP-1 expression, and NF-kB activation. We found that BRAFV600E mutation occurs selectively in PTC nodules and is associated with hyperactivation of NF-kB 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 BRAFV600E mutation. We found that silencing causes a marked decrease in TIMP-1 expression and NF-kB binding activity, as well as decreased invasiveness. After treatment with specific inhibitors of MAPK pathway, we found that only sorafenib was able to increase IkB-a and reduce both TIMP-1 expression and Akt phosphorylation in BCPAP cells, indicating that BRAFV600E activates NF-kB and this pathway is MEK-independent. Taken together, our findings demonstrate that BRAFV600E causes upregulation of TIMP-1 via NF-kB. 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 BRAFV600E determines cancer initiation, progression, and invasiveness in PTC, also identifying new therapeutic targets for the treatment of highly aggressive forms.",
author = "Vito Rodolico and Giuseppe Pizzolanti and Amato, {Marco Calogero} and Aldo Galluzzo and Giovanni Zito and Monica Zerilli and Carla Giordano and Giuseppe Modica and Maria Pitrone and Mario Latteri and Carla Giordano and Gaetano Spinelli and {Di Blasi}, Francesco and Alessandra Bommarito and Angela Criscimanna and Elvira Carissimi and Gabriele Spinelli and Valeria Carina",
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TY - JOUR

T1 - BRAFV600E mutation, TIMP-1 up-regulation and NF-{kappa}B activation: closing the loop on the papillary thyroid cancer trilogy.

AU - Rodolico, Vito

AU - Pizzolanti, Giuseppe

AU - Amato, Marco Calogero

AU - Galluzzo, Aldo

AU - Zito, Giovanni

AU - Zerilli, Monica

AU - Giordano, Carla

AU - Modica, Giuseppe

AU - Pitrone, Maria

AU - Latteri, Mario

AU - Giordano, Carla

AU - Spinelli, Gaetano

AU - Di Blasi, Francesco

AU - Bommarito, Alessandra

AU - Criscimanna, Angela

AU - Carissimi, Elvira

AU - Spinelli, Gabriele

AU - Carina, Valeria

PY - 2011

Y1 - 2011

N2 - BRAFV600E is the most common mutation found in papillary thyroid carcinoma (PTC). Tissue inhibitor of metalloproteinases (TIMP-1) and nuclear factor (NF)-kB 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 esponsible for its antiapoptotic 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 BRAFV600E mutation, TIMP-1 expression, and NF-kB activation. We found that BRAFV600E mutation occurs selectively in PTC nodules and is associated with hyperactivation of NF-kB 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 BRAFV600E mutation. We found that silencing causes a marked decrease in TIMP-1 expression and NF-kB binding activity, as well as decreased invasiveness. After treatment with specific inhibitors of MAPK pathway, we found that only sorafenib was able to increase IkB-a and reduce both TIMP-1 expression and Akt phosphorylation in BCPAP cells, indicating that BRAFV600E activates NF-kB and this pathway is MEK-independent. Taken together, our findings demonstrate that BRAFV600E causes upregulation of TIMP-1 via NF-kB. 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 BRAFV600E determines cancer initiation, progression, and invasiveness in PTC, also identifying new therapeutic targets for the treatment of highly aggressive forms.

AB - BRAFV600E is the most common mutation found in papillary thyroid carcinoma (PTC). Tissue inhibitor of metalloproteinases (TIMP-1) and nuclear factor (NF)-kB 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 esponsible for its antiapoptotic 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 BRAFV600E mutation, TIMP-1 expression, and NF-kB activation. We found that BRAFV600E mutation occurs selectively in PTC nodules and is associated with hyperactivation of NF-kB 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 BRAFV600E mutation. We found that silencing causes a marked decrease in TIMP-1 expression and NF-kB binding activity, as well as decreased invasiveness. After treatment with specific inhibitors of MAPK pathway, we found that only sorafenib was able to increase IkB-a and reduce both TIMP-1 expression and Akt phosphorylation in BCPAP cells, indicating that BRAFV600E activates NF-kB and this pathway is MEK-independent. Taken together, our findings demonstrate that BRAFV600E causes upregulation of TIMP-1 via NF-kB. 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 BRAFV600E determines cancer initiation, progression, and invasiveness in PTC, also identifying new therapeutic targets for the treatment of highly aggressive forms.

UR - http://hdl.handle.net/10447/60579

M3 - Article

VL - 18

SP - 669

EP - 685

JO - Default journal

JF - Default journal

ER -