Abstract Hypoxia-inducible factor-1alpha is found frequently overexpressed in solid tumors cells, exerting an important role in angiogenesis, glucose metabolism, cell proliferation, survival and invasion. In thyroid carcinomas, hypoxia-inducible factor-1alpha expression was found increased in differentiated, poorly differentiated, medullary and anaplastic variants. Hypoxia represents the principal stimulus responsible for hypoxia-inducible factor-1alpha induction. Other nonhypoxic stimuli increase hypoxia-inducible factor-1alpha synthesis through the activation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in a cell-type-specific manner. We have previously shown the role of BRAF(V600E) mutation in papillary thyroid cancer cells as a factor that facilitates tumor cell growth and progression. In this study, we tested the hypothesis that BRAF(V600E) mutation influences hypoxia-inducible factor-1alpha expression in papillary thyroid carcinoma cells. We analyzed 27 papillary thyroid carcinomas, 13 of which presented BRAF(V600E) mutation. In tumor tissues, immunoreactivity for hypoxia-inducible factor-1alpha was detected in the majority of analyzed BRAF(V600E) mutated cases. Transcriptional analyses revealed elevated hypoxia-inducible factor-1alpha levels with significant differences between wild-type and mutated group. A BRAF wild-type papillary thyroid carcinoma cell line and a BRAF(V600E) mutated papillary thyroid carcinoma cell line were selected to study the effects of BRAF mutation on hypoxia-inducible factor-1alpha expression in vitro. Knockdown of mutant BRAF(V600E) or both the wild type and the BRAF(V600E) by RNA interference induced a significant reduction of hypoxia-inducible factor-1alpha expression at mRNA and protein levels. Pharmacological inhibition of BRAF significantly reduces hypoxia-inducible factor-1alpha expression levels in papillary thyroid carcinoma cell line harboring BRAF(V600E) mutation. Our results suggest that hypoxia-inducible factor-1alpha is expressed in papillary thyroid carcinomas and is regulated not only by hypoxia but also by BRAF(V600E)-mediated signaling pathway.

Zerilli, M., Zito, G., Martorana, A., Pitrone, M., Cabibi, D., Cappello, F., et al. (2010). BRAF(V600E) mutation influences hypoxia-inducible factor-1alpha expression levels in papillary thyroid cancer. MODERN PATHOLOGY, 23(23), 1052-1060.

BRAF(V600E) mutation influences hypoxia-inducible factor-1alpha expression levels in papillary thyroid cancer

ZERILLI, Monica;ZITO, Gaetana;MARTORANA, Anna;CABIBI, Daniela;CAPPELLO, Francesco;GIORDANO, Carla;RODOLICO, VITO;ZITO, Giovanni
2010-01-01

Abstract

Abstract Hypoxia-inducible factor-1alpha is found frequently overexpressed in solid tumors cells, exerting an important role in angiogenesis, glucose metabolism, cell proliferation, survival and invasion. In thyroid carcinomas, hypoxia-inducible factor-1alpha expression was found increased in differentiated, poorly differentiated, medullary and anaplastic variants. Hypoxia represents the principal stimulus responsible for hypoxia-inducible factor-1alpha induction. Other nonhypoxic stimuli increase hypoxia-inducible factor-1alpha synthesis through the activation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in a cell-type-specific manner. We have previously shown the role of BRAF(V600E) mutation in papillary thyroid cancer cells as a factor that facilitates tumor cell growth and progression. In this study, we tested the hypothesis that BRAF(V600E) mutation influences hypoxia-inducible factor-1alpha expression in papillary thyroid carcinoma cells. We analyzed 27 papillary thyroid carcinomas, 13 of which presented BRAF(V600E) mutation. In tumor tissues, immunoreactivity for hypoxia-inducible factor-1alpha was detected in the majority of analyzed BRAF(V600E) mutated cases. Transcriptional analyses revealed elevated hypoxia-inducible factor-1alpha levels with significant differences between wild-type and mutated group. A BRAF wild-type papillary thyroid carcinoma cell line and a BRAF(V600E) mutated papillary thyroid carcinoma cell line were selected to study the effects of BRAF mutation on hypoxia-inducible factor-1alpha expression in vitro. Knockdown of mutant BRAF(V600E) or both the wild type and the BRAF(V600E) by RNA interference induced a significant reduction of hypoxia-inducible factor-1alpha expression at mRNA and protein levels. Pharmacological inhibition of BRAF significantly reduces hypoxia-inducible factor-1alpha expression levels in papillary thyroid carcinoma cell line harboring BRAF(V600E) mutation. Our results suggest that hypoxia-inducible factor-1alpha is expressed in papillary thyroid carcinomas and is regulated not only by hypoxia but also by BRAF(V600E)-mediated signaling pathway.
2010
Settore MED/08 - Anatomia Patologica
Settore BIO/11 - Biologia Molecolare
Settore MED/13 - Endocrinologia
Zerilli, M., Zito, G., Martorana, A., Pitrone, M., Cabibi, D., Cappello, F., et al. (2010). BRAF(V600E) mutation influences hypoxia-inducible factor-1alpha expression levels in papillary thyroid cancer. MODERN PATHOLOGY, 23(23), 1052-1060.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/55776
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