BRAF V600E mutation influences hypoxia-inducible factor-1 α expression levels in papillary thyroid cancer

Hypoxia-inducible factor-1 α 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-1 α expression was found increased in differentiated, poorly differentiated, medullary and anaplastic variants. Hypoxia represents the principal stimulus responsible for hypoxia-inducible factor-1 α induction. Other nonhypoxic stimuli increase hypoxia-inducible factor-1 α 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-1 α 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-1 α was detected in the majority of analyzed BRAF V600E mutated cases. Transcriptional analyses revealed elevated hypoxia-inducible factor-1 α 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-1 α 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-1 α expression at mRNA and protein levels. Pharmacological inhibition of BRAF significantly reduces hypoxia-inducible factor-1 α expression levels in papillary thyroid carcinoma cell line harboring BRAF V600E mutation. Our results suggest that hypoxia-inducible factor-1 α is expressed in papillary thyroid carcinomas and is regulated not only by hypoxia but also by BRAF V600E -mediated signaling pathway.