Expression of hypoxia-inducible factor 1α in thyroid carcinomas

Abstract

Hypoxia-inducible factor 1α (HIF-1α) is upregulated by hypoxia and oncogenic signalling in many solid tumours. Its regulation and function in thyroid carcinomas are unknown. We evaluated the regulation of HIF-1α and target gene expression in primary thyroid carcinomas and thyroid carcinoma cell lines (BcPAP, WRO, FTC-133 and 8505c). HIF-1α was not detectable in normal tissue but was expressed in thyroid carcinomas. Dedifferentiated anaplastic tumours (ATCs) exhibited high levels of nuclear HIF-1α staining. The HIF-1 target glucose transporter 1 was expressed to a similar level in all tumour types, whereas carbonic anhydrase-9 was significantly elevated in ATCs. In vitro studies revealed a functionally active HIF-1α pathway in thyroid cells with transcriptional activation observed after graded hypoxia (1% O2, anoxia) or treatment with a hypoxia mimetic cobalt chloride. High basal and hypoxia-induced expression of HIF-1α in FTC-133 cells that harbour a phosphatase and tensin homologue (PTEN) mutation was reduced by introduction of wild-type PTEN. Similarly, pharmacological inhibition of the phosphoinositide 3-kinase (PI3K) pathway using LY294002 inhibited HIF-1α and HIF-1α targets in all cell lines, including those with B-RAF mutations (BcPAP and 8505c). In contrast, the effects of inhibition of the RAF/MEK/extracellular signal-regulated kinase pathway were restricted by environmental condition and B-RAF mutation status. HIF-1 is functionally expressed in thyroid carcinomas and is regulated not only by hypoxia but also via growth factor signalling pathways and, in particular, the PI3K pathway. Given the strong association of HIF-1α with an aggressive disease phenotype and therapeutic resistance, this pathway may be an attractive target for improved therapy in thyroid carcinomas.

An update on molecular biology of thyroid cancers

“…HIF1 induces expression of VEGF, a growth factor, and MET, an oncogene, which are also upregulated in thyroid tumors as compared to normal thyroid tissues [162]. On the other hand, PI3K-AKT and MAPK increase expression of HIF1 in thyroid tumor [161,164,165] while a mutation in BRAF (V600E) also affects expression levels of HIF1␣ in papillary thyroid cancer [165]. Interestingly, inhibition of expression levels of HIF-1␣ and HIF-2␣ by GDC-0941 in four different thyroid tumor cells (BcPAP, WRO, FTC133, and 8505c) resulted in inhibition of VEGF secretion [166].…”

“…It was demonstrated by several groups that HIF1␣ is expressed in thyroid tumors, such as ATC, and is not expressed in healthy thyroid tissues [161,162].…”

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

“…14 HIF-1a expression was found increased at transcripts and protein levels in differentiated, poorly differentiated, medullary and anaplastic carcinoma of the thyroid. [15][16][17] In this study, we tested the hypothesis that BRAF V600E mutation influences HIF-1a expression levels in papillary thyroid carcinoma cells, using RNA interference targeting BRAF and the RAF-1 kinase inhibitor (sorafenib), which target both the wild-type and the V600E mutant BRAF in vitro.…”

Resistance to Kinase Inhibitors in Poorly Differentiated and Anaplastic Thyroid Cancer: Preclinical In vitro Evidences

“…These evidences suggest the crucial role of hypoxia and hypoxiainducible factors in thyroid cancer progression, aggressiveness, and metastasis [37].…”