Endocrine Abstracts

Context: HIF-1α is frequently upregulated in many tumour types and has been shown to be critical for radio- and chemosensitivity in pre-clinical studies. However the regulation and function of HIF-1α is unknown in thyroid carcinomas.

Objectives: Here, we evaluated basal expression and regulation of HIF-1α and target genes in primary thyroid carcinomas and in thyroid cancer cell lines (NPA, FTC-133, ARO).

Design and outcome measurements: We investigated HIF-1α and target genes (Glut-1, CA-IX, VEGF) in snap-frozen tissue from primary thyroid carcinomas by IHC. Functional changes were studied for HIF-1α in NPA, FTC-133 and ARO cells basally, under graded hypoxia (2%, 1%, anoxia and the hypoxia mimetic CoCl₂100 μM) as well as under blockage of PI3K (Ly294002, 50 μM) and MAPK/ERK (PD 98059, 50 μM) signaling. In addition we investigated FTC-133 cells transfected with wtPTEN. IF, western blot for HIF-α and the target genes Glut-1, CA-IX as well as a HIF-specific reporter gene assay were used as read-outs.

Results: HIF-1α is expressed in dedifferentiated primary thyroid carcinomas. HIF-1α and its target genes are expressed as well in NPA, FTC-133 and ARO cells and are clearly up-regulated by hypoxia or via CoCl₂ stimulation. Using the PI3K inhibitor Ly294002 or transfection with wt PTEN in FTC-133 cells revealed that HIF-1α is stimulated by the PI3K pathway. Similarly, blockage of the MAPK/ERK pathway by PD 98059 had a strong inhibitory effect on HIF-1α expression and significantly reduced CA-IX protein levels.

Conclusion: Our data suggest that HIF-1α is expressed in primary thyroid carcinomas and appears upregulated in dedifferentiated tumours. HIF-1α is under oxygen control but is additionally regulated by the PI3K and the MAPK/ERK pathway, central oncogenic pathways in the thyroid. These data may be of major clinical importance when considering the sensitizing role of HIF-1α inhibition in the modulation radiosensitivity in other epithelial type carcinomas.