Differential HIF2α Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions

Simple Summary Thoraco-abdominal paraganglioma and pheochromocytoma (PPGL) are pathogenically linked to mutations in SDH genes. Loss-of-function of SDH has been associated with stabilization of HIF2 alpha, which otherwise would be degraded via oxygen-sensitive mechanisms. SDH dysfunction also predispose to the development of paragangliomas arising at the carotid body or other head and neck paraganglia (HNPGL). Although PPGL and HNPGL share similar features, they have certain clinical and genetic peculiarities. By comparison of HIF2 alpha expression in HNPGL and PPGL, we found that functional HIF2 alpha is overexpressed in 80% of PPGLs, including those with SDH mutations as compared with non-tumor tissue. However, HIF2 alpha is already highly expressed in the carotid body under physiologic conditions, and it is not overexpressed in HNPGL. These data suggest that selective HIF2 alpha inhibitors already in clinical trials may benefit a wide spectrum of PPGL. Hypoxia-inducible factors (HIF) 2 alpha and 1 alpha are the major oxygen-sensing molecules in eukaryotic cells. HIF2 alpha has been pathogenically linked to paraganglioma and pheochromocytoma (PPGL) arising in sympathetic paraganglia or the adrenal medulla (AM), respectively. However, its involvement in the pathogenesis of paraganglioma arising in the carotid body (CB) or other parasympathetic ganglia in the head and neck (HNPGL) remains to be defined. Here, we retrospectively analyzed HIF2 alpha by immunohistochemistry in 62 PPGL/HNPGL and human CB and AM, and comprehensively evaluated the HIF-related transcriptome of 202 published PPGL/HNPGL. We report that HIF2 alpha is barely detected in the AM, but accumulates at high levels in PPGL, mostly (but not exclusively) in those with loss-of-function mutations in VHL and genes encoding components of the succinate dehydrogenase (SDH) complex. This is associated with upregulation of EPAS1 and the HIF2 alpha-regulated genes COX4I2 and ADORA2A. In contrast, HIF2 alpha and HIF2 alpha-regulated genes are highly expressed in CB and HNPGL, irrespective of VHL and SDH dysfunctions. We also found that HIF2 alpha and HIF1 alpha protein expressions are not correlated in PPGL nor HNPGL. In addition, HIF1 alpha-target genes are almost exclusively overexpressed in VHL-mutated HNPGL/PPGL. Collectively, the data suggest that involvement of HIF2 alpha in the physiology and tumor pathology of human paraganglia is organ-of-origin-dependent and HIF1 alpha-independent.

Automated summary

The expression level of HIF2 alpha differs in pheochromocytoma and head and neck paraganglioma and is associated with VHL and SDH dysfunctions. Selective HIF2 alpha inhibitors may be effective in treating pheochromocytoma.