Opposing Effects of HIF1a and HIF2a on Chromaffin Cell Phenotypic Features and Tumor Cell Proliferation: Insights from MAX [rat]

Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To establish whether PPGL phenotypic differences reflect a MAX-mediated mechanism and opposing influences of HIF2a and HIF1a, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2a, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1a has opposing actions to HIF2a. These model systems explain the features observed in PPGLs due to mutations of MAX and other PPGL susceptibility genes.