Endocrine Abstracts

The genetic heterogeneity of pheochromocytomas and paragangliomas (PPGL) offers opportunities to develop individualized treatment approaches for affected patients. Therefore, an improved understanding of the molecular features associated with different tumor phenotypes is required. Hypoxia-inducible factor (HIF) 2α-regulated pathways involving the MYC/MAX complex are directly linked to differentiation and aggressiveness in PPGLs. However, the distinct functions of the two MYC oncogenes, c-MYC and MYCN, in this context remain unclear. We have previously shown that expression of Max in Max-deficient pheochromocytoma cells results in a less aggressive cellular phenotype. Moreover, suppression of c-Myc transcription by JQ1 reduced pro-metastatic behavior, but the involvement of Mycn remained unknown. Expression analysis using TCGA data revealed a significant correlation between c-MYC and MYCN expression in PPGLs. Compared to the normal adrenal, PPGLs showed downregulation of c-MYC, while MYCN expression was increased. Moreover, we found negative correlations between the expression of c-MYC and several differentiation markers including TH, SNAP25, PHOX2B and ASCL1, and the opposite relationship for MYCN. To confirm these findings, we used RNAi to downregulate the expression of c-Myc or Mycn in mouse pheochromocytoma cells with (MPCmCherry-H2A) or without (MPCmCherry-EV) expression of Hif2α. The more aggressive MPCmCherry-H2A cells showed an enhanced expression of Mycn, Snap25, Phox2b and Mash1, while c-Myc was repressed. Knockdown of c-Myc or Mycn revealed no effect on the expression of these proteins, which might be explained by the fact that c-Myc to some extent balances the regulation of Mycn and vice versa. Moreover, MYC downstream signaling is further regulated by several other factors, such as MAX. Further work is needed to fully understand the interaction of HIF and MYC signaling in PPGLs and how we might exploit these molecular differences for more advanced treatment approaches.