The biochemical phenotype of paragangliomas (PGLs) is highly dependent on the underlying genetic background and tumor location. PGLs at extra-adrenal locations usually do not express phenylethanolamine N-methyltransferase (PNMT), the enzyme required for epinephrine production, which was explained by the absence of glucocorticoids. PGLs with pathogenic variants (PVs) in Harvey rat sarcoma viral oncogene homolog (HRAS) can occur in or outside of the adrenal, but always synthesize epinephrine independently of the localization. Here, we characterize the signaling pathways through which PVs in HRAS influence PNMT expression. Catecholamines, cortisol, and transcriptional features of PGL tissues with known genetic background were analyzed. Genetically modified rat pheochromocytoma cells carrying PVs in Hras were generated and analyzed for regulation of Pnmt expression. Elevated epinephrine contents in PGLs with PVs in HRAS were accompanied by enrichment in mitogen-activated protein kinase (MAPK) signaling compared to PGLs with PVs in genes that activate hypoxia pathways. In vitro, Hras PVs increased Pnmt expression and epinephrine biosynthesis through increased phosphorylation of stimulatory protein 1 via MAPK signaling. Here, we provide a molecular mechanism that explains the PV-dependent epinephrine production of PGLs.

副神经节瘤 (PGL) 的生化表型高度依赖于潜在的遗传背景和肿瘤位置。肾上腺外位置的 PGL 通常不表达苯乙醇胺N-甲基转移酶 (PNMT)，这是肾上腺素生成所需的酶，这是由于缺乏糖皮质激素所致。哈维大鼠肉瘤病毒癌基因同源物 ( HRAS ) 中具有致病性变异 (PV) 的 PGL可以发生在肾上腺内部或外部，但始终合成独立于定位的肾上腺素。在这里，我们描述了HRAS中的 PV影响PNMT表达的信号通路。分析了具有已知遗传背景的 PGL 组织的儿茶酚胺、皮质醇和转录特征。生成了Hras中携带 PV 的转基因大鼠嗜铬细胞瘤细胞，并分析了Pnmt表达的调节。与激活缺氧途径的基因中具有 PV 的 PGL相比，HRAS中具有 PV 的 PGL 中的肾上腺素含量升高，伴随着丝裂原激活蛋白激酶 (MAPK) 信号的富集。在体外，Hras PVs通过 MAPK 信号传导增加刺激蛋白 1 的磷酸化，从而增加Pnmt表达和肾上腺素生物合成。在这里，我们提供了一种分子机制来解释 PGL 的 PV 依赖性肾上腺素产生。