Regulation of epinephrine biosynthesis in HRAS-mutant paragangliomas

赫拉 苯乙醇胺N-甲基转移酶 肾上腺素 嗜铬细胞瘤 苯乙醇胺 生物 MAPK/ERK通路 突变体 癌症研究 信号转导 细胞生物学 突变 基因 内分泌学 内科学 遗传学 生物化学 医学 酪氨酸羟化酶 克拉斯
作者
Minghao Li,Susan Richter,Hermine Mohr,Stephan Drukewitz,Isabel Poser,Daniela Stanke,Bruna Calsina,Ángel M. Martínez‐Montes,Marcus Quinkler,Henri Timmers,Svenja Nölting,Felix Beuschlein,Hanna Remde,Giuseppe Opocher,Elena Rapizzi,Karel Pacák,Christina Pamporaki,Mercedes Robledo,Longfei Liu,Jingjing Jiang
出处
期刊:Endocrine-related Cancer [Bioscientifica]
卷期号:30 (12) 被引量:4
标识
DOI:10.1530/erc-23-0230
摘要

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 an 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 SP1 via MAPK signaling. Here, we provide a molecular mechanism that explains the PV-dependent epinephrine-production of PGLs.
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