Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer that is driven by the fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). PKA activity is controlled through regulatory proteins that both inhibit catalytic activity and control localization, and an excess of regulatory subunits ensures PRKACA activity is inhibited. Here, we found an increase in the ratio of catalytic to regulatory units in FLC patient tumors driven by DNAJB1::PRKACA using mass spectrometry, biochemistry, and immunofluorescence, with increased nuclear localization of the kinase. Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA, or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes in primary human hepatocytes, recapitulating the changes observed in FLC. Consistently, tumors in patients missing a regulatory subunit or harboring an ATP1B1::PRKACA fusion were indistinguishable from FLC based on the histopathological, transcriptomic, and drug-response profiles. Together, these findings indicate that the DNAJB1 domain of DNAJB1::PRKACA is not required for FLC. Instead, changes in PKA activity and localization determine the FLC phenotype. Significance: Alterations leading to unconstrained protein kinase A signaling, regardless of the presence or absence of PRKACA fusions, drive the phenotypes of fibrolamellar hepatocellular carcinoma, reshaping understanding of the pathogenesis of this rare liver cancer.

中文翻译：

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蛋白激酶 A 活性增加可诱导独立于 DNAJB1 的纤维层状肝细胞癌特征。


纤维板层肝细胞癌 (FLC) 是一种罕见的肝癌，由 DNAJB1 和 PRKACA（蛋白激酶 A (PKA) 的催化亚基）融合驱动。 PKA 活性通过抑制催化活性和控制定位的调节蛋白进行控制，过量的调节亚基可确保 PRKACA 活性受到抑制。在这里，我们使用质谱、生物化学和免疫荧光发现，由 DNAJB1::PRKACA 驱动的 FLC 患者肿瘤中催化单元与调节单元的比率增加，并且激酶的核定位增加。 DNAJB1::PRKACA、ATP1B1::PRKACA 或 PRKACA 的过表达（但不是催化失活激酶）在原代人肝细胞中引起类似的转录组变化，概括了在 FLC 中观察到的变化。一致的是，根据组织病理学、转录组学和药物反应特征，缺失调节亚基或携带 ATP1B1::PRKACA 融合的患者的肿瘤与 FLC 无法区分。总之，这些发现表明 DNAJB1::PRKACA 的 DNAJB1 结构域不是 FLC 所必需的。相反，PKA 活性和定位的变化决定了 FLC 表型。意义：无论是否存在 PRKACA 融合，导致不受约束的蛋白激酶 A 信号传导的改变都会驱动纤维板层肝细胞癌的表型，从而重塑对这种罕见肝癌发病机制的理解。