Increased activity of protein kinase A, even without DNAJB1, is sufficient to cause Fibrolamellar hepatocellular carcinoma

Most fibrolamellar carcinoma (FLC) is driven by a fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes of primary human hepatocytes; these recapitulated most changes observed in FLC. This is consistent with the observation that FLC is found in patients missing a regulatory subunit or with a ATP1B1::PRKACA fusion. Thus, the DNAJB1 domain is not required for FLC. Overall design: Primary Human Hepatocytes were transduced with either DNAJB1::PRKACA, ATP1B1::PRKACA, PRKACA or kinase inactive DNAJB1::PRKACA or dsRED.

绝大多数纤维板层型肝癌（fibrolamellar carcinoma, FLC）由DNAJB1与蛋白激酶A（protein kinase A, PKA）催化亚基PRKACA的融合基因驱动。过表达DNAJB1::PRKACA、ATP1B1::PRKACA或PRKACA（而非催化失活的激酶），可使原代人肝细胞产生相似的转录组改变；上述改变重现了纤维板层型肝癌中观测到的绝大多数特征。这与“纤维板层型肝癌可在缺失调节亚基或携带ATP1B1::PRKACA融合基因的患者中检出”的观测结果一致。因此，DNAJB1结构域并非纤维板层型肝癌发生所必需。实验整体设计：将原代人肝细胞分别转导DNAJB1::PRKACA、ATP1B1::PRKACA、PRKACA、激酶失活型DNAJB1::PRKACA或dsRED。