原发性肝癌（PLC）可分为肝细胞癌（HCC）、胆管细胞癌（CCA）和混合型肝细胞胆管细胞癌（cHCC-CCA）。PLC发展和表型决定涉及的分子机制仍不完全清楚。蛋白磷酸酶2A（PP2A）的B56δ亚单位编码基因Ppp2r5d的完全缺失会通过c-MYC依赖机制导致小鼠自发性HCC发展。本研究旨在检验Ppp2r5d在二乙基亚硝胺（DEN）诱导的独立小鼠模型中对肝癌发生的作用。Ppp2r5d的缺失（杂合和纯合）加速了HCC的发展，验证了其在肝脏中的抑制肿瘤功能，并提示Ppp2r5d可能存在半足迹。Ppp2r5d缺失的HCCs呈阳性染色，与Ppp2r5d缺失小鼠的癌前和肿瘤组织中AKT激活增加一致。我们还发现Ppp2r5d缺失瘤组织中YAP的激活增加。值得注意的是，在年龄较大的小鼠中，Ppp2r5d缺失导致了在这个模型中的cHCC-CCA发展，CCA成分显示出祖细胞标志物（SOX9和EpCAM）的表达增加。最后，我们观察到在野生型和杂合小鼠的肿瘤中Ppp2r5d的上调，揭示了Ppp2r5d表达的肿瘤特异性控制机制，并暗示了Ppp2r5d参与抑制肿瘤生长的负反馈调节。我们的研究强调了小鼠PP2A-B56δ在HCC和cHCC-CCA中的抑制肿瘤作用，这可能对人类PLC的发展和靶向治疗有重要意义。

Primary liver cancer (PLC) can be classified in hepatocellular (HCC), cholangiocarcinoma (CCA), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The molecular mechanisms involved in PLC development and phenotype decision are still not well understood. Complete deletion of Ppp2r5d, encoding the B56δ subunit of Protein Phosphatase 2A (PP2A), results in spontaneous HCC development in mice via a c-MYC-dependent mechanism. In the present study, we aimed to examine the role of Ppp2r5d in an independent mouse model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Ppp2r5d deletion (heterozygous and homozygous) accelerated HCC development, corroborating its tumor-suppressive function in liver and suggesting Ppp2r5d may be haploinsufficient. Ppp2r5d-deficient HCCs stained positively for c-MYC, consistent with increased AKT activation in pre-malignant and tumor tissues of Ppp2r5d-deficient mice. We also found increased YAP activation in Ppp2r5d-deficient tumors. Remarkably, in older mice, Ppp2r5d deletion resulted in cHCC-CCA development in this model, with the CCA component showing increased expression of progenitor markers (SOX9 and EpCAM). Finally, we observed an upregulation of Ppp2r5d in tumors from wildtype and heterozygous mice, revealing a tumor-specific control mechanism of Ppp2r5d expression, and suggestive of the involvement of Ppp2r5d in a negative feedback regulation restricting tumor growth. Our study highlights the tumor-suppressive role of mouse PP2A-B56δ in both HCC and cHCC-CCA, which may have important implications for human PLC development and targeted treatment.