文章：

一种由二乙基亚硝胺诱导和Ppp2r5d缺失引起的混合型肝细胞-胆管癌新型小鼠模型

A Novel Mouse Model of Combined Hepatocellular-Cholangiocarcinoma Induced by Diethylnitrosamine and Loss ofPpp2r5d

原文发布日期：21 August 2023

DOI: 10.3390/cancers15164193

类型: Article

开放获取: 是

英文摘要：

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 ofPpp2r5d,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 ofPpp2r5din an independent mouse model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis.Ppp2r5ddeletion (heterozygous and homozygous) accelerated HCC development, corroborating its tumor-suppressive function in liver and suggestingPpp2r5dmay be haploinsufficient.Ppp2r5d-deficient HCCs stained positively for c-MYC, consistent with increased AKT activation in pre-malignant and tumor tissues ofPpp2r5d-deficient mice. We also found increased YAP activation inPpp2r5d-deficient tumors. Remarkably, in older mice,Ppp2r5ddeletion 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 ofPpp2r5din tumors from wildtype and heterozygous mice, revealing a tumor-specific control mechanism ofPpp2r5dexpression, and suggestive of the involvement ofPpp2r5din 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.

摘要翻译： 

原发性肝癌（PLC）可分为肝细胞癌（HCC）、胆管细胞癌（CCA）以及混合型肝细胞-胆管细胞癌（cHCC-CCA）。目前对PLC发生发展及表型决定的分子机制尚未完全阐明。蛋白磷酸酶2A（PP2A）的B56δ亚基编码基因Ppp2r5d的完全缺失，会通过c-MYC依赖机制导致小鼠自发性HCC发生。本研究旨在通过二乙基亚硝胺（DEN）诱导的独立小鼠肝癌模型，探究Ppp2r5d的作用机制。Ppp2r5d缺失（杂合与纯合）加速了HCC发展，证实了其在肝脏中的肿瘤抑制功能，并提示该基因可能存在单倍剂量不足效应。Ppp2r5d缺陷型HCC呈现c-MYC阳性染色，这与Ppp2r5d缺陷小鼠癌前病变及肿瘤组织中AKT激活增强现象一致。我们还发现Ppp2r5d缺陷型肿瘤中YAP激活水平升高。值得注意的是，在该模型中，老年小鼠的Ppp2r5d缺失会引发cHCC-CCA发生，其中CCA组分显示祖细胞标志物（SOX9与EpCAM）表达增加。最后，我们观察到野生型与杂合小鼠肿瘤中Ppp2r5d表达上调，揭示了该基因表达受肿瘤特异性调控机制影响，提示Ppp2r5d可能参与限制肿瘤生长的负反馈调节过程。本研究揭示了小鼠PP2A-B56δ在HCC与cHCC-CCA中的肿瘤抑制功能，这对人类PLC发生机制研究与靶向治疗具有重要意义。

原文链接：

A Novel Mouse Model of Combined Hepatocellular-Cholangiocarcinoma Induced by Diethylnitrosamine and Loss ofPpp2r5d