The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation. HCC mimicked this gene expression profile, even in cases that were morphologically classified as well differentiated. HCC with intact chromosome 8p also featured GATA4 loss of function via GATA4 germline mutations that abrogated GATA4 interactions with a coactivator, MED12, or by inactivating mutations directly in GATA4 coactivators, including ARID1A. GATA4 reintroduction into GATA4-haploinsufficient HCC cells or ARID1A reintroduction into ARID1A-mutant/GATA4-intact HCC cells activated hundreds of hepatocyte genes and quenched the proliferative precursor program. Thus, disruption of GATA4-mediated transactivation in HCC suppresses hepatocyte epithelial differentiation to sustain replicative precursor phenotype.

中文翻译：

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GATA4在肝癌中的功能丧失阻止肝细胞转化的前体

肝细胞癌（HCC）中最常见的染色体结构丧失是8号染色体（8p）的短臂。但是，剩余同源染色体上的基因不会被反复突变，并且关键的8p肿瘤抑制基因（TSG）的身份未知。在这项工作中，分析了最小限度的通常缺失的8p片段，以鉴定候选的TSG牵连的GATA4，GATA4是肝细胞上皮世系命运的主要转录因子驱动因子。在鼠模型中，肝脏条件性缺失1 Gata4等位基因用于模拟在HCC中发现的单倍剂量不足，产生了具有持续前体增殖和肝细胞上皮分化失败的基因表达谱的肝脏肿大。HCC模仿了这种基因表达谱，即使在形态学上被分类为高度分化的情况下也是如此。具有完整染色体8p的HCC的特征还在于，通过GATA4种系突变消除了GATA4与共激活因子MED12的相互作用，或者通过直接在GATA4共激活因子（包括ARID1A）中使突变失活，使GATA4功能丧失。GATA4再引入GATA4 -haploinsufficient HCC细胞或ARID1A再引入ARID1A -mutant / GATA4完整的HCC细胞激活了数百个肝细胞基因，并终止了增殖前体程序。因此，肝癌中GATA4介导的反式激活的破坏抑制了肝细胞上皮的分化，以维持复制性前体表型。