Enane Francis O, Shuen Wai Ho, Gu Xiaorong, Quteba Ebrahem, Przychodzen Bartlomiej, Makishima Hideki, Bodo Juraj, Ng Joanna, Chee Chit Lai, Ba Rebecca, Seng Koh Lip, Lim Janice, Cheong Rachael, Teo Marissa, Hu Zhenbo, Ng Kwok Peng, Maciejewski Jaroslaw, Radivoyevitch Tomas, Chung Alexander, Ooi London Lucien, Tan Yu Meng, Cheow Peng-Chung, Chow Pierce, Chan Chung Yip, Lim Kiat Hon, Yerian Lisa, Hsi Eric, Toh Han Chong, Saunthararajah Yogen
Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
J Clin Invest. 2017 Sep 1;127(9):3527-3542. doi: 10.1172/JCI93488. Epub 2017 Jul 31.
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.
肝细胞癌（HCC）中最常见的染色体结构缺失是8号染色体短臂（8p）。然而，剩余同源染色体上的基因并非经常发生突变，关键的8p肿瘤抑制基因（TSG）的身份尚不清楚。在这项研究中，对最小常见缺失的8p片段进行分析以鉴定候选TSG，结果表明GATA4是肝细胞上皮谱系命运的主要转录因子驱动因子。在一个小鼠模型中，肝脏条件性缺失1个Gata4等位基因以模拟HCC中所见的单倍体不足，导致肝脏肿大，其基因表达谱表现为持续的前体细胞增殖和肝细胞上皮分化失败。HCC模仿了这种基因表达谱，即使在形态学上分类为高分化的病例中也是如此。具有完整8号染色体短臂的HCC也通过GATA4种系突变导致GATA4功能丧失，这些突变消除了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）中发生失活突变。将GATA4重新导入GATA4单倍体不足的HCC细胞中，或将ARID1A重新导入ARID1A突变/GATA4完整的HCC细胞中，可激活数百个肝细胞基因，并消除增殖前体细胞程序。因此，HCC中GATA4介导的反式激活的破坏抑制了肝细胞上皮分化，以维持复制前体细胞表型。
