Gene expression levels in Arid1a deficiency mice liver and their littermates. Mus musculus

ARID1A encodes a subunit of chromatin remodeling SWI/SNF complexes and has recently been suggested to be a tumor suppressor gene based on its loss of function somatic mutations, which are frequently found in various human tumors, including hepatocellular carcinoma (HCC). However, the role and mechanism underlying ARID1A mutations in tumorigenesis remain unclear. Here we show that hepatocyte-specific Arid1a deficiency in mice results in steatohepatitis and HCC development, which are accompanied by increased DNA damage, hepatocyte death, mitochondrial damage, innate immune cell infiltration, and large-cell dysplasia, as well as proinflammatory cytokines, TNF-alpha and IL-6 production, and activation of the STAT3 and NF-kappaB pathways. Interestingly, we found that Arid1a ablation-mediated hepatocyte death and liver inflammation are dependent upon Tp53-Bax proapoptotic signaling. In the absence of Tp53, hepatocyte death, immune cell infiltration, and TNF-alpha and IL-6 production were significantly decreased. This study provides an alternative mechanism by which Arid1a deficiency or loss of function mutations contributes to tumorigenesis. Overall design: At each time point (5 day, 2 week and 1 month) total liver RNA from 2 individual mice (2-week-old mice only contain one in each group) was compared to pooled total liver RNA from time-matched control mice (n = 2).

ARID1A编码染色质重塑SWI/SNF复合物的一个亚基，近期基于其在多种人类肿瘤（包括肝细胞癌（hepatocellular carcinoma, HCC））中频繁检出的功能缺失体细胞突变，被提示为肿瘤抑制基因。然而，ARID1A突变在肿瘤发生中的作用与潜在机制仍不明确。本研究发现，小鼠肝细胞特异性Arid1a缺陷可引发脂肪性肝炎及肝细胞癌的发生，伴随DNA损伤加重、肝细胞死亡、线粒体损伤、先天免疫细胞浸润、大细胞异型增生，同时伴有促炎细胞因子肿瘤坏死因子α（TNF-α）与白细胞介素6（IL-6）的生成，以及信号转导与转录激活因子3（STAT3）和核因子κB（NF-κB）通路的激活。值得注意的是，本研究发现Arid1a敲除介导的肝细胞死亡与肝脏炎症依赖于Tp53-Bax促凋亡信号通路。在Tp53缺失的情况下，肝细胞死亡、免疫细胞浸润以及TNF-α与IL-6的生成均显著降低。本研究揭示了Arid1a缺陷或功能缺失突变促进肿瘤发生的一种新机制。总体实验设计：在每个时间点（5天、2周和1个月），将2只独立小鼠的肝脏总RNA（2周龄小鼠每组仅1只）与同时间点对照小鼠的混合肝脏总RNA（n=2）进行比对。