Fang Jia-Zhu, Li Chong, Liu Xiao-Yan, Hu Tao-Tao, Fan Zu-Sen, Han Ze-Guang
Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
PLoS One. 2015 Nov 16;10(11):e0143042. doi: 10.1371/journal.pone.0143042. eCollection 2015.
ARID1A, encoding a subunit of chromatin remodeling SWI/SNF complexes, has recently been considered as a new type of tumor suppressor gene for its somatic mutations frequently found in various human tumors, including hepatocellular carcinoma (HCC). However, the role and mechanism of inactivated ARID1A mutations in tumorigenesis remain unclear. To investigate the role of ARID1A inactivation in HCC pathogenesis, we generated hepatocyte-specific Arid1a knockout (Arid1aLKO) mice by crossing mice carrying loxP-flanked Arid1a exon 8 alleles (Arid1af/f) with albumin promoter-Cre transgenic mice. Significantly, the hepatocyte-specific Arid1a deficiency results in mouse steatohepatitis and HCC development. In Arid1aLKO mice, we found that innate immune cells, including F4/80+ macrophages and CD11c+ neutrophil cells, infiltrate into the liver parenchyma, accompanied by the increased tumor necrosis factor (TNF)-α and interleukin (IL)-6, and activation of STAT3 and NF-κB pathways. In conclusion, hepatocyte-specific Arid1a deficiency could lead to mouse steatohepatitis and HCC development. This study provides an alternative mechanism by which Arid1a deficiency contributes to HCC tumorigenesis.
ARID1A编码染色质重塑SWI/SNF复合物的一个亚基，因其体细胞突变在包括肝细胞癌（HCC）在内的各种人类肿瘤中频繁出现，最近被视为一种新型肿瘤抑制基因。然而，ARID1A失活突变在肿瘤发生中的作用和机制仍不清楚。为了研究ARID1A失活在HCC发病机制中的作用，我们通过将携带loxP侧翼的Arid1a外显子8等位基因（Arid1af/f）的小鼠与白蛋白启动子-Cre转基因小鼠杂交，生成了肝细胞特异性Arid1a敲除（Arid1aLKO）小鼠。值得注意的是，肝细胞特异性Arid1a缺陷导致小鼠脂肪性肝炎和HCC发生。在Arid1aLKO小鼠中，我们发现包括F4/80+巨噬细胞和CD11c+中性粒细胞在内的先天免疫细胞浸润到肝实质中，同时肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6增加，STAT3和NF-κB通路激活。总之，肝细胞特异性Arid1a缺陷可导致小鼠脂肪性肝炎和HCC发生。本研究提供了一种Arid1a缺陷促进HCC肿瘤发生的替代机制。
