Abstract
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 (Arid1a LKO) mice by crossing mice carrying loxP-flanked Arid1a exon 8 alleles (Arid1a f/f) with albumin promoter-Cre transgenic mice. Significantly, the hepatocyte-specific Arid1a deficiency results in mouse steatohepatitis and HCC development. In Arid1a LKO 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.
Highlights
ARID1A, known as BAF250a, is a subunit of the SWI/SNF complex
Nonsense and frame shift mutations throughout ARID1A gene have frequently been found in hepatocellular carcinoma (HCC) [18, 19, 22], indicating that these ARID1A mutations could inactivate ARID1A function in HCC
We constructed conditional hepatocyte-specific Arid1a knockout (KO) (Arid1aLKO) mice to explore its roles in HCC development by crossing mice carrying loxP-flanked Arid1a exon 8 alleles (Arid1af/f) with albumin promoter (Alb)-Cre transgenic mice, resulting in efficient Cre-mediated recombination in hepatocytes (S1A Fig)
Summary
Arid1a Loss Promotes Hepatocellular Carcinoma bladder [15]. ARID1A mutations were frequently identified in gastric cancers with microsatellite instability and Epstein-Barr virus infection [16]. In addition to somatic mutations, ARID1A loss has been found in a variety of human tumor types, such as uterine endometrioid carcinomas, uterine clear-cell carcinomas, uterine serous carcinomas, uterine carcinosarcomas, clear cell renal cell carcinoma, prostate cancers and medulloblastomas [3]. Several groups, including ours, detected ARID1A mutations in 10–15% of hepatocellular carcinoma (HCC) [17,18,19,20]. ARID1A has recently been suggested to be a new type of tumor suppressor gene in many tumors; the role of and mechanism underlying ARID1A mutation or loss in HCC tumorigenesis remain unclear
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