The Study On Role And Mechanism Of ARID1A In Hepatocellular Carcinoma

ARID1A（AT-rich interactive domain-containing protein 1A）,encoding a subunit of chromatin remodeling SWI/SNF complexes,has recently been considered as a new type of tumor suppressor gene for its loss of function somatic mutation frequently found in various human tumors,including hepatocellular carcinoma（HCC）.However,the role and mechanism of the loss of function ARID1A mutation in tumorigenesis remain unclear.To explore the role of ARID1A mutations in tumorigenesis,we constructed the hepatocyte-specific Arid1a deletion mice(Arid1a^LKO)by crossing Arid1a floxed mice with albumin（Alb）-Cre transgenic mice.Interestingly,the hepatocyte-specific Arid1a deficiency results in cell death,followed by steatohepatitis with activated macrophages and neutrophil cells as well as excess tumor necrosis factor（TNF）-?and interleukin-6 production,compensatory hepatic stem/progenitor cell expansion,and finally HCC development.Furthermore,in vivo inducible Arid1a ablation and in vitro ARID1A knockdown experiments revealed that Arid1a deficiency can increase hepatocyte death,serving as a key event that activates liver inflammation.To survey the molecular mechanism underlying the Arid1a deficiency-induced cell death,we examined the genome integrity,and found that the phosphorylated?-H2AX,ATM,ATR and p53-Bax proapoptotic signaling pathway were significantly excited in Arid1a-deficient livers and cells,suggesting that Arid1a deficiency lead to genomic DNA damage.To explore the role of p53-Bax pathway,we generated Arid1a^LKOKO TP53^-/-mice.Surprisingly,although DNA damage existed,these mice did not show the increased hepatocyte death,liver inflammation and steatohepatitis,indicating that Arid1a deficiency increases hepatocyte death in a Tp53-dependent manner,which could be an early event to ARID1A deficiency-induced steatohepatitis and HCC development.The collective data indicate that the increased hepatocyte death triggered by p53-Bax proapoptotic signaling due to Arid1a deficiency could be a crucial event that gradually induced subsequent cascades,including liver inflammation,steatohepatitis,compensatory hepatic stem/progenitor cell proliferation,and HCC.This study provides the cellular and molecular mechanisms for understanding of role of the loss of function ARID1A mutation in tumorigenesis.