It is the suppressed expression of Ku70/80 leading to a persistent DNA damage and ROS/endoplasmic reticulum stress in TLR4mut liver.36 Indeed, isotopic expression of DNA

repair protein Ku70 can reverse the TLR4 mutation-enhanced susceptibility to the DEN-induced HCC through restoring the cellular senescence and activating autophagic flux in TLR4mut liver tissue. Thus, these results place TLR4 activity in the intersection of DNA damage/genome instability and senescence/autophagy/DNA repairing (Fig. 7F). The residual hepatic cells or the liver-infiltrating immune cells have been reported Selleckchem R788 to be involved in the pathogenesis of HCC development.31, 37 Indeed, microbial infection in the liver may recruit www.selleckchem.com/products/INCB18424.html a larger number of immune cells to the liver, and the infiltrated immune cells and secreted soluble factors play a critical role in the promotion of HCC development.10 However, if HCC is primarily caused by chemical agents or metabolic stresses, the residue liver cells undergoing premature senescence are predominant party to initiate and sustain inflammation participating in the regulation of HCC development.5 Obviously, the immunity against tumorigenesis is constituted by both liver-infiltrating

immune cells and residual hepatic cells. Interestingly, in addition to its expression in immune cells, functional TLR4 is also expressed by residual hepatic cells and the TLR4-mediated responses can therefore be derived from the activated residual hepatic cells or from the liver-infiltrating immune cells. In our current work, however, a failure of cellular senescence induction in the residual hepatic cells is more likely to link to loss of TLR4-mediated immunity, enhancing susceptibility to DEN-induced hepatocellular carcinogenesis and progression. This observation is supported by the fact that the filtration of macrophages was decreased and the wide-spectrum Carbohydrate inflammatory response was

suppressed in the TLR4mut liver tissue; in addition, DNA damage, genomic instability, and malignant transformation were caused by DEN, a hepatic- but not immune-specific oncotoxic agent and a major trigger of senescent response. Thus, our study demonstrates a critical protection role of TLR4 against tumorigenesis and may help to develop new prophylactic and treatment approaches for HCC. The defects in DNA damage repair leading to genome instability is the hallmark of cancer, including HCC.38 Indeed, HCC is commonly secondary to cirrhosis following chronic microbe infection, genotoxic agents, and metabolic stress, which is often associated with genotoxic DNA damage and mutations of known DNA repair genes.39 For instance, the DNA repair complex and its regulatory proteins may critically influence vital cellular processes such as programmed cell death, cell proliferation, and inflammation, and thereby may play a critical role in the pathogenesis of human cancer.