These data indicate that IFN-γ treatment reverses the TLR2 deficiency-enhanced progression of HCC by restoring the p53/p21/pRb-dependent

senescence and autophagy flux in TLR2−/− liver tissue (Fig. 8F). We observed increased ROS accumulation, cellular proliferation, and p62 aggregation as well as decreased DNA repair, programmed cell death, and autophagy flux in the TLR2−/− liver tissue in this study. All of these changes are attributable to the ICG-001 cell line loss of cellular senescence as a result of TLR2 deficiency in the liver. Because ASK1/P38MAPK/NF-κB signaling or inflammatory cytokines can initiate and sustain cellular senescence,26-29 the failure of senescence induction can be attributed to the broad-spectrum reductions in the immune responses to DEN injury in the TLR2−/− livers. Indeed, senescent cells enter a unique state characterized by senescence-associated changes, including growth arrest, an arrested cell cycle, SA β-gal expression, a lack of responsiveness

to cell death signals, and the senescence-associated secretory phenotype (SASP).33 SASP causes a robust increase in the expression and secretion of numerous cytokines, chemokines, growth factors, and proteases in these cells. These factors, particularly IL-1α, can activate tumor-suppressive pathways to establish and/or maintain senescent growth arrest.33 These findings are supported by observations that treatment of TLR2−/− mice with IFN-γ, a typical Th1 cytokine and positive modulator of senescence,30 attenuates HCC progression by restoring p53/p21-dependent Small molecule library ic50 senescence in the liver. Thus, our studies demonstrate a protective role for TLR2-mediated p21- and p16/pRB-dependent

senescence in DEN-induced carcinogenesis. Indeed, DEN-induced ROS production and DNA damage can trigger programmed cell death and maintain a low level of cell proliferation in check details WT mice because intact TLR2 activity can induce a senescence response after DEN administration.20-22 Moreover, the accumulated ROS can be cleared, and damaged DNA can be repaired by the activation of the ASK1/p38 MAPK/NF-κB signaling networks26, 29 in DEN-treated mice. Together, these networks diminish the development and progression of DEN-induced HCC in WT mice. However, suppressed activation of the ASK1/p38 MAPK/NF-κB signaling pathway results in the persistent accumulation of ROS, which prevents the repair of damaged DNA, decreases programmed cell death, and increases hepatocyte proliferation; the ultimate result is the promotion of HCC development and progression in TLR2−/− mice. These observations are consistent with the findings presented in previous studies. Specifically, it has been reported that the activation of the ASK1/p38 MAPK/NF-κB pathway is critical for both neutralizing ROS/ER stress and repairing damaged DNA in stressed cells.29 The activation of this pathway is sufficient to activate and maintain cellular senescence.