2-6 JNK and p38 have complex functions and modulate a wide range of cellular effects, including apoptosis, proliferation, differentiation, migration, and inflammation.7 Evidence implicating the JNK and p38 signaling pathways in the development of various types of cancer is strong, Talazoparib cost although certain cells use these signaling pathways to combat cancer development, whereas others use these pathways as cancer promoters.8, 9 Crosstalk between the JNK and p38 pathways further complicates the roles of these pathways in carcinogenesis.7 Although determining the mechanisms regulating these complex and multifunctional signaling pathways is essential for

the development of new therapeutic approaches, these mechanisms are not yet well understood. The activities of JNK and p38 are tightly regulated by upstream MAPK kinases and MAPK kinase kinases (MAP3Ks). Acting far upstream in the intracellular MAPK signaling cascade, MAP3Ks respond to intracellular and extracellular stimuli and determine cell fate.10 Apoptosis

signal-regulating kinase 1 (ASK1), a ubiquitously expressed MAP3K, selectively activates the JNK and p38 signaling pathways in response to a variety of stimuli, including reactive oxygen species and cytokines, selleck and has been widely accepted as a major player in the modulation of JNK and p38 activities regulating cell death.11 In liver disease, ASK1 is involved in acetaminophen-induced acute liver injury.12 Furthermore, recent reports revealed that ASK1 participates in colon and skin cancer development through the regulation of apoptosis and inflammation.13, 14 However, involvement of ASK1 in hepatocarcinogenesis has not been reported. In this study we examined whether ASK1 plays a role in hepatocarcinogenesis using

a diethylnitrosamine (DEN)-induced mouse HCC model. We found that ASK1 deficiency promoted the development of HCC, and ASK1 inhibited hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated MAPK. ALT, alanine aminotransferase; ASK1, apoptosis signal-regulating kinase 1; DEN, diethylnitrosamine; GalN, galactosamine; HCC, hepatocellular carcinoma; MCE JNK, c-Jun NH2-terminal kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MAP3K, mitogen-activated protein kinase kinase kinase; TNF-α, tumor necrosis factor-α. Male ASK1-deficient (ASK1−/−), JNK1−/−, JNK2−/−, and C57BL/6 wildtype (WT) mice (Clea Japan, Tokyo, Japan) were used in the experiments. ASK1−/−, JNK1−/−, and JNK2−/− mice were generated as described12, 15 and backcrossed into the C57BL/6 strain at least 14 times. Mice were maintained under conventional conditions under a light/dark cycle. All of the experimental protocols were approved by the Ethics Committee for Animal Experimentation and conducted in accordance with the National Institutes of Health (NIH) Guidelines for the Care and Use of Laboratory Animals. In the DEN-induced HCC model, DEN (Sigma, St.