Department of Gastroenterology, University of Tokyo, Tokyo, Japan.
Hepatology. 2011 Jul;54(1):185-95. doi: 10.1002/hep.24357.
The stress-activated mitogen-activated protein kinases (MAPKs), c-Jun NH2-terminal kinase (JNK), and p38 have been implicated in hepatocarcinogenesis. Although the many interrelated functions of JNK and p38 are precisely regulated by upstream signaling molecules, little is known about upstream regulators. We investigated the role of apoptosis signal-regulating kinase 1 (ASK1), a major player in the regulation of JNK and p38 activities, in hepatocarcinogenesis using a mouse hepatocellular carcinoma (HCC) model. ASK1-deficient (ASK1(-/-) ) and wildtype (WT) mice were treated with diethylnitrosamine on postnatal day 14. Strikingly, after 7 months, approximately three times as many tumors developed in ASK1(-/-) mice as in WT mice. Although JNK and p38 activation were attenuated in ASK1(-/-) HCCs relative to WT HCCs, cell proliferation was comparable in HCCs from both types of mice. On the other hand, both cancer cell apoptosis and hyperphosphorylation of BimEL, a proapoptotic Bcl-2 family member, were suppressed in the ASK1(-/-) HCCs. ASK1(-/-) mice showed remarkable resistance to Fas-induced hepatocyte apoptosis in vivo, probably because of attenuated JNK-mediated BimEL phosphorylation and mitochondrial apoptotic pathway activation. The reintroduction of ASK1 to ASK1(-/-) mouse liver using an adenoviral vector restored Fas-induced hepatocyte death and phosphorylation of JNK and BimEL. Similar findings were obtained in tumor necrosis factor alpha-induced hepatocyte apoptosis. Furthermore, ASK1 was involved in DNA damage-induced p21 up-regulation through a p38 pathway.
ASK1 is involved in death receptor-mediated apoptosis and DNA-damage response by way of stress-activated MAPK in the liver, and thus acts as a tumor suppressor in hepatocarcinogenesis. This study provides new insight into the regulation of stress- activated MAPK signaling in hepatocarcinogenesis.
应激激活的丝裂原活化蛋白激酶（MAPKs）、c-Jun NH2-末端激酶（JNK）和 p38 已被牵涉到肝癌发生中。尽管 JNK 和 p38 的许多相互关联的功能受到上游信号分子的精确调控，但对于上游调节剂知之甚少。我们使用小鼠肝细胞癌（HCC）模型研究了凋亡信号调节激酶 1（ASK1）在肝癌发生中的作用，ASK1 是 JNK 和 p38 活性调节的主要参与者。ASK1 缺陷（ASK1(-/-)）和野生型（WT）小鼠在出生后第 14 天接受二乙基亚硝胺处理。引人注目的是，7 个月后，ASK1(-/-)小鼠中的肿瘤数量约为 WT 小鼠的 3 倍。尽管 ASK1(-/-)HCC 中相对于 WT HCC，JNK 和 p38 的激活减弱，但两种类型的 HCC 中的细胞增殖相当。另一方面，在 ASK1(-/-)HCC 中，细胞凋亡和促凋亡 Bcl-2 家族成员 BimEL 的过度磷酸化均受到抑制。ASK1(-/-)小鼠在体内对 Fas 诱导的肝细胞凋亡表现出显著的抗性，可能是由于 JNK 介导的 BimEL 磷酸化和线粒体凋亡途径激活减弱。使用腺病毒载体将 ASK1 重新引入 ASK1(-/-)小鼠肝脏中，恢复了 Fas 诱导的肝细胞死亡和 JNK 和 BimEL 的磷酸化。在肿瘤坏死因子 α 诱导的肝细胞凋亡中也得到了类似的发现。此外，ASK1 通过 p38 途径参与 DNA 损伤诱导的 p21 上调。
ASK1 通过应激激活的 MAPK 参与死亡受体介导的凋亡和 DNA 损伤反应，因此在肝癌发生中作为肿瘤抑制因子发挥作用。本研究为应激激活的 MAPK 信号在肝癌发生中的调控提供了新的见解。
