Dataset Information

Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation.

ABSTRACT: It is critical to understand the molecular mechanisms of hepatocarcinogenesis in order to prevent or treat hepatocellular carcinoma (HCC). The development of HCC is commonly associated with hepatocyte death and compensatory proliferation. However, the role of Caspase-3, a key apoptotic executor, in hepatocarcinogenesis is unknown. In this study, we used Caspase-3-deficient mice to examine the role of Caspase-3 in hepatocarcinogenesis in a chemical (diethylnitrosamine, DEN)-induced HCC model. We found that Caspase-3 deficiency significantly increased DEN-induced HCC. Unexpectedly, Caspase-3 deficiency increased apoptosis induced by DEN and the subsequent compensatory proliferation. Intriguingly, we discovered that Caspase-3 deficiency increased the activation of p38 with and without DEN treatment. Moreover, we demonstrated that TNF? and IL1? stimulated increased activation of p38 in Caspase-3 KO hepatocytes compared with wild-type hepatocytes. Finally, we found that inhibition of p38 by SB202190 abrogated enhanced hepatocyte death, compensatory proliferation and HCC induced by DEN in Caspase-3-deficient mice. Overall, our data suggest that Caspase-3 inhibits chemical-induced hepatocarcinogenesis by suppressing p38 activation and hepatocyte death.

SUBMITTER: Shang N

PROVIDER: S-EPMC5948202 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation.

Shang Na N Bank Thomas T Ding Xianzhong X Breslin Peter P Li Jun J Shi Baomin B Qiu Wei W

Cell death & disease 20180501 5

It is critical to understand the molecular mechanisms of hepatocarcinogenesis in order to prevent or treat hepatocellular carcinoma (HCC). The development of HCC is commonly associated with hepatocyte death and compensatory proliferation. However, the role of Caspase-3, a key apoptotic executor, in hepatocarcinogenesis is unknown. In this study, we used Caspase-3-deficient mice to examine the role of Caspase-3 in hepatocarcinogenesis in a chemical (diethylnitrosamine, DEN)-induced HCC model. We ...[more]

PMID: 29752472

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Project description:Liver cancer is a major health-care concern and its oncogenic mechanisms are still largely unclear. Persistent hepatocyte cell death is a common feature among various chronic liver diseases, the blocking of which presents as logical treatment. Therefore, we aimed at investigating tumor development in mice with hepatocyte-specific Bid depletion--a BH3-only Bcl-2 family member that amplifies apoptotic death signals. Hepatocyte-specific conditional Bid-knockout mice (Bid(?hep)) were injected with 25 mg/kg diethylnitrosamine (DEN) at 14 days of age, and liver tumorigenesis was investigated 9 months later. Additionally, different models of acute liver injury were used including: acute high-dose DEN challenge, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and carbon tetrachloride (CCL4) injection. Bid(?hep) mice developed significantly fewer tumors, showed smaller maximal and average tumor size and reduced tumor incidence. In the acute DEN model, 48 h post injection we observed a significant reduction in liver injury in Bid(?hep) animals, assessed via serum transaminases and liver histopathology. Furthermore, TNF-?, IL-1ß, cJUN and IL-6 mRNA expression was reduced. These findings were accompanied by reduced compensatory hepatocyte proliferation in Bid(?hep) mice when compared with controls by immunohistochemistry for Ki67 and proliferating cell nuclear antigen 48 h after DEN injection. In the acute CCL4 model, Bid(?hep) mice displayed reductions in liver injury and inflammation when compared with controls. No differences in liver injury and serum bilirubin levels were detected in Bid(?hep) and Bid(flo/flo) mice fed with DDC, which induces bile duct injury and a ductular reaction. Our study demonstrates that in DEN-induced hepatocellular carcinoma, the inhibition of hepatocyte death pathways through Bid deletion protects animals from tumorigenesis. These results suggest that reducing hepatocyte cell death, liver inflammation and compensatory proliferation has a stronger beneficial effect than the potential side effect of enhancing tumor cell survival.

Dataset Information

Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation.

Publications

Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation.

Similar Datasets

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