D Farnesoid X Receptor Antagonizes JNK Signaling Pathway in Liver Carcinogenesis by Activating SOD3
D Farnesoid X Receptor Antagonizes JNK Signaling Pathway in Liver Carcinogenesis by Activating SOD3
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D Farnesoid X 受体通过激活 SOD3 拮抗肝癌发生中的 JNK 信号通路
DOI：
10.1210/me.2014-1225
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发表时间：
2015-02-01
影响因子：
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通讯作者：
Huang, Wendong
中科院分区：
文献类型：
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作者：
Wang, Yan-Dong;Chen, Wei-Dong;Huang, Wendong
法尼醇X受体（FXR）是肝脏中关键的代谢和稳态调节剂。在本工作中，我们确定了FXR通过激活超氧化物歧化酶3（SOD 3）转录来拮抗肝癌发生中c-Jun N末端激酶（JNK）信号通路的新作用。与野生型小鼠肝脏相比，FXR-/-小鼠肝脏显示JNK磷酸化升高。JNK 1缺失抑制FXR-/-小鼠中二乙基亚硝胺诱导的肿瘤数量的增加。这些结果表明JNK 1在FXR-/-小鼠化学诱导的肝癌发生中起关键作用。我们发现，配体激活的FXR能够减轻H2 O2或十四烷酰佛波醇醋酸酯诱导的JNK磷酸化在人肝母细胞瘤（HepG 2）细胞或小鼠原代肝细胞。FXR配体降低H2 O2诱导的活性氧（ROS）水平在野生型，但不FXR-/-小鼠肝细胞。FXR基因敲除可消除3-[2-[2-氯-4-[[3-（2，6-二氯苯基）-5-（1-甲基乙基）-4-异恶唑基]甲氧基]苯基]乙烯基]-苯甲酸（GW 4064）对H2 O2诱导的HepG（2）细胞JNK磷酸化和ROS产生的抑制作用。在体外和体内，FXR激活增加了抗氧化防御酶SOD 3的基因表达。通过转录报告基因分析、EMSA和染色质免疫沉淀分析的组合，鉴定了SOD 3启动子中由1个核苷酸分隔的反向重复序列的FXR响应元件，这表明SOD 3可能是FXR的直接靶基因。GW 4064对H2 O2诱导的HepG 2细胞JNK磷酸化的抑制作用可被SOD 3基因敲除所消除。总之，FXR可能通过调节SOD 3的表达来抑制ROS的产生，从而降低JNK的活性。这些结果表明，FXR，作为一种新的JNK抑制剂，可能是一个有吸引力的治疗肝癌的治疗靶点。
The farnesoid X receptor (FXR) is a key metabolic and homeostatic regulator in the liver. In the present work, weidentify a novel role of FXR in antagonizing c-Jun N-terminal kinase (JNK) signaling pathway in liver carcinogenesis by activating superoxide dismutase 3(SOD3) transcription. Compared with wild-type mouse liver, FXR-/- mouse liver showed elevated JNK phosphorylation. JNK1 deletion suppressed the increase of diethylnitrosamine-induced tumor number in FXR-/- mice. These results suggest that JNK1 plays a key role in chemical-induced liver carcinogenesis in FXR-/- mice. We found that ligand-activated FXR was able to alleviate H2O2 or tetradecanoylphorbol acetate-induced JNK phosphorylation in human hepatoblastoma (HepG2) cells or mouse primary hepatocytes. FXR ligand decreased H2O2-induced reactive oxygen species (ROS) levels in wild-type but not FXR-/- mouse hepatocytes. FXR knockdown abolished the inhibition of 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5(1-methylethyl)-4-isoxazolyl] methoxy] phenyl] ethenyl]-Benzoic acid (GW4064) on JNK phosphorylation andROSproduction induced by H2O2 in HepG(2) cells. The gene expression of SOD3, an antioxidant defense enzyme, was increased by FXR activation in vitro and in vivo. An FXR-responsive element, inverted repeat separated by 1 nucleotide in SOD3 promoter, was identified by a combination of transcriptional reporter assays, EMSAs, and chromatin immunoprecipitation assays, which indicated that SOD3 could be a direct FXR target gene. SOD3 knockdown abolished the inhibition of GW4064 on JNK phosphorylation induced by H2O2 in HepG2 cells. In summary, FXR may regulate SOD3 expression to suppress ROS production, resulting in decreasing JNK activity. These results suggest that FXR, as a novel JNK suppressor, may be an attractive therapeutic target for liver cancer treatment.