Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice.
Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice.
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DOI：
10.1186/s13046-015-0254-2
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发表时间：
2015-11-11
期刊：
影响因子：
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通讯作者：
Wang XD
中科院分区：
文献类型：
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作者：
Li X;Liu C;Ip BC;Hu KQ;Smith DE;Greenberg AS;Wang XD
肿瘤进展基因座2（TPL 2）是一种丝氨酸-苏氨酸激酶，作为炎症途径的关键调节剂发挥作用并介导致癌事件。Tpl 2在非酒精性脂肪肝病（NAFLD）相关肝细胞癌（HCC）发展中的潜在作用仍然未知。野生型和Tp 12敲除雄性小鼠均在2周龄时通过肝致癌物（二乙基亚硝胺，i. p.，单次剂量为25 mg.kg-1）引发，然后给予高碳水化合物饮食喂养以诱导肝脂肪变性、炎症、腺瘤和HCC，持续24周。Tpl 2敲除小鼠具有显著较低的肝肿瘤发生率，并且仅发展肝细胞腺瘤，这与野生型小鼠形成对比，在野生型小鼠中它们都发展HCC。Tp 12基因敲除小鼠JNK和ERK磷酸化水平以及促炎细胞因子（IL-1β、IL-18、Mcp-1和Nalp 3）mRNA表达水平显著下调，这与肝脏炎症灶的发生率和数量减少相关。此外，Tpl 2消融导致肝脂肪变性和从头脂肪生成相关标志物（ACC、SCD 1、SREBP 1C和AKT磷酸化）的表达减少，以及内质网应激生物标志物PERK和eIF-2a的减少。该研究首次揭示了Tp 12通过其促炎作用在促进HCC发展中起重要作用，这表明Tp 12可能是HCC预防的分子靶点。
Tumor progression locus 2 (TPL2), a serine-threonine kinase, functions as a critical regulator of inflammatory pathways and mediates oncogenic events. The potential role of Tpl2 in nonalcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) development remains unknown. Both wild-type and Tpl2 knockout male mice were initiated by a hepatic carcinogen (diethylnitrosamine, i.p. with a single dose of 25 mg.kg−1)at 2 weeks of age, and then were given the high carbohydrate diet feeding to induce hepatic steatosis, inflammation, adenoma and HCC for 24 weeks. Tpl2 knockout mice had significantly lower incidences of liver tumor and developed hepatocellular adenoma only, which is contrast to wild-type mice where they all developed HCC. Tpl2 knockout mice had significantly down-regulated phosphorylation of JNK and ERK, and levels of mRNA expression of pro-inflammatory cytokines (Il-1β, Il-18, Mcp-1 and Nalp3), which correlated with the reduced incidence and number of hepatic inflammatory foci. Furthermore, Tpl2 ablation resulted in decreased hepatic steatosis and expression of de novo lipogenesis related markers (ACC, SCD1, SREBP1C and AKT phosphorylation), as well as reduction of endoplasmic reticulum stress biomarkers PERK and eIF-2a. The study revealed for the first time that Tpl2 plays a significant role in promoting HCC development by its pro-inflammatory effect, which suggested that Tpl2 could be a molecular target for HCC prevention.