Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice.
Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice.
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DOI：
10.1158/1940-6207.capr-14-0154
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Wang XD
中科院分区：
文献类型：
--
作者：
Ip BC;Liu C;Ausman LM;von Lintig J;Wang XD
肥胖与肝癌风险和死亡率增加有关。我们最近发现，apo-10'-番茄红素酸是一种由 β-胡萝卜素-9',10'-加氧酶 (BCO2) 产生的番茄红素代谢物，可抑制致癌物引发、高脂饮食 (HFD) 促进的肝脏炎症和肝脏肿瘤发生发展。目前的研究探讨了番茄红素是否可以抑制 HFD 促进的肝细胞癌 (HCC) 进展，以及 BCO2 在 BCO2 敲除 (BCO2-KO) 和野生型雄性小鼠中是否重要的悬而未决的问题。结果显示，补充番茄红素（100 mg/kg 饮食）24 周可导致肝脏番茄红素积累相当（19.4 vs 18.2 nmol/g），并且在抑制 HFD 促进的 HCC 发病率（19% vs 20%）和多重性（58% vs 62%）方面分别具有相似的效果。有趣的是，番茄红素对野生型小鼠的化学预防作用与肝脏促炎症信号传导（核因子-κB p65 的磷酸化以及信号转导子和转录激活子 3；白细胞介素 6 蛋白）和炎症灶的减少有关。相比之下，番茄红素在 BCO2-KO 中的保护作用（但在野生型小鼠中则不然）与减少肝内质网应激介导的未折叠蛋白反应 (ERUPR) 相关，通过减少 ERUPR 介导的蛋白激酶 RNA 激活（如激酶真核起始因子 2α 激活）和需要 1α-X-box 结合蛋白 1 信号传导的肌醇。 BCO2-KO 小鼠中补充番茄红素可抑制致癌信号，包括 Met mRNA、β-连环蛋白和哺乳动物雷帕霉素靶点 (mTOR) 复合物 1 激活，这与肝脏 microRNA (miR)-199a/b 和 miR-214 水平增加有关。这些结果提供了新的实验证据，表明膳食番茄红素可以预防 HFD 促进的小鼠 HCC 发病率和多重性，并且可能根据 BCO2 表达而引发不同的机制。
Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10’-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9’,10’-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)-promoted liver inflammation and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether the lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 is important in BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs 20%) and multiplicity (58% vs 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic pro-inflammatory signaling (phosphorylation of nuclear factor-κB p65 and signal transducer and activator of transcription 3; interleukin-6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress-mediated unfolded protein response (ERUPR), through decreasing ERUPR-mediated protein kinase RNA-activated like kinase– eukaryotic initiation factor 2α activation, and inositol requiring 1α–X-box binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals including Met mRNA, β-catenin protein, and mammalian target of rapamycin (mTOR) complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR-214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression.