Dietary restriction protects against diethylnitrosamine-induced hepatocellular tumorigenesis by restoring the disturbed gene expression profile.
Dietary restriction protects against diethylnitrosamine-induced hepatocellular tumorigenesis by restoring the disturbed gene expression profile.
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饮食限制通过恢复受干扰的基因表达谱来防止二乙基亚硝胺诱导的肝细胞肿瘤发生
DOI：
10.1038/srep43745
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发表时间：
2017-03-06
影响因子：
4.6
通讯作者：
Yu P
中科院分区：
文献类型：
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作者：
Duan T;Sun W;Zhang M;Ge J;He Y;Zhang J;Zheng Y;Yang W;Shen HM;Yang J;Zhu X;Yu P
肝细胞癌（Hepatocellular carcinoma，HCC）是世界上最常见、最致命的恶性肿瘤之一，目前治疗手段有限，临床效果不佳。饮食限制（Dietary restriction，DR）可以抑制几种动物的自发性和诱发性肿瘤，但其机制尚不清楚。在本研究中，通过使用二乙基亚硝胺（DEN）诱导的肝癌小鼠模型，我们发现DR显着减少肝肿瘤的数量和大小，延迟肿瘤的发展，抑制增殖和促进凋亡。进一步对DEN和DEN伴DR（DEN+DR）小鼠肝组织的转录组测序表明，DEN诱导了基因表达谱的深刻变化，特别是在癌症相关途径中，而DR治疗逆转了DEN诱导的大部分干扰基因表达。最后，转录因子富集分析发现转录因子特异性蛋白1（SP1）可能是基因变化的主要调节因子，协调DR对DEN诱导的HCC的保护作用。综上所述，通过首次全面的转录组分析，我们阐明了DR通过恢复受干扰的基因表达谱来保护DEN诱导的HCC，这有望为癌症治疗提供有效的分子靶点。
Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent malignancies, worse still, there are very limited therapeutic measures with poor clinical outcomes. Dietary restriction (DR) has been known to inhibit spontaneous and induced tumors in several species, but the mechanisms are little known. In the current study, by using a diethylnitrosamine (DEN)-induced HCC mice model, we found that DR significantly reduced the hepatic tumor number and size, delayed tumor development, suppressed proliferation and promoted apoptosis. Further transcriptome sequencing of liver tissues from the DEN and the DEN accompanied with DR (DEN+DR) mice showed that DEN induced profound changes in the gene expression profile, especially in cancer-related pathways while DR treatment reversed most of the disturbed gene expression induced by DEN. Finally, transcription factor enrichment analysis uncovered the transcription factor specificity protein 1 (SP1) probably functioned as the main regulator of gene changes, orchestrating the protective effects of DR on DEN induced HCC. Taken together, by the first comprehensive transcriptome analysis, we elucidate that DR protects aginst DEN-induced HCC by restoring the disturbed gene expression profile, which holds the promise to provide effective molecular targets for cancer therapies.