Identification of novel transcriptional networks in response to treatment with the anticarcinogen 3H-1,2-dithiole-3-thione
Identification of novel transcriptional networks in response to treatment with the anticarcinogen 3H-1,2-dithiole-3-thione
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DOI：
10.1152/physiolgenomics.00258.2005
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发表时间：
2006-01-12
影响因子：
4.6
通讯作者：
Sutter, TR
中科院分区：
文献类型：
--
作者：
Huang, Y;Yan, J;Sutter, TR
3h -1,2-二硫基-3硫酮（D3T）是一种抗氧化和2期基因的诱导剂，已知可增强环境致癌物的解毒，预防肿瘤，并引发其他保护作用。然而，该化合物诱导的调控途径的全面观点尚未得到阐述。每天用载药或D3T （0.3 mmol/ kg）灌胃Fischer F344大鼠5 d。采用Affymetrix RG-U34A芯片检测肝脏基因表达的全局变化。利用功能类评分法（一种探索基因表达模式和功能注释的半监督方法），根据D3T治疗影响的显著性对基因本体类进行排序。在D3T治疗中，发现了两个意想不到的功能类别：90%的基因增加的细胞质核糖体成分，91%的基因抑制的胆固醇生物合成。在另一种新方法中，通过独创性计算途径分析工具评估差异表达基因，以确定对D3T治疗有反应的特定调控网络和典型途径。除了已知的谷胱甘肽代谢途径（P = 0.0011）外，还发现了其他一些重要的途径，包括抗原呈递（P = 0.000476）、雄激素/雌激素生物合成（P = 0.000551）、脂肪酸（P = 0.000216）和色氨酸代谢（P = 0.000331）途径。这些发现表明D3T对脂质代谢和抗炎/免疫抑制反应有深远的影响，表明该化合物具有比先前预期更广泛的细胞保护作用。
3H-1,2-dithiole-3thione (D3T), an inducer of antioxidant and phase 2 genes, is known to enhance the detoxification of environmental carcinogens, prevent neoplasia, and elicit other protective effects. However, a comprehensive view of the regulatory pathways induced by this compound has not yet been elaborated. Fischer F344 rats were gavaged daily for 5 days with vehicle or D3T (0.3 mmol/ kg). The global changes of gene expression in liver were measured with Affymetrix RG-U34A chips. With the use of functional class scoring, a semi-supervised method exploring both the expression pattern and the functional annotation of the genes, the Gene Ontology classes were ranked according to the significance of the impact of D3T treatment. Two unexpected functional classes were identified for the D3T treatment, cytosolic ribosome constituents with 90% of those genes increased, and cholesterol biosynthesis with 91% of the genes repressed. In another novel approach, the differentially expressed genes were evaluated by the Ingenuity computational pathway analysis tool to identify specific regulatory networks and canonical pathways responsive to D3T treatment. In addition to the known glutathione metabolism pathway (P = 0.0011), several other significant pathways were also revealed, including antigen presentation (P = 0.000476), androgen/ estrogen biosynthesis (P = 0.000551), fatty acid (P = 0.000216), and tryptophan metabolism (P = 0.000331) pathways. These findings showed a profound impact of D3T on lipid metabolism and anti-inflammatory/ immune-suppressive response, indicating a broader cytoprotective effect of this compound than previously expected.