Mitochondrial Prohibitins and Septin 9 Are Implicated in the Onset of Rat Hepatocarcinogenesis
Mitochondrial Prohibitins and Septin 9 Are Implicated in the Onset of Rat Hepatocarcinogenesis
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DOI：
10.1093/toxsci/kfq307
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发表时间：
2011-01-01
影响因子：
3.8
通讯作者：
Wanibuchi, Hideki
中科院分区：
文献类型：
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作者：
Kakehashi, Anna;Ishii, Naomi;Wanibuchi, Hideki
在本研究中，采用QSTAR Elite液相色谱串联质谱和iTRAQ技术，分析了n -二乙基亚硝胺和苯巴比妥分别以0和500 ppm剂量处理10周和33周的大鼠肝脏微解剖谷胱甘肽s -转移酶胎盘形式阳性（GST-P+）灶和肝细胞癌的蛋白质裂解物。75个蛋白中，在起始对照组和促进组的GST-P+病灶中分别鉴定出27个和50个与相邻正常肝组织相比有显著定量变化的蛋白，这些蛋白与转录、蛋白折叠、细胞骨架丝重组、细胞周期控制、核因子（红细胞衍生2）样2 （NRF2）介导的氧化应激反应、脂质代谢、谷胱甘肽代谢、氧化磷酸化和信号转导。此外，独创性途径和生物信息学分析显示，GST-P+病灶中检测到的表达改变蛋白编码基因的表达变化可能受c-myc、NRF2、芳烃受体、核因子κ B和肝细胞核因子4转录因子的控制。在大鼠肝癌发生的起始和/或促进阶段，线粒体伴侣蛋白禁止蛋白（PHB）和禁止蛋白2 （PHB2）、septin 9 （SEPT9）、神经素1和其他细胞骨架蛋白和功能蛋白在GST-P+病灶区域的协调过表达与细胞增殖的诱导有关，并可能与大鼠肝脏肿瘤前病变的肿瘤转化有关。新发现的PHB、PHB2和SEPT9在GST-P+灶和肿瘤中升高，提示它们可能在肝癌发病中起重要作用，在肝癌发生研究中具有潜在价值。
In the present study, protein lysates from microdissected glutathione S-transferase placental-form-positive (GST-P+) foci and hepatocellular carcinomas from livers of rats treated with N-diethylnitrosamine followed by phenobarbital at doses of 0 and 500 ppm in the diet for 10 and 33 weeks were analyzed using QSTAR Elite liquid chromatography with tandem mass spectrometry and iTRAQ technology. Among 75 proteins, a total of 27 and 50 proteins displaying significant quantitative changes comparing with adjacent normal-appearing liver tissue were identified in GST-P+ foci of initiation control and promotion groups, respectively, which are related to transcription, protein folding, cytoskeleton filaments reorganization, cell cycle control, nuclear factor (erythroid-derived 2)-like 2 (NRF2)-mediated oxidative stress responses, lipid metabolism, glutathione metabolism, oxidative phosphorylation, and signal transduction. Furthermore, Ingenuity Pathway and bioinformatic analyses revealed that expression changes of genes encoding proteins with altered expression detected in GST-P+ foci are likely to be controlled by c-myc, NRF2, aryl hydrocarbon receptor, nuclear factor kappa B, and hepatocyte nuclear factor 4 transcriptional factors. Coordinated overexpression of mitochondrial chaperons prohibitin (PHB) and prohibitin 2 (PHB2), septin 9 (SEPT9), neurabin 1, and other cytoskeletal and functional proteins in areas of GST-P+ foci during initiation and/or promotion stages of rat hepatocarcinogenesis was associated with induction of cell proliferation and might be responsible for the neoplastic transformation of rat liver preneoplastic lesions. Newly discovered elevation of PHB, PHB2, and SEPT9 in GST-P+ foci and tumors, imply that they might play important role in the onset of liver cancer and be of potential values in the studies of hepatocarcinogenesis.