Involvement of multiple cell cycle aberrations in early preneoplastic liver cell lesions by tumor promotion with thioacetamide in a two-stage rat hepatocarcinogenesis model
Involvement of multiple cell cycle aberrations in early preneoplastic liver cell lesions by tumor promotion with thioacetamide in a two-stage rat hepatocarcinogenesis model
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DOI：
10.1016/j.etp.2013.01.012
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发表时间：
2013-11-01
影响因子：
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通讯作者：
Shibutani, Makoto
中科院分区：
文献类型：
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作者：
Kimura, Masayuki;Fujii, Yuta;Shibutani, Makoto
硫代乙酰胺（TAA）诱导大鼠氧化应激和肝癌。我们以前报道，TAA促进引起各种破坏细胞周期蛋白在大鼠中的表达，包括下调p16（Ink 4a），这是与外显子内高甲基化在肝细胞增生性病变。本研究进一步研究了细胞周期畸变的贡献与TAA诱导的早期肝癌过程中使用抗氧化剂，酶改性异槲皮苷（EMIQ）和α-硫辛酸（ALA），在两个阶段的大鼠肝癌模型。TAA促进后开始与N-二乙基亚硝胺增加的数量和面积的肝细胞病灶免疫反应谷胱甘肽S-转移酶胎盘型（GST-P）和增殖和凋亡细胞的数量。与EMIQ和ALA的共同治疗抑制了这些增加。TAA诱导的与GST-P+病灶一致的p16（Ink 4a-）病灶的形成不受EMIQ或ALA联合治疗的抑制。TAA促进增加了细胞增殖标记Ki-67、G（2）/M和纺锤体检查点蛋白（磷酸化检查点激酶1和Mad 2）、DNA损伤相关蛋白磷酸化组蛋白H2 AX和G（2）-M期相关蛋白（拓扑异构酶II α、磷酸化组蛋白H3和Cdc 2）在GST-P+病灶内的细胞分布，而与EMIQ或ALA共同处理抑制了这些增加。这些结果表明，下调p16（Ink 4a）可能允许选择性增殖的癌前细胞的TAA促进。然而，抗氧化剂并不能抵消这种基因控制。此外，抗氧化剂有效抑制TAA诱导的癌前病变内的细胞群体变化可能反映了细胞周期的促进和DNA损伤的积累，导致细胞周期检查点的激活，导致TAA促进的肝癌发生早期阶段的G（2）和M期阻滞。(C)2013年爱思唯尔有限公司。All rights reserved.
Thioacetamide (TAA) induces oxidative stress and hepatocarcinogenicity in rats. We previously reported that TAA promotion caused various disruptions in cell cycle protein expression in rats, including downregulation of p16(Ink4a), which is associated with intraexonic hypermethylation in hepatocellular proliferative lesions. This study further investigated the contribution of cell cycle aberrations associated with early hepatocarcinogenic processes induced by TAA using antioxidants, enzymatically modified isoquercitrin (EMIQ) and alpha-lipoic acid (ALA), in a two-stage rat hepatocarcinogenesis model. TAA-promotion after initiation with N-diethylnitrosamine increased the number and area of hepatocellular foci immunoreactive for glutathione S-transferase placental form (GST-P) and the numbers of proliferating and apoptotic cells. Co-treatment with EMIQ and ALA suppressed these increases. TAA-induced formation of p16(Ink4a-) foci in concordance with GST-P+ foci was not suppressed by co-treatment with EMIQ or ALA. TAA-promotion increased cellular distributions of cell proliferation marker Ki-67, G(2)/M and spindle checkpoint proteins (phosphorylated checkpoint kinase 1 and Mad2), the DNA damage-related protein phosphorylated histone H2AX, and G(2)-M phase-related proteins (topoisomerase II alpha, phosphorylated histone H3 and Cdc2) within GST-P+ foci, and co-treatment with EMIQ or ALA suppressed these increases. These results suggest that downregulation of p16(Ink4a) may allow selective proliferation of preneoplastic cells by TAA promotion. However, antioxidants did not counteract this gene control. Moreover, effective suppression of TAA-induced cellular population changes within preneoplastic lesions by antioxidants may reflect facilitation of cell cycling and accumulation of DNA damage causing the activation of cell cycle checkpoints, leading to G(2) and M phase arrest at the early stages of hepatocarcinogenesis promoted by TAA. (C) 2013 Elsevier GmbH. All rights reserved.