Hepatotoxin-induced changes in the adult murine liver promote MYC-induced tumorigenesis.
Hepatotoxin-induced changes in the adult murine liver promote MYC-induced tumorigenesis.
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DOI：
10.1371/journal.pone.0002493
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发表时间：
2008-06-18
期刊：
影响因子：
3.7
通讯作者：
Felsher DW
中科院分区：
文献类型：
--
作者：
Beer S;Komatsubara K;Bellovin DI;Kurobe M;Sylvester K;Felsher DW
人类c-MYC（MYC）癌基因的过表达是肝细胞癌（HCC）发病机制中最常见的事件之一。以前，我们已经表明，在条件转基因小鼠模型中，MYC过表达抑制诱导有丝分裂细胞分裂和成年肝脏中的肿瘤发生;然而，与此形成鲜明对比的是，MYC诱导与胚胎和新生小鼠中肿瘤发生的非常快速的发病相关的稳健增殖。在这里，我们表明，非遗传毒性肝毒素诱导肝细胞环境的变化与细胞增殖增加和增强肿瘤发生。5-二乙氧羰基-1，4-二氢可力丁（DDC）和四氯化碳（CCl 4）都与MYC协同作用，大大加速了成年宿主肝癌的发病，使其发病时间少于7天，而单独使用MYC的平均发病潜伏期超过35周。这些肝毒素增强的肝肿瘤在大体和组织学上类似于胚胎和新生儿肝肿瘤。重要的是，我们发现MYC过表达仅能够在用任一致癌物处理的胚胎/新生儿宿主或成人宿主中诱导有丝分裂细胞周期蛋白B1的表达。我们的研究结果表明，癌基因可以保持潜伏激活的模型，但成人肝脏暴露于肝毒素，促进肝细胞增殖，可以迅速发现其恶性潜力。
Overexpression of the human c-MYC (MYC) oncogene is one of the most frequently implicated events in the pathogenesis of hepatocellular carcinoma (HCC). Previously, we have shown in a conditional transgenic mouse model that MYC overexpression is restrained from inducing mitotic cellular division and tumorigenesis in the adult liver; whereas, in marked contrast, MYC induces robust proliferation associated with the very rapid onset of tumorigenesis in embryonic and neonatal mice. Here, we show that non-genotoxic hepatotoxins induce changes in the liver cellular context associated with increased cellular proliferation and enhanced tumorigenesis. Both 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4) cooperate with MYC to greatly accelerate the onset of liver cancer in an adult host to less than 7 days versus a mean latency of onset of over 35 weeks for MYC alone. These hepatotoxin-enhanced liver tumors grossly and histologically resemble embryonic and neonatal liver tumors. Importantly, we found that MYC overexpression is only capable of inducing expression of the mitotic Cyclin B1 in embryonic/neonatal hosts or adult hosts that were treated with either carcinogen. Our results suggest a model whereby oncogenes can remain latently activated, but exposure of the adult liver to hepatotoxins that promote hepatocyte proliferation can rapidly uncover their malignant potential.
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DOI：
10.1083/jcb.126.1.223
发表时间：
1994-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nagy P;Bisgaard HC;Thorgeirsson SS
通讯作者：
Thorgeirsson SS
影响因子：
3.4
作者：
MACSWEEN, RN;SCOTT, AR
通讯作者：
SCOTT, AR
DOI：
10.1073/pnas.082005599
发表时间：
2002-04-30
影响因子：
11.1
作者：
Menssen, A;Hermeking, H
通讯作者：
Hermeking, H
DOI：
10.1073/pnas.93.20.10933
发表时间：
1996-10-01
影响因子：
11.1
作者：
Kistner, A;Gossen, M;Bujard, H
通讯作者：
Bujard, H
影响因子：
9.8
作者：
Beer S;Zetterberg A;Ihrie RA;McTaggart RA;Yang Q;Bradon N;Arvanitis C;Attardi LD;Feng S;Ruebner B;Cardiff RD;Felsher DW
通讯作者：
Felsher DW