Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad.
Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad.
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DOI：
10.1016/j.semcancer.2010.12.010
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发表时间：
2011-02
影响因子：
14.5
通讯作者：
Monga SP
中科院分区：
文献类型：
--
作者：
Nejak-Bowen KN;Monga SP
在成人器官中，肝脏的再生能力是独一无二的。一个协调一致的信号级联能够在手术或毒物带来的损伤后最佳地启动再生过程。此外，存在细胞冗余，即当肝脏分化细胞在实验和临床情况下无法增殖时，短暂扩增的祖细胞群出现并扩大以确保再生。其中一个与这些现象相关的途径是Wnt/β-catenin信号，它在再生过程中相对较早被激活，主要是通过翻译后修饰。一旦被激活，β-catenin信号会驱动靶基因的表达，这些基因对细胞周期进程至关重要，并有助于启动再生过程。Wnt/β-catenin信号传导的作用和调控现已在大鼠、小鼠、斑马鱼和患者中得到证实。最近，据报道，β-catenin过表达小鼠的肝脏具有再生优势，外源性Wnt-1递送到肝脏后也是如此，为评估刺激肝衰竭治疗途径的方法铺平了道路。β-连环蛋白也与肝卵圆细胞的活化和分化有关。然而，Wnt/β-catenin信号的异常激活在肝细胞癌（HCC）的一个重要亚群中被报道。虽然这种激活的许多机制已经被报道，但最有效的异常和持续激活方式是通过β-连环蛋白基因或AXIN1/2的突变，AXIN1/2编码对β-连环蛋白降解至关重要的支架蛋白。有趣的是，在实验模型中，正常或突变β-catenin的肝脏过度表达不足以导致肿瘤的发生。事实上，β-连环蛋白的丢失促进了肝脏的化学癌变，这是由于其他的机制。由于大多数HCC发生在慢性肝损伤的背景下，肝再生是维持肝功能所必需的，但同时也是发育不良改变的基础，这种普罗米修斯属性表现出一种双重人格的行为，随着个性化医疗在临床实践中成为常态，区分良好的再生和不良的再生对于靶向选择性分子途径至关重要。β-连环蛋白信号是否可能是再生过程中冗余的途径之一，而在部分HCC病例中是不可缺少的？
Among the adult organs, liver is unique for its ability to regenerate. A concerted signaling cascade enables optimum initiation of the regeneration process following insults brought about by surgery or a toxicant. Additionally, there exists a cellular redundancy, whereby a transiently amplifying progenitor population appears and expands to ensure regeneration, when differentiated cells of the liver are unable to proliferate in both experimental and clinical scenarios. One such pathway of relevance in these phenomena is Wnt/β-catenin signaling, which is activated relatively early during regeneration mostly through post-translational modifications. Once activated, β-catenin signaling drives the expression of target genes that are critical for cell cycle progression and contribute to initiation of the regeneration process. The role and regulation of Wnt/β-catenin signaling is now documented in rats, mice, zebrafish and patients. More recently, a regenerative advantage of the livers in β-catenin overexpressing mice was reported, as was also the case after exogenous Wnt-1 delivery to the liver paving the way for assessing means to stimulate the pathway for therapeutics in liver failure. β-Catenin is also pertinent in hepatic oval cell activation and differentiation. However, aberrant activation of the Wnt/β-catenin signaling is reported in a significant subset of hepatocellular cancers (HCC). While many mechanisms of such activation have been reported, the most functional means of aberrant and sustained activation is through mutations in the β-catenin gene or in AXIN1/2, which encodes for a scaffolding protein critical for β-catenin degradation. Intriguingly, in experimental models hepatic overexpression of normal or mutant β-catenin is insufficient for tumorigenesis. In fact β-catenin loss promoted chemical carcinogenesis in the liver due to alternate mechanisms. Since most HCC occur in the backdrop of chronic hepatic injury, where hepatic regeneration is necessary for maintenance of liver function, but at the same time serves as the basis of dysplastic changes, this Promethean attribute exhibits a Jekyll and Hyde behavior that makes distinguishing good regeneration from bad regeneration essential for targeting selective molecular pathways as personalized medicine becomes a norm in clinical practice. Could β-catenin signaling be one such pathway that may be redundant in regeneration and indispensible in HCC in a subset of cases?
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影响因子：
8
作者：
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