Department of Pathology, University of Pittsburgh, SOM, Pittsburgh, PA 15261, United States.
Semin Cancer Biol. 2011 Feb;21(1):44-58. doi: 10.1016/j.semcancer.2010.12.010. Epub 2010 Dec 21.
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?
在成人器官中，肝脏具有独特的再生能力。一个协调的信号级联反应使肝脏能够在手术或毒物引起的损伤后最佳地启动再生过程。此外，还存在细胞冗余，即在实验和临床情况下，当肝脏的分化细胞无法增殖时，短暂扩增的祖细胞群体出现并扩大以确保再生。在这些现象中，一个相关的途径是 Wnt/β-连环蛋白信号通路，它在再生过程中相对较早被激活，主要通过翻译后修饰。一旦被激活，β-连环蛋白信号通路驱动靶基因的表达，这些基因对于细胞周期进展至关重要，并有助于启动再生过程。Wnt/β-连环蛋白信号通路的作用和调节在大鼠、小鼠、斑马鱼和患者中都有记载。最近，研究报道了β-连环蛋白过表达小鼠肝脏的再生优势，以及外源性 Wnt-1 递送到肝脏后也会出现这种情况，这为评估刺激肝衰竭治疗途径的方法铺平了道路。β-连环蛋白在肝卵圆细胞的激活和分化中也很重要。然而，在很大一部分肝细胞癌 (HCC) 中，Wnt/β-连环蛋白信号通路的异常激活已被报道。虽然已经报道了许多这种激活的机制，但异常和持续激活的最有效手段是通过β-连环蛋白基因或 AXIN1/2 基因突变，AXIN1/2 编码一种对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，正常或突变的β-连环蛋白在肝脏中的过表达不足以导致肿瘤发生。事实上，由于其他机制，β-连环蛋白的缺失促进了肝脏的化学致癌作用。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变化的基础，这种普罗米修斯属性表现出一种ekyll 和 Hyde 的行为，这使得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，因为个性化医学在临床实践中已成为一种常态。β-连环蛋白信号通路是否是一种在再生中冗余但在某些情况下在 HCC 中不可或缺的途径？
