Cho Kwang-Hyun, Baek Songjoon, Sung Myong-Hee
College of Medicine, Seoul National University, Jongno-gu, Seoul 110-799, South Korea.
FEBS Lett. 2006 Jun 26;580(15):3665-70. doi: 10.1016/j.febslet.2006.05.053. Epub 2006 Jun 5.
Mutations in components of the Wnt/beta-catenin pathway are observed to be the earliest initiating event for most colorectal tumors. The majority of the mutations occur in the tumor suppressor adenomatous polyposis coli (APC), even though there are other genes that are capable of modulating the pathway activity. Moreover, the specific APC mutations associated in colon cancer indicate the possibility that the tumor selects for certain truncated forms of APC that partially retain its function, namely, inhibition of beta-catenin. We estimated the effects of various mutations in APC and other known mutations using a recent mathematical model of the Wnt pathway that was constructed to represent the conserved core molecular events. We provide evidence that APC mutations are selected not based on the maximal level of beta-catenin but rather based on distinct state of activity that appears to be optimal for the tissue-specific tumorigenesis. This optimal level is determined by balancing beta-catenin signaling and the induction of Axin2 that acts as a potent negative feedback. The predominant pattern of APC mutations may provide synergistic oncogenic effects that promote colorectal tumorigenesis: the optimal signaling for cell survival and renewal, disrupted cell adhesion, chromosomal instability, and altered asymmetric division of stem cells.
在大多数结直肠癌中，Wnt/β-连环蛋白信号通路成分的突变被认为是最早的起始事件。大多数突变发生在肿瘤抑制基因腺瘤性息肉病基因（APC）中，尽管还有其他基因能够调节该信号通路的活性。此外，与结肠癌相关的特定APC突变表明，肿瘤可能选择了某些部分保留其功能（即抑制β-连环蛋白）的截短形式的APC。我们使用最近构建的一个代表保守核心分子事件的Wnt信号通路数学模型，估计了APC中各种突变以及其他已知突变的影响。我们提供的证据表明，APC突变的选择并非基于β-连环蛋白的最大水平，而是基于一种明显对组织特异性肿瘤发生最为有利的独特活性状态。这种最佳水平是通过平衡β-连环蛋白信号传导和作为有效负反馈的Axin2的诱导来确定的。APC突变的主要模式可能提供协同致癌作用，促进结直肠癌的发生：为细胞存活和更新提供最佳信号、破坏细胞粘附、导致染色体不稳定以及改变干细胞的不对称分裂。
