Danielsen Stine Aske, Eide Peter Wold, Nesbakken Arild, Guren Tormod, Leithe Edward, Lothe Ragnhild A
Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway.
Biochim Biophys Acta. 2015 Jan;1855(1):104-21. doi: 10.1016/j.bbcan.2014.09.008. Epub 2014 Nov 22.
PI3K/AKT signaling leads to reduced apoptosis, stimulates cell growth and increases proliferation. Under normal conditions, PI3K/AKT activation is tightly controlled and dependent on both extracellular growth signals and the availability of amino acids and glucose. Genetic aberrations leading to PI3K/AKT hyper-activation are observed at considerable frequency in all major nodes in most tumors. In colorectal cancer the most commonly observed pathway changes are IGF2 overexpression, PIK3CA mutations and PTEN mutations and deletions. Combined, these alterations are found in about 40% of large bowel tumors. In addition, but not mutually exclusive to these, KRAS mutations are observed at a similar frequency. There are however additional, less frequent and more poorly understood events that may also push the PI3K/AKT pathway into overdrive and thus promote malignant growth. Here we discuss aberrations of components at the genetic, epigenetic, transcriptional, post-transcriptional, translational and post-translational level where perturbations may drive excessive PI3K/AKT signaling. Integrating multiple molecular levels will advance our understanding of this cancer critical circuit and more importantly, improve our ability to pharmacologically target the pathway in view of clonal development, tumor heterogeneity and drug resistance mechanisms. In this review, we revisit the PI3K/AKT pathway cancer susceptibility syndromes, summarize the known aberrations at the different regulatory levels and the prognostic and predictive values of these alterations in colorectal cancer.
PI3K/AKT信号传导可减少细胞凋亡，刺激细胞生长并增加细胞增殖。在正常情况下，PI3K/AKT的激活受到严格控制，并且依赖于细胞外生长信号以及氨基酸和葡萄糖的可用性。在大多数肿瘤的所有主要节点中，均可频繁观察到导致PI3K/AKT过度激活的基因畸变。在结直肠癌中，最常观察到的通路变化是IGF2过表达、PIK3CA突变以及PTEN突变和缺失。综合来看，约40%的大肠肿瘤中存在这些改变。此外，与此并非相互排斥的是，KRAS突变也以相似的频率被观察到。然而，还存在其他一些不太常见且了解较少的事件，这些事件也可能促使PI3K/AKT通路过度激活，从而促进恶性生长。在此，我们讨论在基因、表观遗传、转录、转录后、翻译和翻译后水平上各组分的畸变情况，其中这些扰动可能会驱动PI3K/AKT信号过度传导。整合多个分子水平将增进我们对这个癌症关键通路的理解，更重要的是，鉴于克隆发展、肿瘤异质性和耐药机制，提高我们从药理学角度靶向该通路的能力。在本综述中，我们重新审视PI3K/AKT通路相关的癌症易感性综合征，总结不同调控水平上已知的畸变情况以及这些改变在结直肠癌中的预后和预测价值。
