文章：

RAS癌基因：编织一个致瘤网

RAS oncogenes: weaving a tumorigenic web

原文发布日期：2011-10-13

DOI: 10.1038/nrc3106

类型: Review Article

开放获取: 否

要点：

1. RAS is a GTPase that is frequently mutated in cancer and that affects a variety of cancer-driving processes. Unique properties of RAS isoforms, and of particular activating mutations, may distinctly affect the process of neoplastic conversion in different tissues.
2. RAS drives cellular proliferation by providing both cell-autonomous and non-cell-autonomous cues, which ultimately converge in the transformed cells to promote pro-growth and to inhibit anti-growth signals. RAS-mediated proliferative overdrive may induce replicative stress and activation of DNA damage responses.
3. The suppression of a cell death response by oncogenic RAS is a consequence of a perturbation of homeostatic balance between pro-apoptotic and anti-apoptotic signals. To keep up with the high energy needs of growing cells, the survival of RAS-transformed cells is further aided by metabolic reprogramming towards glycolysis that is mediated by MAPK- and PI3K-dependent regulation of hypoxia-inducible factor 1α (HIF1α).
4. Oncogenic RAS modulates the tumour microenvironment by promoting pro-angiogenic mechanisms and by altering host-mediated immune responses. Transformation by RAS can also promote changes in motility and cellular adhesion, leading to the acquisition of invasive and metastatic properties of cancer cells.
5. Breakthroughs in real-time imaging, computational approaches, high-throughput screening and genetically engineered mouse modelling promise to advance our capacity to integrate the complexity of RAS signalling pathways with the context specificity of their oncogenic activities, undoubtedly aiding the implementation of successful remedial strategies in the clinic.

要点翻译：

1. RAS是一种GTP酶，在癌症中常发生突变，并影响多种癌症驱动进程。RAS亚型的独特性质以及特定的激活突变，可能对不同组织中的肿瘤转化过程产生截然不同的影响。
2. RAS通过提供细胞自主与非细胞自主信号驱动细胞增殖，这些信号最终在转化细胞中汇聚，促进生长信号并抑制抗生长信号。RAS介导的增殖过度激活可能诱发复制应激并激活DNA损伤应答。
3. 致癌RAS对细胞死亡反应的抑制，是促凋亡与抗凋亡信号之间稳态平衡被扰乱的结果。为满足生长细胞的高能量需求，RAS转化细胞的存活还通过代谢重编程得以增强——这一过程由MAPK和PI3K介导的低氧诱导因子1α（HIF1α）调控所实现。
4. 致癌RAS通过促进血管生成机制和改变宿主介导的免疫反应来调节肿瘤微环境。RAS介导的转化还可促进细胞运动性与黏附性的改变，导致癌细胞获得侵袭和转移特性。
5. 实时成像技术、计算方法、高通量筛选及基因工程小鼠模型领域的突破，有望提升我们整合RAS信号通路复杂性与其致癌活性背景特异性的能力，这无疑将推动临床成功治疗策略的实施。

英文摘要：

RAS proteins are essential components of signalling pathways that emanate from cell surface receptors. Oncogenic activation of these proteins owing to missense mutations is frequently detected in several types of cancer. A wealth of biochemical and genetic studies indicates that RAS proteins control a complex molecular circuitry that consists of a wide array of interconnecting pathways. In this Review, we describe how RAS oncogenes exploit their extensive signalling reach to affect multiple cellular processes that drive tumorigenesis.

摘要翻译： 

RAS蛋白是源自细胞表面受体的信号通路中的关键组分。由于错义突变导致的这些蛋白的致癌激活在多种癌症中频繁被检测到。大量生化与遗传学研究表明，RAS蛋白调控着一个由众多相互连接通路构成的复杂分子网络。在本综述中，我们描述了RAS癌基因如何利用其广泛的信号影响范围，作用于多种细胞过程，从而驱动肿瘤发生。

原文链接：

RAS oncogenes: weaving a tumorigenic web