文章：

Netrin-1及其受体在肿瘤发生中的作用

Netrin-1 and its receptors in tumorigenesis

原文发布日期：2004-12-01

DOI: 10.1038/nrc1504

类型: Review Article

开放获取: 否

要点：

1. Axon guidance molecules are frequently inactivated in various human cancers. In particular, the netrin-1 receptors DCC and the UNC5H family are downregulated in more than half of all colorectal cancers.
2. DCC and the UNC5H proteins regulate apoptosis; positively in the absence of netrin-1, or negatively in the presence of netrin-1. This is designated as the 'dependence receptor' concept.
3. DCC-induced apoptosis defines a novel apoptotic pathway that is dependent on caspase activation, but independent of both the mitochondrial- and death-receptor-mediated apoptotic pathways.
4. The netrin-1-mediated anti-apoptotic signal that inhibits p53-induced apoptosis implies that NTN1 (which encodes netrin-1) could function as an oncogene.
5. A netrin-1 gradient is evident in normal colonic epithelium, with highest expression in the crypts and lowest expression in the upper portion of the villi, correlating with the pattern of cell survival and death in this tissue.
6. NTN1-transgenic mice have reduced apoptosis of intestinal epithelial cells, leading to an increase in the spontaneous formation of hyperplasia and adenoma.
7. The tumour suppressor p53 regulates the expression of netrin-1 and some of its receptors. Therefore, p53 might determine cell fate through regulation of the netrin-1 pathway.

要点翻译：

1. 轴突导向分子在多种人类癌症中常处于失活状态。尤其值得注意的是，netrin-1受体DCC及UNC5H家族在超过半数结直肠癌中表达下调。
2. DCC与UNC5H蛋白具有调控细胞凋亡的双重功能：在netrin-1缺失时促进凋亡，而在netrin-1存在时抑制凋亡。这一现象被定义为"依赖受体"概念。
3. DCC诱导的细胞凋亡开辟了一条新型凋亡通路，该通路依赖于caspase的激活，但独立于线粒体途径和死亡受体介导的凋亡途径。
4. Netrin-1通过抑制p53诱导的细胞凋亡发挥抗凋亡作用，提示NTN1（编码netrin-1的基因）可能具有原癌基因功能。
5. 正常结肠上皮组织中存在明显的netrin-1梯度表达：隐窝区域表达最高，绒毛顶端表达最低，这种分布模式与该组织的细胞存活/死亡区域分布高度吻合。
6. NTN1转基因小鼠肠道上皮细胞凋亡减少，导致自发性增生和腺瘤形成增加。
7. 抑癌基因p53可调控netrin-1及其部分受体的表达。因此，p53可能通过调节netrin-1通路来决定细胞命运。

英文摘要：

Netrin-1 and its receptors DCC (deleted in colorectal cancer) and the UNC5 orthologues (human UNC5A–D and rodent UNC5H1–4) define a new mechanism for both the positive (induction) and negative (suppression) regulation of apoptosis. Accumulating evidence implies that for human cancers, this positive signalling pathway is frequently inactivated. Surprisingly, binding of netrin-1 to its receptors inhibits tumour suppressor p53-dependent apoptosis, and p53 is directly involved in transcriptional regulation of netrin-1 and its receptors. So, the netrin-1 receptor pathways probably play an important part in tumorigenesis.

摘要翻译： 

Netrin-1 及其受体 DCC（结直肠癌中缺失）和 UNC5 同源物（人类 UNC5A–D 和啮齿类 UNC5H1–4）定义了一种新的机制，既能正向（诱导）也能负向（抑制）调控细胞凋亡。越来越多的证据表明，在人类癌症中，这一正向信号通路常被失活。令人惊讶的是，netrin-1 与其受体结合可抑制肿瘤抑制因子 p53 依赖的细胞凋亡，而 p53 又直接参与 netrin-1 及其受体的转录调控。因此，netrin-1 受体通路可能在肿瘤发生中发挥重要作用。

原文链接：

Netrin-1 and its receptors in tumorigenesis