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首页> 外文期刊>Cell cycle >Netrin-1, a missing link between chronic inflammation and tumor progression.
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Netrin-1, a missing link between chronic inflammation and tumor progression.

机译:Netrin-1是慢性炎症和肿瘤进展之间的缺失环节。

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Netrin-1, discovered as a neuronal navigation cue, has been recently proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. This survival activity is mediated via the inhibition of the so-called netrin-1 dependence receptors. The netrin-1 receptors, DCC (for Deleted in Colorectal Cancer) and UNC5H (UNC5 homologues), indeed belong to the functional family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands and such a trait has been hypothesized to confer these receptors a tumor suppressor activity as their presence render cell survival dependent on ligand availability. As a consequence, human tumors show either a loss of dependence receptors or a gain of netrin-1, allowing tumors to escape this safeguard mechanism. We recently found that netrin-1 is a direct transcriptional target of the transcription factor NFkappaB, and that a fraction of colorectal tumors show a netrin-1 gain parallel to NFkappaB activation. Moreover, colorectal cancers from patients affected by inflammatory bowel diseases (IBD) show upregulation of netrin-1. Several evidences suggest a tight link between chronic inflammation and tumorigenesis, mainly through NFkappaB activation. We propose that induction of netrin-1 expression via NFkappaB in IBD patients could affect colorectal tumor promotion and progression and that inhibition of netrin-1 could be an innovative target for drug therapy in inflammation-driven colorectal cancers.
机译:Netrin-1被发现为神经元导航提示,最近已提出通过调节细胞凋亡在结直肠肿瘤发生中起关键作用。这种存活活性是通过抑制所谓的netrin-1依赖性受体来介导的。 netrin-1受体DCC(在大肠癌中已缺失)和UNC5H(UNC5同源物)确实属于依赖受体的功能家族,它们在不存在配体的情况下也具有诱导细胞凋亡的能力,并且已经假设这种特性赋予这些受体肿瘤抑制活性,因为它们的存在使细胞存活取决于配体的可用性。结果,人类肿瘤显示出依赖性受体的丢失或netrin-1的获得,从而使肿瘤逃脱了这种保护机制。最近,我们发现netrin-1是转录因子NFkappaB的直接转录靶标,并且一部分结直肠肿瘤显示出与NFkappaB激活平行的netrin-1增益。此外,患有炎症性肠病(IBD)的患者的大肠癌显示了netrin-1的上调。一些证据表明,慢性炎症与肿瘤发生之间存在紧密联系,主要是通过NFkappaB激活。我们建议在IBD患者中通过NFkappaB诱导netrin-1表达可以影响结直肠肿瘤的促进和进展,并且抑制netrin-1可以成为炎症驱动结直肠癌药物治疗的创新目标。

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