GUCY2C Opposes Systemic Genotoxic Tumorigenesis by Regulating AKT-Dependent Intestinal Barrier Integrity
GUCY2C Opposes Systemic Genotoxic Tumorigenesis by Regulating AKT-Dependent Intestinal Barrier Integrity
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DOI：
10.1371/journal.pone.0031686
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发表时间：
2012-02-22
期刊：
影响因子：
3.7
通讯作者：
Waldman, Scott Arthur
中科院分区：
文献类型：
--
作者：
Lin, Jieru Egeria;Snook, Adam Eugene;Waldman, Scott Arthur
分隔粘膜和系统隔间的屏障由上皮细胞组成，通过紧密的连接进行退火，限制了通透性。GUCY2C最近作为一种肠道肿瘤抑制因子出现，协调AKT1依赖的隐窝绒毛动态平衡。在这里，GUCY2C对对抗结肠炎和系统性肿瘤发生的屏障完整性的贡献被定义。缺乏GUCY2C的小鼠(GUCY2C(-/-))表现出与结合蛋白减少相关的屏障高通透性。相反，小鼠体内GUCY2C的激活降低了与结合蛋白增加相关的屏障通透性。此外，沉默GUCY2C加剧了，而激活减少，化学屏障破坏和结肠炎。此外，消除GUCY2C放大了系统的氧化DNA损伤，而激活则减少了系统的氧化DNA损伤。这种遗传毒性与GUCY2C(-/-)小鼠的自发性和致癌物诱导的全身肿瘤形成增加有关。GUCY2C通过抑制AKT1调节屏障的完整性，AKT1与小鼠和Caco 2细胞体外增加的连接蛋白occludin和claudin 4相关。因此，GUCY2C保护肠道屏障，对抗结肠炎和全身遗传毒性和肿瘤发生。口服GUCY2C配体的新临床开发突显了这一观察的治疗潜力，这种配体可用于炎症性肠病和癌症的化学预防。
The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c(-/-)) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated with increased spontaneous and carcinogen-induced systemic tumorigenesis in Gucy2c(-/-) mice. GUCY2C regulated barrier integrity by repressing AKT1, associated with increased junction proteins occludin and claudin 4 in mice and Caco2 cells in vitro. Thus, GUCY2C defends the intestinal barrier, opposing colitis and systemic genotoxicity and tumorigenesis. The therapeutic potential of this observation is underscored by the emerging clinical development of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and cancer.