Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Curr Mol Pharmacol. 2009 Nov;2(3):285-92. doi: 10.2174/1874467210902030285.
Guanylyl cyclase C (GCC) is the receptor specifically expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin and diarrheagenic bacterial heat-stable enterotoxins. This tissue-specific receptor coordinates lineage-dependent regulation of epithelial homeostasis, and its disruption contributes to intestinal tumorigenesis. It coordinates regenerative and metabolic circuits by restricting the cell cycle and proliferation and programming metabolic transitions central to organizing the dynamic crypt-surface axis. Further, mice deficient in GCC signaling are more susceptible to colon cancer induced by Apc mutations or the carcinogen azoxymethane. Moreover, guanylin and uroguanylin are gene products most commonly lost, early, in colon cancer in animals and humans. The role of GCC as a tumor suppressing receptor regulating proliferation and metabolism, together with the universal loss of guanylin and uroguanylin in tumorigenesis, suggests a model in which colorectal cancer is a paracrine hormone deficiency syndrome. In that context, activation of GCC reverses the tumorigenic phenotype by limiting growth of colorectal cancer cells by restricting progression through the G1/S transition and reprogramming metabolic circuits from glycolysis to oxidative phosphorylation, limiting bioenergetic support for rapid proliferation. These observations suggest a pathophysiological hypothesis in which GCC is a lineage-dependent tumor suppressing receptor coordinating proliferative homeostasis whose dysregulation through hormone loss contributes to neoplasia. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands.
鸟苷酸环化酶 C（GCC）是肠道细胞特异性表达的受体，可识别旁分泌激素鸟苷素和尿鸟苷素以及致泻性细菌热稳定肠毒素。这种组织特异性受体协调上皮细胞内稳态的谱系依赖性调节，其功能障碍会导致肠道肿瘤发生。它通过限制细胞周期和增殖来协调再生和代谢回路，并对代谢进行编程，这是组织动态隐窝-表面轴的关键。此外，缺乏 GCC 信号的小鼠更容易发生 Apc 突变或致癌剂氧化偶氮甲烷诱导的结肠癌。此外，在动物和人类结肠癌中，鸟苷素和尿鸟苷素通常是最早丢失的基因产物。GCC 作为一种抑制肿瘤的受体，调节增殖和代谢，同时在肿瘤发生过程中普遍丢失鸟苷素和尿鸟苷素，这表明结直肠癌是一种旁分泌激素缺乏综合征。在这种情况下，通过限制结直肠癌细胞通过 G1/S 转换的进展和将代谢回路从糖酵解重编程为氧化磷酸化，从而限制快速增殖的生物能量支持，激活 GCC 可逆转肿瘤发生表型。这些观察结果提出了一个病理生理学假设，即 GCC 是一种谱系依赖性抑制肿瘤的受体，可协调增殖稳态，其通过激素丢失的失调会导致肿瘤发生。相关的治疗学假设表明，结直肠癌是一种激素不足的疾病，可以通过口服补充 GCC 配体来预防或治疗。
