Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
Clin Transl Sci. 2008 Sep;1(2):163-7. doi: 10.1111/j.1752-8062.2008.00040.x.
The most commonly lost gene products in colorectal carcinogenesis include the paracrine hormones guanylin and uroguanylin, the endogenous ligands for guanylyl cyclase C (GCC), the intestinal receptor for diarrheagenic bacterial enterotoxins. Recently, GCC-cGMP signaling has emerged as a principal regulator of proliferation, genetic integrity and metabolic programming in normal human enterocytes and colon cancer cells. Elimination of GCC in mice produced hyperplasia of the proliferating compartment associated with increases in rapidly cycling progenitor cells, and reprogrammed enterocyte metabolism, with a shift from oxidative phosphorylation to glycolysis. In addition, in colons of mice carrying mutations in Apc (Apc(Min) (/+)) or exposed to the carcinogen azoxymethane, elimination of GCC increased tumor initiation and promotion by disrupting genomic integrity and releasing cell cycle restriction. These previously unrecognized roles for GCC as a fundamental regulator of intestinal homeostasis and as an intestinal tumor suppressor suggest that receptor dysregulation reflecting paracrine hormone insufficiency is a key event during the initial stages of colorectal tumorigenesis. Together with the uniform over-expression of GCC in human tumors, these novel roles for GCC underscore the potential of oral replacement with GCC ligands for targeted prevention and therapy of colorectal cancer.
在结直肠肿瘤发生过程中，最常丢失的基因产物包括旁分泌激素鸟苷酸环化酶 C（GCC）的内源性配体 guanylin 和 uroguanylin，以及致泻性细菌肠毒素的肠道受体。最近，GCC-cGMP 信号转导已成为正常人类肠细胞和结肠癌细胞增殖、遗传完整性和代谢编程的主要调节因子。在小鼠中消除 GCC 会导致与快速循环祖细胞增加相关的增殖区室的增生，并重新编程肠细胞代谢，从氧化磷酸化转向糖酵解。此外，在携带 APC 基因突变（Apc(Min)（/+））或暴露于致癌剂氧化偶氮甲烷的小鼠的结肠中，消除 GCC 会通过破坏基因组完整性和释放细胞周期限制来增加肿瘤起始和促进。GCC 作为肠道内稳态的基本调节剂和肠道肿瘤抑制因子的这些先前未被认识的作用表明，反映旁分泌激素不足的受体失调是结直肠肿瘤发生初始阶段的一个关键事件。结合 GCC 在人类肿瘤中的一致过表达，这些 GCC 的新作用突出了口服替代 GCC 配体用于结直肠癌靶向预防和治疗的潜力。
