Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis.

中文翻译：

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APC-β-连环蛋白-TCF 信号使肠道鸟苷酸-GUCY2C 肿瘤抑制轴沉默。

散发性结直肠癌始于 APC 或其降解靶 β-连环蛋白的突变，产生 TCF 依赖性核转录驱动肿瘤发生。肠上皮受体 GUCY2C 及其典型的旁分泌激素鸟苷，调节沿隐窝表面轴的稳态信号传导，以对抗肿瘤发生。在这里，我们揭示了在人类和小鼠的 APC 依赖性肿瘤转化的最早阶段，鸟苷素激素的表达，而不是 GUCY2C 受体的表达。使 GUCY2C 信号通路沉默的激素损失反映了由细胞核中突变的 APC-β-catenin-TCF 程序介导的转录抑制。这些研究支持肠道肿瘤发生的病理生理模型，其中突变的 APC-β-连环蛋白-TCF 转录调节消除了肿瘤起始时的鸟苷酸表达，沉默 GUCY2C 信号，进而失调导致肿瘤进展的肠道稳态机制。他们将结直肠癌的机制范式从 APC 和 β-连环蛋白中不可逆突变的疾病扩展到鸟苷激素丢失之一，其替代和 GUCY2C 信号传导的重建可以预防肿瘤发生。