Guanylin GUCY2C axis in Colorectal Cancer Initiation

鸟苷素 GUCY2C 轴在结直肠癌发生中的作用

• 批准号: 9237630
• 负责人: SCOTT A WALDMAN
• 金额: $ 37.2万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237630
• 关键词: Alpha Cell; Automobile Driving; Binding Sites; Carcinogens; Chemoprevention; Chronic; Colon Carcinoma; Colorectal; Colorectal Cancer; Constipation; DNA Sequence Alteration; Data; Disease; Elements; Epithelial; Event; FRAP1 gene; Functional disorder; Gastrointestinal Hormone Receptors; Gene Mutation; Genetic Transcription; Hormones; Human; In Vitro; Induced Mutation; Intestinal Neoplasms; Ligands; Link; Mediating; Messenger RNA; Molecular; Mus; Mutation; Nuclear Translocation; Oncogenic; Oral; Organoids; Outcome; Polyubiquitination; Prevention; Process; Proteins; Proto-Oncogene Proteins c-akt; Signal Pathway; Signal Transduction; Surface; Testing; Transcript; Transgenes; Transgenic Mice; Transgenic Organisms; Translations; Tumor Suppressor Proteins; base; beta catenin; cancer cell; cancer initiation; colorectal cancer prevention; gene product; guanylin; in vivo; insight; mouse model; mutant; mutant mouse model; novel; prevent; programs; promoter; receptor; reconstitution; repaired; transcription factor; tumor; tumor initiation; tumorigenesis

PROJECT SUMMARY/ABSTRACT Mutations in APC (~85%) or β-catenin (~5%) initiate >90% of sporadic colorectal cancers. These mutations produce β-catenin accumulation and nuclear translocation, activating Tcf which drives transcriptional programs underlying tumorigenesis. GUCY2C is the intestinal receptor for the hormone guanylin expressed in colorectum. In the healthy state, guanylin-GUCY2C signaling regulates homeostatic processes that organize the crypt-surface axis, in part through an unknown mechanism which blocks β-catenin accumulation. Of significance, guanylin is the most commonly lost mRNA transcript in colorectal cancer. Hormone loss, which silences GUCY2C, occurs at the earliest stages of transformation through an unknown mechanism conserved in mice and humans. Preliminary studies reveal that guanylin loss is mediated by mutant APC-β-catenin-Tcf signaling. Moreover, transgenic guanylin expression eliminated carcinogen-induced tumor formation in mice. Based on these observations, we propose that mutant APC-β-catenin-Tcf signaling transcriptionally silences guanylin as an obligatory step in tumorigenesis because guanylin-GUCY2C signaling blocks β-catenin accumulation required for transformation. The correlative chemoprevention hypothesis suggests that guanylin replacement should eliminate tumorigenesis driven by APC-β-catenin signaling. Here, the Pathophysiologic Aim will identify the transcriptional mechanisms mediating guanylin loss by mutant APC-β-catenin-Tcf. These studies will establish a novel molecular link between mutant APC-β-catenin-Tcf signaling, guanylin suppression, and GUCY2C silencing which is obligatory for tumorigenesis. The Mechanistic Aim tests the hypothesis that guanylin is lost because GUCY2C blocks β-catenin accumulation required for tumorigenesis. These studies will demonstrate that the guanylin-GUCY2C axis restricts β-catenin accumulation by blocking protein translation (synthesis) and inducing proteosomal degradation. The Prevention Aim tests the hypothesis that colorectal cancer reflects suppression of guanylin expression and GUCY2C signaling which can be overcome by hormone replacement. These studies will demonstrate the ability of transgenic guanylin expression to repair oncogenic β-catenin signaling, reconstitute endogenous GUCY2C hormone expression, and prevent tumorigenesis following biallelic APC inactivation in mice. Together, these studies will reveal a previously unanticipated required step in colorectal cancer initiation involving guanylin loss and GUCY2C silencing. They will shift the pathophysiological paradigm for colorectal cancer from a disease of irreversible gene mutations to one of reversible hormone insufficiency. Mechanistically, they will identify a unique vulnerability at the apex of the oncogenic cascade in which β-catenin-dependent events required for tumorigenesis can be overcome by GUCY2C signaling. Moreover, they will establish the proof of principle that colorectal cancer can be prevented by hormone replacement. The potential for immediate translation is underscored by the approval of the oral GUCY2C ligand linaclotide to treat chronic constipation.

项目总结/摘要 APC（~85%）或β-连环蛋白（~5%）突变引发>90%的散发性结直肠癌。这些突变 产生β-catenin积累和核转位，激活Tcf，驱动转录程序 潜在的肿瘤发生。GUCY 2C是鸟苷素激素的肠受体，在大肠杆菌中表达。 结肠直肠在健康状态下，鸟苷酸-GUCY 2C信号调节体内平衡过程， 隐窝表面轴，部分通过一个未知的机制，阻止β-连环蛋白的积累。的 鸟苷素是结肠直肠癌中最常见的mRNA转录物。荷尔蒙流失， 沉默GUCY 2C，发生在转化的最早阶段，通过一种未知的机制保守 在老鼠和人类身上。初步研究表明鸟苷素丢失是由突变型APC-β-catenin-Tcf介导的 发信号。此外，转基因鸟苷素表达消除了致癌物诱导的肿瘤形成， 小鼠基于这些观察结果，我们提出突变型APC-β-catenin-Tcf信号转导通路在转录水平上可能是一种新的信号转导途径。 由于鸟苷素-GUCY 2C信号传导阻断β-连环蛋白，鸟苷素作为肿瘤发生中的一个必要步骤沉默 转化需要积累。相关的化学预防假说表明鸟苷素 替代应该消除由APC-β-连环蛋白信号传导驱动的肿瘤发生。在这里，病理生理学 目的研究突变型APC-β-catenin-Tcf介导鸟苷素丢失的转录机制。这些 研究将在突变型APC-β-catenin-Tcf信号传导、鸟苷素 抑制和GUCY 2C沉默，这是肿瘤发生的必要条件。机械目标测试 鸟苷素丢失是因为GUCY 2C阻断了肿瘤发生所需的β-连环蛋白积累。 这些研究将证明鸟苷酶-GUCY 2C轴通过阻断β-连环蛋白的表达来限制β-连环蛋白的积累。 蛋白质翻译（合成）和诱导蛋白体降解。预防目标测试 假设结肠直肠癌反映了鸟苷素表达和GUCY 2C信号传导的抑制， 可以通过激素替代来克服。这些研究将证明转基因鸟苷素 表达以修复致癌β-连环蛋白信号传导，重建内源性GUCY 2C激素表达， 并防止小鼠中双等位基因APC失活后的肿瘤发生。总之，这些研究将揭示一个 涉及鸟苷素丢失和GUCY 2C的结肠直肠癌启动中先前未预期的必需步骤 沉默他们将改变结直肠癌的病理生理学范式， 一种可逆性激素不足的基因突变从机制上讲，他们会识别一个独特的 在致癌级联反应的顶点处的脆弱性，其中β-连环蛋白依赖性事件需要 肿瘤发生可以通过GUCY 2C信号传导来克服。此外，他们将建立原则证明 结肠直肠癌可以通过激素替代来预防。即时翻译的潜力是 通过口服GUCY 2C配体利那洛肽治疗慢性便秘的批准强调了这一点。