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.

项目摘要/摘要 APC（〜85％）或β-catenin（约5％）的突变> 90％的零星结直肠癌。这些突变 产生β-catenin的积累和核转运，激活TCF，驱动转录程序 潜在的肿瘤发生。 gucy2c是在 大肠。在健康状态下，鸟苷蛋白 - gucy2c信号传导调节组织的稳态过程 加密表面轴部分通过阻断β-catenin积累的未知机制。的 意义上，鸟根是结直肠癌中最常见的mRNA转录本。激素损失，这 沉默gucy2c，通过未知机制的最早转化阶段发生 在老鼠和人类中。初步研究表明，鸟根损失是由突变体APC-β-Catenin-TCF介导的 信号。此外，转基因鸟苷表达消除了致癌物诱导的肿瘤形成 老鼠。基于这些观察结果，我们提出了突变的APC-β-β-catenin-TCF信号转录 沉默鸟苷作为肿瘤发生的强制性步骤，因为鸟嘌呤 - gucy2c信号传导阻断β-catenin 转换所需的积累。相关化学预防假设表明鸟苷蛋白 替换应通过APC-β-catenin信号传导消除肿瘤发生驱动。在这里，病理生理学 AIM将确定突变体APC-β-Catenin-TCF介导鸟苷损失的转录机制。这些 研究将建立突变体APC-β-catenin-TCF信号传导之间的新分子联系 抑制和gucy2c沉默，是对肿瘤发生的必要性。机械目标测试 假设鸟苷丢失，因为GuCy2c阻断了肿瘤发生所需的β-catenin积累。 这些研究将表明，鸟苷蛋白 - gucy2c轴通过阻塞限制β-catenin的积累 蛋白质翻译（合成）和诱导的蛋白体降解。预防目标测试 结直肠癌反映了鸟苷表达和Gucy2c信号的抑制假设，这些抑制 可以通过替代激素来克服。这些研究将证明转基因鸟苷的能力 修复致癌β-catenin信号传导的表达，重构内源性Gucy2c激素表达， 并防止小鼠双重APC失活后的结核病。这些研究在一起将揭示 以前意外的涉及鸟根损失和GUCY2C的结直肠癌开始所需的步骤 沉默。他们将从不可逆的疾病中转移结直肠癌的病理生理范例 可逆的马酮不足之一的基因突变。从机械上讲，他们将确定一个独特的 致癌级联的顶点的脆弱性，其中β-catenin依赖性事件需要 肿瘤发生可以通过GUCY2C信号传导来克服。而且，他们将建立原则的证明 该大肠癌可以通过本人替代来预防。立即翻译的潜力是 由口服GuCy2C配体Linaclotide的批准强调以治疗慢性便秘。