(PQ1) GUCY2C hormone loss translates APC-Beta-catenin mutations into epithelial transformation

(PQ1)GUCY2C激素损失将APC-β-连环蛋白突变转化为上皮转化

基本信息

批准号：
9101320
负责人：
SCOTT A WALDMAN
金额：
$ 35.69万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-09 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9101320
关键词：
Address Adenomatous Polyposis Coli Alleles Automobile Driving Azoxymethane Binding Cancer Etiology Carcinogens Cell Nucleus Cells Cessation of life Chemoprevention Chromosomal Stability Chronic Colorectal Colorectal Cancer Colorectal Neoplasms Constipation Creativeness Data Development Disease Epithelial Epithelial Cells Epithelium Event Feedback Functional disorder Future Genetic Genetic Transcription Hereditary Disease Homeostasis Hormone replacement therapy Hormones Induced Mutation Intestines Knowledge Ligands Link Malignant Neoplasms Mediating Metabolic Molecular Mus Mutation Nuclear Oral Outcome Patients Premalignant Property Rectum Regulation Role Signal Transduction Supplementation Testing Transgenic Organisms Translating Translations adenoma base beta catenin cancer chemoprevention colorectal cancer prevention design guanylin hormone deficiency innovation insight mouse model mutant mutant mouse model novel originality paracrine peptide hormone prevent programs public health relevance receptor reconstitution tumor tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer is the 4th most common cancer and 2nd leading cause of cancer death. In >90% of sporadic cases, colorectal cancer initiates as mutations in APC (~85%) or its downstream degradation target, β-catenin (~5%). These mutations result in accumulation of β-catenin which translocates to the nucleus and regulates transcription driving epithelial dysfunction and formation of the premalignant field (adenomas). While a role for APC and β-catenin mutations in transformation is established, gaps in knowledge reflect an incomplete understanding of the pathophysiological events linking these mutations to formation of the premalignant field, the mechanisms mediating those events, and their reversibility as a basis for cancer chemoprevention. In that context, guanylin is a paracrine peptide hormone produced by epithelial cells in the colo-rectum. Guanylin binds to GUCY2C, a receptor which maintains epithelial homeostasis by regulating proliferation, chromosomal stability, and metabolic programming, in part, by preventing β-catenin accumulation. Recently, we revealed that guanylin loss silencing GUCY2C occurs in all colorectal tumors. Further, guanylin is lost in all adenomas, and in premalignant epithelia that precede adenoma formation. Unexpectedly, transgenic expression of guanylin (cannot be lost) in mice eliminated transformation induced by the carcinogen azoxymethane (AOM) which produces β-catenin mutations. Based on these observations, we propose testing the novel hypothesis that that there is a reciprocal feedback loop in which nuclear signaling by mutant APC-β-catenin induces guanylin loss required for transformation because guanylin-GUCY2C blocks β-catenin accumulation necessary for tumorigenesis. Here, the Pathophysiological Aim will test the hypothesis that guanylin loss silencing GUCY2C is required to form the premalignant field produced by mutant APC-β-catenin. These studies will demonstrate that eliminating guanylin in intestinal cells recapitulates the pathophysiology of transformation (guanylin loss mediates the disease). The Mechanistic Aim will test the hypothesis that mutant APC-β-catenin suppresses guanylin transcription because guanylin-GUCY2C blocks β-catenin accumulation required for transformation (this molecular mechanism mediates guanylin loss). These studies will shift the paradigm in colorectal cancer from a genetic disease of irreversible APC-β-catenin mutations to a disease of reversible guanylin insufficiency. The Chemoprevention Aim will test the hypothesis that transgenic guanylin replacement blocks β-catenin accumulation, epithelial dysfunction, and transformation induced by APC-β-catenin mutations (blocking guanylin loss prevents the disease). These studies will establish the chemoprevention paradigm that guanylin replacement eliminates intestinal transformation. In turn, these novel mechanistic insights will provide new opportunities for colorectal cancer prevention, including oral GUCY2C ligand supplementation. The potential for immediate translation is underscored by the approval of the oral GUCY2C ligand, linaclotide, to treat chronic constipation.

描述（由适用提供）：大肠癌是第四大癌症，是癌症死亡的第二大原因。在> 90％的零星病例中，大肠癌在APC（〜85％）或其下游降解靶标β-catenin（〜5％）中引发。这些突变导致β-catenin的积累，从而易位到细胞核，并调节驱动上皮功能障碍的转录和前态场（腺瘤）的形成。尽管建立了APC和β-catenin突变在转化中的作用，但知识中的差距反映了对将这些突变联系起来形成前态度领域的病理生理事件的不完整理解，介导这些事件的机制以及它们作为癌症化学预防的基础的可逆性。在这种情况下，鸟苷是旁分泌由上皮细胞中的上皮细胞产生的肽赛。鸟根与GuCy2c结合，GuCy2c是一种接收器，通过调节增殖，染色体稳定性和代谢编程来维持上皮稳态，部分地是通过预防β-catenin的积累。最近，我们透露，鸟苷损失沉默的GuCy2c发生在所有结直肠肿瘤中。此外，在所有腺瘤中均丢失了鸟苷，并且在腺瘤形成之前的上皮症中丧失。出乎意料的是，在产生β-catenin突变的癌变甲氧甲烷（AOM）引起的小鼠中，鸟苷蛋白（不能丢失）的转化表达。基于这些观察结果，我们提出了一个新的假设，即存在一个相互反馈回路，其中突变体APC-β-catenin核信号传导诱导转化所需的鸟根损失，因为鸟苷蛋白 - gucy2c阻断了肿瘤发生所需的β-catenin积累。在这里，病理生理目标将检验以下假设：鸟根丧失沉默GuCy2c需要形成突变体APC-β-catenin产生的预立场。这些研究将表明，消除肠细胞中的鸟苷蛋白概括了转化的病理生理（鸟苷损失介导了疾病）。机械目的将检验以下假设：突变体APC-β-catenin抑制鸟苷蛋白转录，因为鸟苷蛋白 - gucy2c阻断了转化所需的β-catenin累积（该分子机制介导鸟根损失）。这些研究将把大肠癌的范式从不可逆的APC-β-catenin突变的遗传疾病转移到可逆鸟苷蛋白不足的疾病中。化学预防的目标将检验以下假设：转基因鸟苷替代剂会阻断β-catenin的积累，上皮功能障碍以及由APC-β-catenin突变引起的转化（阻断鸟苷损失可预防该疾病）。这些研究将建立化学预防范例，即鸟苷替代消除了肠道转化。反过来，这些新型的机械见解将为预防大肠癌的新机会，包括口服GuCy2C配体补充。口服GUCY2C配体Linaclotide的批准强调了立即翻译的潜力，以治疗慢性便秘。