(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：
9922880
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 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922880
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 Diseases Genetic Transcription Homeostasis Hormone replacement therapy Hormones Induced Mutation Intestines Knowledge Ligands Link Malignant Neoplasms Mediating Metabolic Molecular Mus Mutation Nuclear Oral Outcome Patients Property 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 premalignant 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（由申请人提供）：结直肠癌是第四大常见癌症，也是癌症死亡的第二大原因。在 >90% 的散发病例中，结直肠癌始于 APC (~85%) 或其下游降解靶点 β 的突变。 -连环蛋白（~5%）。这些突变导致 β-连环蛋白积累，易位至细胞核并调节转录，驱动上皮功能障碍和癌前区域的形成。虽然 APC 和 β-连环蛋白突变在转化中的作用已经确定，但知识上的空白反映了对这些突变与癌前区域形成的病理生理事件、介导这些事件的机制及其可逆性的不完全理解。癌症化学预防的基础在这种情况下，鸟苷酸是一种旁分泌。结肠直肠上皮细胞产生的肽激素与 GUCY2C 结合，GUCY2C 是一种通过调节增殖、染色体稳定性和代谢编程来维持上皮稳态的受体，部分是通过防止 β-连环蛋白积累。 GUCY2C 缺失沉默发生在所有结直肠肿瘤中。此外，鸟苷蛋白在所有腺瘤和癌前病变中均缺失。出乎意料的是，小鼠中鸟苷蛋白的转基因表达（不会丢失）消除了产生β-连环蛋白突变的致癌物质氧化偶氮甲烷（AOM）诱导的转化。是一个相互反馈循环，其中突变型 APC-β-连环蛋白的核信号传导诱导转化所需的鸟苷蛋白损失，因为鸟苷蛋白-GUCY2C 会阻止 β-连环蛋白积累在此，病理生理学目标将验证鸟苷蛋白缺失沉默 GUCY2C 是形成突变 APC-β-连环蛋白产生的癌前区域所必需的假设。这些研究将证明消除肠道细胞中的鸟苷蛋白可概括转化的病理生理学。鸟苷蛋白丢失介导了该疾病）。机制目标将检验突变型 APC-β-连环蛋白抑制鸟苷蛋白转录的假设，因为鸟苷蛋白-GUCY2C 阻断转化所需的 β-连环蛋白积累（这种分子机制介导鸟苷蛋白丢失）。 Aim 将检验转基因鸟苷蛋白替代阻断 β-连环蛋白积累、上皮功能障碍以及 APC-β-连环蛋白诱导的转化的假设这些研究将建立鸟苷蛋白替代消除预防肠道转化的化学预防范式，反过来，这些新的机制见解将为结直肠癌预防提供新的机会，包括立即补充口服GUCY2C配体的潜力。口服 GUCY2C 配体利那洛肽（linaclotide）获批用于治疗慢性便秘，强调了这一点。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phase I double-blind, placebo-controlled trial of dolcanatide (SP-333) 27 mg to explore colorectal bioactivity in healthy volunteers.

多卡那肽 (SP-333) 27 mg 的 I 期双盲、安慰剂对照试验，旨在探索健康志愿者的结直肠生物活性。

DOI：
发表时间：
2021-12-02
期刊：
影响因子：
3.6
作者：
Weinberg, David S;Foster, Nathan R;Della'Zanna, Gary;McMurray, Ryan P;Kraft, Walter K;Pallotto, Angela;Kastenberg, David M;Katz, Leo C;Henry, Christopher H;Moleski, Stephanie M;Limburg, Paul J;Waldman, Scott A
通讯作者：
Waldman, Scott A

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Catalytic receptors.

药理学简明指南 2021/22：催化受体。

DOI：
发表时间：
2021-10
期刊：
影响因子：
7.3
作者：
Alexander, Stephen Ph;Fabbro, Doriano;Kelly, Eamonn;Mathie, Alistair;Peters, John A;Veale, Emma L;Armstrong, Jane F;Faccenda, Elena;Harding, Simon D;Pawson, Adam J;Southan, Christopher;Davies, Jamie A;Beuve, Annie;Brouckaert, Peter;Bryant, C
通讯作者：
Bryant, C

Mechanisms of Action of Current Pharmacologic Options for the Treatment of Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation.

当前治疗慢性特发性便秘和便秘肠易激综合征的药物选择的作用机制。

DOI：
发表时间：
2022-04-01
期刊：
影响因子：
0
作者：
Sayuk, Gregory S;Waldman, Scott A;Brenner, Darren M
通讯作者：
Brenner, Darren M

Non-Thermal Plasma-Induced Immunogenic Cell Death in Cancer: A Topical Review.

癌症中非热等离子体诱导的免疫原性细胞死亡：专题综述。

DOI：
发表时间：
2019-10-22
期刊：
影响因子：
0
作者：
Khalili, Marian;Daniels, Lynsey;Lin, Abraham;Krebs, Fred C;Snook, Adam E;Bekeschus, Sander;Bowne, Wilbur B;Miller, Vandana
通讯作者：
Miller, Vandana

Real-World Treatment Strategies to Improve Outcomes in Patients With Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation.

改善慢性特发性便秘和便秘肠易激综合征患者预后的现实治疗策略。

DOI：
发表时间：
2022-04-01
期刊：
影响因子：
0
作者：
Brenner, Darren M;Harris, Lucinda A;Chang, Christopher H;Waldman, Scott A;Poppers, David M;Kassebaum;Sayuk, Gregory S
通讯作者：
Sayuk, Gregory S