Guanylin GUCY2C axis in Colorectal Cancer Initiation

鸟苷素 GUCY2C 轴在结直肠癌发生中的作用

基本信息

  • 批准号:
    9237630
  • 负责人:
  • 金额:
    $ 37.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
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项目成果

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SCOTT A WALDMAN其他文献

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{{ truncateString('SCOTT A WALDMAN', 18)}}的其他基金

Neuroprotection by the GUCY2C gut-brain axis in Parkinson's disease
GUCY2C 肠脑轴对帕金森病的神经保护作用
  • 批准号:
    10740951
  • 财政年份:
    2023
  • 资助金额:
    $ 37.2万
  • 项目类别:
(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
  • 批准号:
    9922880
  • 财政年份:
    2016
  • 资助金额:
    $ 37.2万
  • 项目类别:
(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
  • 批准号:
    9101320
  • 财政年份:
    2016
  • 资助金额:
    $ 37.2万
  • 项目类别:
GUCY2C hormone signaling at the intersection of obesity and colorectal cancer(PQ1
肥胖与结直肠癌交叉点上的 GUCY2C 激素信号传导(PQ1
  • 批准号:
    8680189
  • 财政年份:
    2012
  • 资助金额:
    $ 37.2万
  • 项目类别:
GUCY2C hormone signaling at the intersection of obesity and colorectal cancer(PQ1
肥胖与结直肠癌交叉点上的 GUCY2C 激素信号传导(PQ1
  • 批准号:
    8517056
  • 财政年份:
    2012
  • 资助金额:
    $ 37.2万
  • 项目类别:
GUCY2C hormone signaling at the intersection of obesity and colorectal cancer(PQ1
肥胖与结直肠癌交叉点上的 GUCY2C 激素信号传导(PQ1
  • 批准号:
    8895861
  • 财政年份:
    2012
  • 资助金额:
    $ 37.2万
  • 项目类别:
Occult lymph node metastases and racial disparities in colon cancer outcomes
结肠癌结果中的隐匿性淋巴结转移和种族差异
  • 批准号:
    7828432
  • 财政年份:
    2009
  • 资助金额:
    $ 37.2万
  • 项目类别:
Occult lymph node metastases and racial disparities in colon cancer outcomes
结肠癌结果中的隐匿性淋巴结转移和种族差异
  • 批准号:
    7941015
  • 财政年份:
    2009
  • 资助金额:
    $ 37.2万
  • 项目类别:
Guanylyl Cyclase C in Blood and Colorectal Cancer
血液和结直肠癌中的鸟苷酸环化酶 C
  • 批准号:
    6772420
  • 财政年份:
    2003
  • 资助金额:
    $ 37.2万
  • 项目类别:
Guanylyl Cyclase C in Blood and Colorectal Cancer
血液和结直肠癌中的鸟苷酸环化酶 C
  • 批准号:
    6685481
  • 财政年份:
    2003
  • 资助金额:
    $ 37.2万
  • 项目类别:

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  • 批准号:
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    25330237
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