The Functional Role of LGR5 in Colon Cancer
LGR5 在结肠癌中的功能作用
基本信息
- 批准号:9764643
- 负责人:
- 金额:$ 35.69万
- 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:2017-04-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AdenocarcinomaAreaBindingBinding SitesBiologicalCancer EtiologyCellsColonColon CarcinomaColorectal CancerComplexDataDevelopmentDiseaseEventFutureGene TargetingGeneticGrowthHumanIntestinesKnowledgeLGR5 geneLigandsMADHIP geneMAPK8 geneMEKsMalignant NeoplasmsMediatingModelingMolecularNeoplasm MetastasisNormal tissue morphologyOncogenicPathologicPathway interactionsPatientsPharmacologyPlayProliferatingRegulationReportingRoleSamplingSignal TransductionSmall IntestinesSpecimenSurvival RateTestingTherapeuticTransforming Growth Factor betaTumor PromotersTumor Suppressor ProteinsWNT Signaling PathwayWorkadult stem celladvanced diseasebasecancer cellcancer therapycell motilityclinically relevantclinically significantcolon cancer metastasiscolon cancer progressioncolon cancer treatmenteffective therapyimprovedin vivo Modelinhibitor/antagonistknock-downmortalitymouse modelnovelpreventpromoterreceptorrestorationstem cellstumortumor progressiontumorigenesis
项目摘要
Abstract
Colorectal cancer is the second leading cause of cancer mortality in the US, in part due
to the lack of effective therapies for advanced disease. Thus, there is an urgent need to identify
molecules/pathways involved in oncogenic transformation and progression for cancer treatment.
LGR5 has been discovered as a proliferating adult stem cell marker in the small
intestine. It has been reported that, after binding R-spondins, LGR5 forms a physical complex
with the Wnt receptor Frizzled and its co-receptor LRP6 to amplify Wnt canonical signaling. In
addition, LGR5 expression has been shown to be upregulated in colon cancer as compared to
normal tissues. Therefore, LGR5 has been proposed to be a tumor promoter in the intestine and
colon. However, our studies of patient samples indicate that although expression of LGR5 is
higher in stage I/II adenocarcinomas than in normal crypts (* P < 0.05), its expression
decreases in stage III/IV tumors as compared to stage I/II tumors (** P < 0.01). These results
suggest that loss of LGR5 is associated with advanced stage cancer, which argues against a
promoting role, especially at later stages. We showed that LGR5 inhibits clonogenecity and
survival in colon cancer cells and that knockdown of LGR5 expression increases their
metastatic potential in an orthotopic model. Mechanistically, LGR5 activates TGFβ signaling,
which occurs even in the absence of TGFβ RII, and the presence of RII further enhances the
activation by LGR5. In addition, LGR5 inhibits Wnt signaling in a Smad4-dependent manner.
Our results point to a suppressive role of LGR5 in colon cancer progression/metastasis.
In this proposal, we will determine the mechanism(s) by which LGR5 activates TGFβ
signaling and inhibits Wnt activation. We will also determine the functional role of LGR5 in colon
cancer development/progression using genetic mouse models, investigate whether restoration
of LGR5 expression elicits metastasis regression and whether LGR5 functions through the
activation of TGFβsignaling and/or inhibition of Wnt signaling in an orthotopic mouse model and
in patient specimens. The completion of these studies will identify RSPO/LGR5 /RI as a novel
TGFβ transduceome and a colon cancer metastasis suppressor and substantially advance our
understanding of the molecular mechanisms of LGR5, an intestinal stem cell marker, in
suppressing colon cancer progression and metastasis.
摘要
项目成果
期刊论文数量(0)
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专利数量(0)
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Jing Wang其他文献
Electrochemical performance of high-capacity nanostructured Li[Li0.2Mn0.54Ni0.13Co0.13]O2 cathode material for lithium ion battery by hydrothermal method
水热法制备锂离子电池高容量纳米结构Li[Li0.2Mn0.54Ni0.13Co0.13]O2正极材料的电化学性能
- DOI:
10.1016/j.electacta.2013.05.118 - 发表时间:
2013-09 - 期刊:
- 影响因子:6.6
- 作者:
Xin Wei;Shichao Zhang;Zhijia Du;Puheng Yang;Jing Wang;Yanbiao Ren - 通讯作者:
Yanbiao Ren
Jing Wang的其他文献
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