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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：
Jing Wang
金额：
$ 35.69万
依托单位：
OHIO STATE UNIVERSITY
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：
https://reporter.nih.gov/project-details/9764643
关键词：
Adenocarcinoma Area Binding Binding Sites Biological Cancer Etiology Cells Colon Colon Carcinoma Colorectal Cancer Complex Data Development Disease Event Future Gene Targeting Genetic Growth Human Intestines Knowledge LGR5 gene Ligands MADHIP gene MAPK8 gene MEKs Malignant Neoplasms Mediating Modeling Molecular Neoplasm Metastasis Normal tissue morphology Oncogenic Pathologic Pathway interactions Patients Pharmacology Play Proliferating Regulation Reporting Role Sampling Signal Transduction Small Intestines Specimen Survival Rate Testing Therapeutic Transforming Growth Factor beta Tumor Promoters Tumor Suppressor Proteins WNT Signaling Pathway Work adult stem cell advanced disease base cancer cell cancer therapy cell motility clinically relevant clinically significant colon cancer metastasis colon cancer progression colon cancer treatment effective therapy improved in vivo Model inhibitor/antagonist knock-down mortality mouse model novel prevent promoter receptor restoration stem cells tumor tumor progression tumorigenesis

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 TGFβsignaling 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