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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.

摘要结直肠癌是美国癌症死亡率的第二大原因，部分原因是对晚期疾病缺乏有效的治疗方法。因此，迫切需要查明参与致癌转化和进展的分子/途径用于癌症治疗。 LGR 5已被发现是小细胞中增殖的成体干细胞标志物。肠子据报道，在结合R-脊椎蛋白后，LGR 5形成物理复合物与Wnt受体Frizzled及其共受体LRP 6一起放大Wnt经典信号传导。在此外，与结肠癌相比，结肠癌中LGR 5表达上调。正常组织因此，已经提出LGR 5是肠中的肿瘤促进剂，结肠然而，我们对患者样本的研究表明，尽管LGR 5的表达是 I/II期腺癌中的表达高于正常腺泡（P < 0.05），与I/II期肿瘤相比，III/IV期肿瘤中的细胞数减少（** P < 0.01）。这些结果这表明LGR 5的缺失与晚期癌症有关，这与促进作用，特别是在后期阶段。我们发现LGR 5抑制克隆形成，在结肠癌细胞中存活和LGR 5表达的敲低增加了它们的在原位模型中的转移潜力。在机制上，LGR 5激活TGFβ信号传导，即使在没有TGFβ RII的情况下也会发生，RII的存在进一步增强了激活LGR 5。此外，LGR 5以Smad 4依赖性方式抑制Wnt信号传导。我们的结果指出LGR 5在结肠癌进展/转移中的抑制作用。在这个提议中，我们将确定LGR 5激活TGFβ的机制信号传导并抑制Wnt活化。我们还将确定LGR 5在结肠中的功能作用。使用遗传小鼠模型研究癌症发展/进展， LGR 5表达的增加可促进转移消退，以及LGR 5是否通过肿瘤细胞的增殖发挥作用。在原位小鼠模型中激活TGFβ 1信号传导和/或抑制Wnt信号传导，在病人标本中。这些研究的完成将确定RSPO/LGR 5/RI作为一种新的 TGFβ转导体和结肠癌转移抑制因子，并大大提高了我们的研究水平。了解肠道干细胞标志物LGR 5的分子机制，抑制结肠癌进展和转移。