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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.

抽象的结直肠癌是美国癌症死亡的第二大原因，部分原因是缺乏针对晚期疾病的有效疗法。因此，迫切需要识别参与癌症治疗的致癌转化和进展的分子/途径。 LGR5 已被发现作为小细胞中增殖的成体干细胞标记物。肠。据报道，LGR5与R-spondins结合后形成物理复合物与 Wnt 受体 Frizzled 及其辅助受体 LRP6 一起放大 Wnt 经典信号传导。在此外，与癌症相比，LGR5 表达在结肠癌中上调。正常组织。因此，LGR5被认为是肠道中的肿瘤促进剂，并且冒号。然而，我们对患者样本的研究表明，尽管 LGR5 的表达 I/II 期腺癌中的表达量高于正常隐窝中的表达量 (* P < 0.05) 与 I/II 期肿瘤相比，III/IV 期肿瘤减少 (** P < 0.01)。这些结果表明 LGR5 的缺失与晚期癌症有关，这反对促进作用，特别是在后期。我们发现 LGR5 抑制克隆发生结肠癌细胞的存活率以及 LGR5 表达的敲低会增加其存活率原位模型中的转移潜力。从机制上讲，LGR5 激活 TGFβ 信号传导，即使在没有 TGFβ RII 的情况下也会发生这种情况，并且 RII 的存在进一步增强了 LGR5 激活。此外，LGR5 以 Smad4 依赖性方式抑制 Wnt 信号传导。我们的结果表明 LGR5 在结肠癌进展/转移中具有抑制作用。在本提案中，我们将确定 LGR5 激活 TGFβ 的机制信号传导并抑制 Wnt 激活。我们还将确定 LGR5 在结肠中的功能作用使用遗传小鼠模型研究癌症的发展/进展，研究是否可以恢复 LGR5 表达的变化引起转移消退以及 LGR5 是否通过在原位小鼠模型中激活 TGFβ 信号传导和/或抑制 Wnt 信号传导，以及在患者标本中。这些研究的完成将确定 RSPO/LGR5/RI 是一种新颖的 TGFβ 转导组和结肠癌转移抑制剂，大大推进了我们的研究了解肠道干细胞标记物 LGR5 的分子机制抑制结肠癌的进展和转移。