The Functional Role of LGR5 in Colon Cancer

LGR5 在结肠癌中的功能作用

• 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
• 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

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 在美国，结直肠癌是癌症死亡的第二大原因，部分原因是 对于晚期疾病缺乏有效的治疗方法。因此，迫切需要确定 癌症治疗中涉及致癌转化和进展的分子/途径。 Lgr5已被发现是一种在小鼠中增殖的成体干细胞标志物 肠子。有报道称，LGR5在与R-Spinins结合后形成物理复合体 用Wnt受体FrizzledLRP6和它的辅助受体LRP6来扩增Wnt的典型信号。在……里面 此外，与结肠癌相比，LGR5在结肠癌中的表达上调 正常组织。因此，LGR5被认为是一种肠道肿瘤促进剂和 冒号。然而，我们对患者样本的研究表明，尽管LGR5的表达是 其在I/II期腺癌中的表达高于正常隐窝(P&lt；0.05)。 与I/II期肿瘤相比，III/IV期肿瘤减少(**P&lt；0.01)。这些结果 提示LGR5的缺失与晚期癌症有关，这反对 促进作用，特别是在后期阶段。我们发现LGR5抑制克隆形成和 结肠癌细胞存活和LGR5表达下调增加了它们的 原位模型中的转移潜能。从机制上讲，LGR5激活转化生长因子β信号， 即使在没有转化生长因子βRII的情况下也会发生这种情况，并且RII的存在进一步增强了 由LGR5激活。此外，LGR5以Smad4依赖的方式抑制Wnt信号转导。 我们的结果表明LGR5在结肠癌进展/转移中具有抑制作用。 在本方案中，我们将确定LGR5激活转化生长因子β的机制(S 信号转导并抑制Wnt激活。我们还将确定LGR5在结肠中的功能作用 利用小鼠遗传模型研究癌症的发生/发展 LGR5的表达诱导转移消退以及LGR5是否通过 原位小鼠模型中转化生长因子β信号的激活和/或Wnt信号的抑制 在病人的标本中。这些研究的完成将确定RSPO/LGR5/RI为一部小说 转化生长因子β转导体和结肠癌转移抑制因子 肠道干细胞标志物LGR5分子机制的研究进展 抑制结肠癌的进展和转移。