The Functional Role of LGR5 in Colon Cancer

LGR5 在结肠癌中的功能作用

• 批准号: 9311599
• 负责人: Jing Wang
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311599
• 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; 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; Stem cells; 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; effective therapy; improved; in vivo Model; inhibitor/antagonist; knock-down; mortality; mouse model; novel; prevent; promoter; receptor; restoration; 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.

抽象的 结直肠癌是美国癌症死亡率的第二大原因，部分原因是 缺乏有效的晚期疾病疗法。那迫切需要确定 参与癌症治疗的致癌转化和进展的分子/途径。 LGR5已被发现为小型成年干细胞标记物 肠。据报道，在结合R-Spondins之后，LGR5形成了物理复合物 Wnt受体曲折及其共受体LRP6，以扩大Wnt canonical信号传导。在 此外，与LGR5表达相比已显示在结肠癌中进行更新 正常组织。因此，已提出LGR5是肠中的肿瘤启动子， 冒号。但是，我们对患者样品的研究表明，尽管LGR5的表达是 I/II阶段腺癌高于正常隐窝（* p <0.05），其表达 与I/II期肿瘤相比，III/IV期肿瘤的减少（** P <0.01）。这些结果 表明LGR5的丧失与晚期阶段癌有关，该癌症反对A 促进角色，尤其是在后期。我们表明LGR5抑制了克隆生成，并且 结肠癌细胞的生存和LGR5表达的敲低增加了它们 在原位模型中的转移潜力。从机械上讲，LGR5激活TGFβ信号传导， 即使在没有TGFβRII的情况下，也会发生RII的存在进一步增强 LGR5激活。另外，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/转移中的抑制作用。 在此提案中，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在颜色中的功能作用 使用遗传小鼠模型的癌症发展/进展，研究是否恢复 LGR5表达的转移回归以及LGR5是否通过 在原位小鼠模型中激活TGFβ的信号和/或抑制Wnt信号传导 在患者标本中。这些研究的完成将确定RSPO/LGR5/RI是一种新颖 TGFβ替代体和结肠癌转移抑制剂，并大大提高了我们的 了解LGR5的分子机制，肠道干细胞标记物中的分子机制 抑制结肠癌的进展和转移。