The Functional Role of GRM3 in Colon Cancer

GRM3 在结肠癌中的功能作用

• 批准号: 9290224
• 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: 2017-03-14 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9290224
• 关键词: Adverse effects; Anchorage-Independent Growth; Biological; Blood - brain barrier anatomy; Cancer Etiology; Cell Survival; Cells; Cessation of life; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Cyclic AMP-Dependent Protein Kinases; DNA Sequence Alteration; Data; Development; Essential Amino Acids; Event; Genetic; Glioma; Glutamate Receptor; Glutamates; Growth; Heterogeneity; In Vitro; Knock-out; Legal patent; Maintenance; Malignant Neoplasms; Mediating; Melanoma Cell; Metabotropic Glutamate Receptors; Molecular; Molecular Target; Mutant Strains Mice; Mutate; Neoplasm Metastasis; Neuraxis; Neurologic; Neurotransmitters; Organ; Outcome; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Play; Proto-Oncogene Proteins c-akt; Reporting; Role; Sampling; Signal Transduction; Specimen; Survival Rate; System; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Tumor Suppressor Proteins; Tumor stage; Tumorigenicity; Ubiquitination; United States; Up-Regulation; Xenograft Model; advanced disease; base; cancer cell; cancer therapy; clinically relevant; clinically significant; colon cancer patients; colon tumorigenesis; effective therapy; glutamatergic signaling; improved; in vivo; in vivo Model; knock-down; melanoma; migration; mortality; mouse model; mutant; neuropsychiatric disorder; novel; small hairpin RNA; therapeutic target; tumor; tumor growth; tumorigenic; vector

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 colon cancer development and metastasis for cancer treatment. Glutamate is an essential amino acid that plays important roles in signaling as a major neurotransmitter in mammalian central nervous system (CNS). Glutamate signaling is mediated by glutamate receptors. GRM3 is one of the group II metabotropic glutamate receptors. The glutamatergic system is mainly restricted to the CNS. However, it has been recently shown that GRM3 is frequently mutated in melanoma and that mutant GRM3 increased anchorage- independent growth and migration of melanoma cells. In addition, activation of GRM3 has been reported to sustain tumorigenic potential of glioma-initiating cells. Pharmacological blockade of GRM3 reduced growth of glioma cells in vitro and in vivo. These studies suggest that GRM3 may play a role in cancer. Our preliminary data showed that expression of GRM3 is significantly elevated in more than 90% of colon cancer specimens examined. Knockdown of GRM3 in colon cancer cells suppresses cell survival and anchorage-independent growth in vitro and inhibits tumor growth in a xenograft model in vivo. Mechanistically GRM3 inactivates protein kinase A (PKA) and activates AKT. In addition, TGFβ increases GRM3 expression and that knockdown of GRM3 enhances TGFβ-mediated tumor suppressor function. These studies suggest that upregulation of GRM3 expression is a functionally important molecular event during colon cancer development and progression. Therefore, GRM3 may play an important role in colon cancer tumorigenesis and metastasis and could be a potential target for colon cancer treatment. In this proposal, we will investigate the mechanisms by which TGFβ regulates GRM3 expression and whether their crosstalk plays a role in colon cancer metastasis. We will also determine GRM3 function in colon cancer using genetic mouse models and whether GRM3 contributes to development and/or maintenance of colon cancer metastasis using an orthotopic mouse model. Furthermore, we will demonstrate the clinical relevance and significance of elevated GRM3 in colon cancer patient samples. The completion of these studies will identify TGFβ/GRM3/PKA as a novel signaling axis regulating colon cancer development and progression and establish GRM3 as a potential therapeutic target for colon cancer treatment.

结直肠癌是美国癌症死亡的第二大原因，部分原因是 由于缺乏针对晚期疾病的有效疗法，因此迫切需要确定。 参与结肠癌发展和癌症治疗转移的分子/途径。 谷氨酸是一种必需氨基酸，作为主要氨基酸在信号传导中发挥着重要作用。 哺乳动物中枢神经系统 (CNS) 中的神经递质是介导的。 GRM3 是 II 类代谢型谷氨酸受体之一。 谷氨酸能系统主要局限于中枢神经系统，但最近的研究表明， GRM3 在黑色素瘤中经常发生突变，并且突变的 GRM3 增加了锚定- 此外，GRM3 的激活也已被证实。 据报道可维持神经胶质瘤起始细胞的药理学封锁。 GRM3 在体外和体内均能抑制神经胶质瘤细胞的生长。 我们的初步数据显示GRM3的表达可能在癌症中发挥作用。 超过 90% 的结肠癌标本中 GRM3 表达水平升高。 癌细胞在体外抑制细胞存活和不依赖贴壁的生长，并抑制 体内异种移植模型中的肿瘤生长通过机制使蛋白激酶 A 失活。 (PKA) 并激活 AKT 此外，TGFβ 会增加 GRM3 的表达并导致敲低。 GRM3 增强 TGFβ 介导的肿瘤抑制功能。 GRM3 表达上调是结肠过程中功能上重要的分子事件 因此，GRM3可能在结肠癌的发生和进展中发挥重要作用。 癌症肿瘤发生和转移，可能是结肠癌治疗的潜在靶点。 在本提案中，我们将研究 TGFβ 调节 GRM3 的机制 我们还将研究它们的表达以及它们的串扰是否在结肠癌转移中发挥作用。 使用遗传小鼠模型确定 GRM3 在结肠癌中的功能以及 GRM3 是否 使用原位有助于结肠癌转移的发展和/或维持 小鼠模型。此外，我们将证明其临床相关性和意义 这些研究的完成将确定结肠癌患者样本中 GRM3 的升高。 TGFβ/GRM3/PKA 作为调节结肠癌发展的新型信号轴 建立GRM3作为结肠癌治疗的潜在治疗进展靶点。