The Functional Role of GRM3 in Colon Cancer

GRM3 在结肠癌中的功能作用

• 批准号: 10080029
• 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: 2017-03-14 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080029
• 关键词: 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; Drug Antagonism; Essential Amino Acids; Event; Excitatory Amino Acid Antagonists; 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; 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 metastasis; colon cancer patients; colon cancer treatment; colon tumorigenesis; effective therapy; glutamatergic signaling; improved; in vivo; in vivo Model; knock-down; melanoma; migration; mortality; mouse model; mutant; neuropsychiatric disorder; novel; side effect; 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 涉及结肠癌发展和转移的分子/途径进行癌症治疗。 谷氨酸是一种必需的氨基酸，在信号传导中起重要作用 哺乳动物中枢神经系统（CNS）中的神经递质。谷氨酸信号传导是介导的 由谷氨酸受体。 GRM3是II组代谢型谷氨酸受体之一。这 谷氨酸能系统主要局限于中枢神经系统。但是，最近已经证明 GRM3经常在黑色素瘤中突变，突变体GRM3增加了锚固 此外，GRM3的激活已经 据报道，可维持神经胶质瘤发射细胞的致瘤潜力。药理学封锁 GRM3在体外和体内降低了神经胶质瘤细胞的生长。这些研究表明GRM3 可能在癌症中发挥作用。我们的初步数据表明，GRM3的表达显着 在检查了90％以上的结肠癌标本中，已升高。结肠中的grm3敲低 癌细胞在体外抑制细胞的存活和锚定非依赖性生长，并抑制 体内肿瘤生长。机械上的GRM3使蛋白激酶A失活 （PKA）并激活Akt。此外，TGFβ增加了GRM3的表达和敲低 GRM3的GR可以增强TGFβ介导的肿瘤抑制功能。这些研究表明 GRM3表达的上调是在颜色期间功能上重要的分子事件 癌症发展和进展。因此，GRM3可能在颜色中起重要作用 癌症肿瘤发生和转移，可能是结肠癌治疗的潜在靶标。 在此提案中，我们将研究TGFβ调节GRM3的机制 表达以及它们的串扰是否在结肠癌转移中起作用。我们也会 使用遗传小鼠模型确定结肠癌中的GRM3功能以及GRM3是否是否 使用原动体有助于结肠癌转移的发展和/或维持 鼠标模型。此外，我们将证明 结肠癌患者样品中的GRM3升高。这些研究的完成将确定 TGFβ/GRM3/PKA作为调节结肠癌发展和 进展和建立GRM3是结肠癌治疗的潜在治疗靶点。