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The Functional Role of GRM3 in Colon Cancer

GRM3 在结肠癌中的功能作用

基本信息

批准号：
10335190
负责人：
Jing Wang
金额：
$ 34.97万
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：
2017-03-14 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335190
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

项目摘要

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