The Functional Role of GRM3 in Colon Cancer

GRM3 在结肠癌中的功能作用

• 批准号: 10240298
• 负责人: Liying Geng
• 金额: $ 13.6万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2022-06-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240298
• 关键词: AKT inhibition; Anchorage-Independent Growth; Award; Cancer Etiology; Cell Survival; Collaborations; Colon Adenocarcinoma; Colon Carcinoma; Colorectal Cancer; Cyclic AMP-Dependent Protein Kinases; Development; Drug resistance; Funding; Genetic; Human; In Vitro; Incidence; Lead; Mediating; Mentors; Metabotropic Glutamate Receptors; Neoplasm Metastasis; Neuraxis; Patient-Focused Outcomes; Postdoctoral Fellow; Recurrence; Research; Research Personnel; Role; Sampling; Signal Transduction; Testing; Time; Transforming Growth Factor beta; United States; Universities; Work; anticancer research; base; cancer cell; cancer diagnosis; clinically relevant; clinically significant; colon cancer cell line; colon cancer patients; colon cancer progression; colon cancer treatment; colon tumorigenesis; effective therapy; experience; improved; in vivo; knock-down; mortality; mouse model; novel; novel strategies; programs; protein activation; student training; therapeutic target; tumor growth

Project Summary/Abstract Colorectal cancer is the second leading cause of cancer mortality and the third most common cancer diagnosed in the United States, largely due to metastasis, recurrence and drug resistance. Therefore, there is an urgent need to identify new targets and develop novel target-specific therapies. Our previous study has shown for the first time that expression of GRM3, a metabotropic glutamate receptor mainly expressed in mammalian central nervous system, is significantly upregulated in the majority of human colonic adenocarcinomas tested and colon cancer cell lines. Knockdown of GRM3 expression in colon cancer cells reduces cell survival and anchorage- independent growth in vitro and inhibits tumor growth in vivo. Mechanistically, GRM3 antagonizes TGFβ- mediated activation of protein kinase A and inhibition of AKT. As a long-term researcher with 10 year experience and expertise in colon cancer research in Dr. Jing Wang lab, I will continue to work on this project to understand the mechanisms of TGFβ-mediated GRM3 expression, determine the functional role of GRM3 in colon cancer development, progression and metastasis in vivo using orthotopic and genetic mouse models and demonstrate clinical relevance and significance of elevated GRM3 expression and TGFβ/GRM3 crosstalk in colon cancer patient samples. With this award support, 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. Additionally, I will also continue to contribute to collaborations with researchers inside and outside of university in NCI funded research programs and take responsibilities in mentoring and training students and postdocs this proposed project.

项目摘要/摘要 结直肠癌是导致癌症死亡的第二大原因，也是诊断出的第三大常见癌症。 在美国，主要是由于转移、复发和耐药性。因此，当务之急是 需要确定新的靶点并开发新的靶点特异性疗法。我们之前的研究表明， GRM3是一种主要在哺乳动物中枢表达的代谢性谷氨酸受体 神经系统，在大多数检测的人类结肠腺癌和结肠癌中显著上调 癌细胞系。GRM3在结肠癌细胞中的表达下调降低了细胞的存活和锚定。 体外独立生长，体内抑制肿瘤生长。GRM3在机制上拮抗转化生长因子β- 介导蛋白激酶A的激活和AKT的抑制。作为一名有10年经验的长期研究人员 和王静博士在结肠癌研究方面的专业知识，我会继续在这个项目上工作，以了解 转化生长因子β介导GRM3表达的机制及其在结肠癌中的作用 利用原位和遗传小鼠模型体内发育、进展和转移 结肠癌组织中GRM3表达升高与转化生长因子β/GRM3串扰的临床意义 病人样本。在这一奖项的支持下，这些研究的完成将确定转化生长因子β/GRM3/PKA是一种 调控结肠癌发生发展的新信号轴及其与GRM3的关系 结肠癌治疗的治疗靶点。此外，我还将继续为与 NCI的大学内外的研究人员资助研究项目并承担责任 指导和培训学生和博士后这一提议的项目。