The Functional Role of GRM3 in Colon Cancer

在美国，结直肠癌是癌症死亡的第二大原因，部分原因是 对于晚期疾病缺乏有效的治疗方法。因此，迫切需要确定 分子/途径参与结肠癌的发展和转移的癌症治疗。 谷氨酸是一种必需的氨基酸，在信号转导中起着重要的作用 哺乳动物中枢神经系统中的神经递质。谷氨酸信号转导 通过谷氨酸受体。GRM3是第二类代谢性谷氨酸受体之一。这个 谷氨酸能系统主要局限于中枢神经系统。然而，最近的研究表明， GRM3在黑色素瘤中经常发生突变，突变的GRM3增加了锚定- 黑色素瘤细胞的独立生长和迁移。此外，GRM3的激活已经被 据报道，可维持胶质瘤启动细胞的致瘤潜能。药理阻滞剂 GRM3在体内外均能抑制胶质瘤细胞的生长。这些研究表明，GRM3 可能在癌症中起作用。我们的初步数据显示，GRM3的表达显著 在接受检查的结肠癌标本中，超过90%的标本呈升高状态。GRM3基因在结肠中的敲除 癌细胞在体外抑制细胞存活和锚定非依赖性生长 肿瘤在体内异种移植模型中的生长。GRM3对蛋白激酶A的机械失活作用 (PKA)并激活AKT。此外，转化生长因子β增加GRM3GRM3表达和下调 GRM3可增强转化生长因子β介导的肿瘤抑制功能。这些研究表明 GRM3表达上调是结肠发育过程中一个重要的功能分子事件 癌症的发展和进展。因此，GRM3可能在结肠中起重要作用。 肿瘤的发生和转移，可能成为结肠癌治疗的潜在靶点。 在这个方案中，我们将研究转化生长因子β调节GRM3的机制。 以及它们的串扰是否在结肠癌转移中起作用。我们还将 用小鼠遗传模型确定GRM3在结肠癌中的功能以及GRM3是否 使用原位移植促进结肠癌转移的发展和/或维持 老鼠模型。此外，我们还将展示其临床相关性和意义。 结肠癌患者标本中GRM3升高。这些研究的完成将确定 转化生长因子β/GRM3/PKA作为新的信号轴调控结肠癌的发生和发展 研究进展并建立GRM3作为结肠癌治疗的潜在靶点。

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.