The Functional Role of GRM3 in Colon Cancer

结直肠癌是美国癌症死亡率的第二大原因，部分原因是 对晚期疾病缺乏有效的治疗方法。因此，迫切需要查明 用于癌症治疗的分子/途径，所述分子/途径涉及结肠癌发展和转移。 谷氨酸是一种重要的氨基酸，在信号传导中起着重要作用， 哺乳动物中枢神经系统（CNS）中的神经递质。谷氨酸信号是由 由谷氨酸受体。GRM 3是II组代谢型谷氨酸受体之一。的 神经系统主要局限于中枢神经系统。然而，最近的研究表明， GRM 3在黑色素瘤中经常发生突变，突变的GRM 3增加了锚定- 黑色素瘤细胞的独立生长和迁移。此外，GRM 3的激活已经被证实是一种新的生物学机制。 据报道维持神经胶质瘤起始细胞的致瘤潜力。药理学阻断 GRM 3在体外和体内减少胶质瘤细胞的生长。这些研究表明，GRM 3 可能在癌症中发挥作用。我们的初步数据显示，GRM 3的表达显著增加。 在90%以上的结肠癌样本中检测到的升高。结肠中GRM 3的敲除 癌细胞在体外抑制细胞存活和非贴壁依赖性生长， 体内异种移植模型中的肿瘤生长。GRM 3使蛋白激酶A失活的机制 (PKA)激活AKT此外，TGFβ增加GRM 3的表达， GRM 3增强TGFβ介导的肿瘤抑制功能。这些研究表明 GRM 3表达的上调是结肠癌发生过程中功能上重要的分子事件， 癌症的发展和进展。因此，GRM 3可能在结肠癌的发生发展中起重要作用。 肿瘤的发生和转移，并可能成为结肠癌治疗的潜在靶点。 在本研究中，我们将研究TGFβ调节GRM 3的机制， 表达以及它们的串扰是否在结肠癌转移中起作用。我们还将 使用遗传小鼠模型确定GRM 3在结肠癌中的功能， 有助于结肠癌转移的发展和/或维持 小鼠模型此外，我们将证明临床相关性和意义， 结肠癌患者样品中GRM 3升高。这些研究的完成将确定 TGFβ/GRM 3/PKA作为调控结肠癌发展的新信号轴 进展，并确立GRM 3作为结肠癌治疗的潜在治疗靶点。

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.