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 TGF?- 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 TGF?-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 TGF?/GRM3 crosstalk in colon cancer patient samples. With this award support, the completion of these studies will identify TGF?/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.
/Relevance Colorectal cancer is a leading cause of cancer incidence and mortality largely due to the lack of effective therapies. Based on our novel findings that the miR-487b-3p/GRM3/TGF? signaling axis is an important regulator of colon cancer tumorigenesis, this proposed project will continue to determine the mechanisms of TGF?-mediated GRM3 expression, the functional role of GRM3 in colon cancer progression and metastasis, and the clinical relevance and significance of elevated GRM3 expression and TGF?/GRM3 crosstalk in colon cancer patient samples. This will potentially lead to the development of novel strategies to treat colon cancer efficiently and so improve patient outcome.
