PGE2调控转录因子Gli1活性对大肠癌细胞增殖的影响及其作用机制研究

cyclooxygenase-2(COX2) promotes the initiation and progression of colon cancers mainly via its metabolite proglandin E2 (PGE2). Given that the potential risk of cardiovascular side effects of selective COX2 inhibitors, a better understanding how PGE2 promotes the initiation and progression of colon cancers will identify novel and safer therapeutic targets downstream of COX2. Many studies have shown the essential role of transcriptional factor Gli in the progression of colon cancer. This proposal is aimed to investigate whether PGE2 can promote the grwoth of colon cancer cells via stimulating the activity of transcriptional factor Gli1 and its underlying mechanisms, including a) whether PGE2 can promote the growth of colon cancer cells via enhancing the transcriptional activity of transcriptional factor Gli1;b) the possibility of JNK involved in the promotion of transcriptional activity of Gli1 by PGE2. These studies will provide bench foundations for prevention and treatment of colon cancers by targeting PGE2-JNK-Gli signaling pathway.

环氧酶2(COX2)促进大肠癌发生和发展主要是通过其代谢产物前列腺素E2(PGE2)实现。选择性COX2抑制剂具有一定的、潜在的心血管副作用，而靶向COX2下游PGE2信号通路或可避免这种副作用,因此是更为理想的预防和治疗大肠癌策略，也是当前COX2研究领域中的热点及趋势之一。所以，阐明PGE2促进大肠癌发生和发展的机理，将为靶向COX2下游的PGE2信号通路，预防和治疗大肠癌的策略奠定理论基础。研究发现转录因子Gli活性在大肠癌生长增殖中起着非常重要的作用。本项目拟探讨PGE2能否通过JNK刺激Gli1转录活性，从而促进大肠癌细胞增殖。

环氧酶2(COX2)促进大肠癌发生和发展主要是通过其代谢产物前列腺素E2(PGE2)实现。选择性COX2抑制剂具有一定的、潜在的心血管副作用，而靶向COX2下游PGE2信号通路或可避免这种副作用,因此是更为理想的预防和治疗大肠癌策略，也是当前COX2研究领域中的热点及趋势之一。本项目从分子、细胞所水平，发现PGE2能促进大肠癌细胞转录因子Gli2的转录活性，从而促进大肠癌细胞的增殖。进一步研究发现，PGE2促进大肠癌细胞的增殖依赖于JNK激酶的激活。实验发现阻断JNK激酶的功能能抑制PGE2调控的大肠癌细胞的GLI2转录活性及增殖。因此，本项目的研究成果将为从靶向PGE2下游的JNK激酶预防、治疗COX2、PGE2相关的大肠癌提供理论依据。