FGFRL1/ENO1复合体调控AMPK/YAP通路促进结直肠癌发生发展的机制研究

CRC是一种严重威胁人类健康的疾病，揭示其发生发展机制并形成靶向治疗新策略至关重要。已知糖酵解酶ENO1促进CRC的发生发展；FGFRL1在多种肿瘤中表达升高，但其在CRC中的作用及机制尚不明确。我们前期研究发现：FGFRL1在CRC组织中表达升高并与ENO1呈正相关；FGFRL1在CRC细胞中与ENO1结合，调节ENO1的转录后水平，并能逆转FBXW7对ENO1的降解；FGFRL1和ENO1均能激活YAP，且FGFRL1通过YAP促进CRC细胞的增殖和转移。据此我们推测：FGFRL1/ENO1复合体抑制FBXW7与ENO1的结合，减少FBXW7对ENO1的降解，导致AMPK的失活及YAP的活化，促进CRC的发生发展。本课题拟从细胞、动物及组织等多方面，探讨FGFRL1在CRC发生发展中的作用及FGFRL1/ENO1复合体调控Hippo-YAP通路的具体机制，拟为CRC靶向治疗提供新思路。

Colorectal cancer (CRC) is a serious disease which threatens human health, so it is important to reveal the mechanism of its occurrence and establish new strategies for CRC targeted therapy. α-enolase (ENO1), as a key glycolytic enzyme, plays a tumor-promoting role in the development and progression of CRC. Fibroblast growth factor receptor-like 1 (FGFRL1) is highly expressed in multiple types of cancer, but its role and the underlying mechanism in CRC remain unclear. Our preliminary results showed that FGFRL1 expression was upregulated in human CRC tissues and was positively correlated with ENO1. FGFRL1 bound to ENO1 in CRC cells, regulated the post-transcriptional level of ENO1, and reversed the degradation of ENO1 by F-box and WD40 domain protein 7 (FBXW7). Both FGFRL1 and ENO1 can activate YAP, and FGFRL1 promotes the proliferation and migration of CRC cells via regulating YAP. Therefore, we speculated that the FGFRL1/ENO1 complex inhibits the binding of FBXW7 to ENO1, reduces the degradation of ENO1, leading to AMPK inactivation and YAP activation, which enhances CRC cell proliferation and migration. Our present study intends to explore the role of FGFRL1 in the development of CRC and to clarify the specific mechanism of FGFRL1/ENO1 complex regulation of the Hippo-YAP pathway from various aspects including cells, animal models and tissue specimens, so as to provide new ideas and theoretical basis for CRC targeted therapy.