Aquaporin 9 is involved in CRC metastasis through DVL2-dependent Wnt/β-catenin signaling activation  

作　　者：Yiting Liu Qianling Gao Xingzhi Feng Guanxing Chen Xuefei Jiang Daici Chen Zihuan Yang 

机构地区：[1]Guangdong Institute of Gastroenterology,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases,Guangzhou,Guangdong,P.R.China [2]Department of General Surgery(Colorectal Surgery),The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [3]Artificial Intelligence Medical Research Center,School of Intelligent Systems Engineering,Sun Yat-sen University,Shenzhen,Guangdong,P.R.China [4]Department of Clinical Laboratory,The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong,P.R.China

出　　处：《Gastroenterology Report》2023年第1期350-364,共15页胃肠病学报道（英文）

基　　金：supported by the National Natural Science Foundation of China[No.81702330 to Z.Y.];Guangdong Natural Science Foundation[No.2021A1515011400 to Z.Y.].

摘　　要：Background:Aquaporin 9(AQP9)is permeable to water or other small molecules,and plays an important role in various cancers.We previously found that AQP9 was related to the efficacy of chemotherapy in patients with colorectal cancer(CRC).This study aimed to identify the role and regulatory mechanism of AQP9 in CRC metastasis.Methods:The clinical significance of AQP9 was analysed by using bioinformatics and tissue microarray.Transcriptome sequencing,Dual-Luciferase Reporter Assay,Biacore,and co-immunoprecipitation were employed to demonstrate the regulatory mechanism of AQP9 in CRC.The relationship between AQP9 and CRC metastasis was verified in vitro and in vivo by using real-time cell analysis assay,high content screening,and liver metastasis models of nude mice.Results:We found that AQP9 was highly expressed in metastatic CRC.AQP9 overexpression reduced cell roundness and enhanced cell motility in CRC.We further showed that AQP9 interacted with Dishevelled 2(DVL2)via the C-terminal SVIM motif,resulting in DVL2 stabilization and the Wnt/b-catenin pathway activation.Additionally,we identified the E3 ligase neural precursor cell expressed developmentally downregulated 4-like(NEDD4L)as a modulator regulating the ubiquitination and degradation of AQP9.Conclusions:Collectively,our study revealed the important role of AQP9 in regulating DVL2 stabilization and Wnt/β-catenin signaling to promote CRC metastasis.Targeting the NEDD4L–AQP9–DVL2 axis might have therapeutic usefulness in metastatic CRC treatment.

关 键 词：aquaporin 9 colorectal cancer metastasis Dishevelled 2 Wnt/b-catenin signaling 

分 类 号：R73[医药卫生—肿瘤]