YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling  

作　　者：Hua Sui Wanli Deng Qiong Chai Bing Han Yuli Zhang Zhenzhen Wei Zan Li Ting Wang Jiling Feng Man Yuan Qingfeng Tang Hongxi Xu 

机构地区：[1]Medical Experiment Center,Jiading Branch of Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,201803,China [2]Translational Medicine Research Center for Cancer Prevention and Treatment,Shanghai General Hospital Jiading Branch-School of Pharmacy of Shanghai University of Traditional Chinese Medicine Joint Laboratory,Shanghai,201803,China [3]Department of Medical Oncology,Putuo Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai,200062,China [4]School of Pharmacy,Shanghai University of Traditional Chinese Medicine,Shanghai,201203,China [5]The Second Clinical Medical College of Henan University of Traditional Chinese Medicine,Zhengzhou,450000,China [6]Shanghai University of Traditional Chinese Medicine,Shanghai,201203,China [7]Precision Research Center for Refractory Diseases,Institute for Clinical Research,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,201620,China

出　　处：《Journal of Pharmaceutical Analysis》2024年第4期525-541,共17页药物分析学报（英文版）

基　　金：supported by“Jiaotong University Star”Program,China(Grant No.:YG2022QN082);the National Natural Science Foundation of China(Grant No.:82204887);the Science Foundation for Shanghai Committee of Science Project,China(Grant Nos.:21S21901400,23S21901200);the Natural Science Research Foundation of Jiading District,China(Grant No.:JDKW-2021-0023).

摘　　要：The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer.Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis(YTE-17),attributing these effects to the regu-lation of multiple signaling pathways.However,knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited.In this study,we conducted isobaric tags for relative and absolute quantification(iTRAQ)analysis on intestinal epithelial cells(IECs)exposed YTE-17,both in vitro and in vivo,revealing a significant inhibition of the Wnt family member 5a(Wnt5a)/c-Jun N-terminal kinase(JNK)signaling pathway.Subsequently,we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment(TME),specifically focusing on macrophage-mediated T helper 17(Th17)cell induction in a colitis-associated cancer(CAC)model with Wnt5a deletion.Additionally,we performed the single-cell RNA sequencing(scRNA-seq)on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition,lineage,and functional status of immune mesenchymal cells during different stages of colorectal cancer(CRC)progression.Remarkably,our findings demon-strate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17,leading to the restoration of regulatory T(Treg)/Th17 cell balance in azoxymethane(AOM)/dextran sodium sulfate(DSS)model.Furthermore,we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages.Notably,our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical b-catenin oncogenic pathway in vivo.Specifically,we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with b-catenin activity within the TME,involving macrophages and T cells.In su

关 键 词：Tumor microenvironment Intestinal epithelial cells Treg/Th17 cells Metabolism Wnt5a/JNK signaling TUMORIGENESIS 

分 类 号：R917[医药卫生—药物分析学]