YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signalingOA
YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling
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 β-catenin oncogenic pathway in vivo.Specifically,we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with β-catenin activity within the TME,involving macrophages and T cells.In summary,our study undergoes the po-tential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment,thereby mitigating the risk of malignancies.
Hua Sui;Man Yuan;Qingfeng Tang;Hongxi Xu;Wanli Deng;Qiong Chai;Bing Han;Yuli Zhang;Zhenzhen Wei;Zan Li;Ting Wang;Jiling Feng
Medical Experiment Center,Jiading Branch of Shanghai Ceneral Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,201803,China||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,ChinaSchool of Pharmacy,Shanghai University of Traditional Chinese Medicine,Shanghai,201203,ChinaMedical Experiment Center,Jiading Branch of Shanghai Ceneral Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,201803,ChinaTranslational 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||School of Pharmacy,Shanghai University of Traditional Chinese Medicine,Shanghai,201203,ChinaDepartment of Medical Oncology,Putuo Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai,200062,ChinaThe Second Clinical Medical College of Henan University of Traditional Chinese Medicine,Zhengzhou,450000,ChinaTranslational 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,ChinaShanghai University of Traditional Chinese Medicine,Shanghai,201203,ChinaPrecision Research Center for Refractory Diseases,Institute for Clinical Research,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,201620,China
Tumor microenvironmentIntestinal epithelial cellsTreg/Th17 cellsMetabolismWnt5a/JNK signalingTumorigenesis
《药物分析学报（英文）》 2024 (004)
525-541 / 17
This research was supported by"Jiaotong University Star"Pro-gram,China(Grant No.:YG2022QN082),the National Natural Sci-ence Foundation of China(Grant No.:82204887),the Science Foundation for Shanghai Committee of Science Project,China(Grant Nos.:21S21901400 and 23S21901200),and the Natural Science Research Foundation of Jiading District,China(Grant No.:JDKW-2021-0023).
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