μ-opioid receptor agonist facilitates circulating tumor cell formation in bladder cancer via the MOR/AKT/Slug pathway: a comprehensive study including randomized controlled trial

Cancer Communications

article

Xiaoqiang Wang¹  Song Zhang¹  Di Jin²  Jiamei Luo¹  Yumiao Shi¹  Yiqi Zhang¹  Lingling Wu³  Yanling Song⁴  Diansan Su¹  Zhiying Pan¹  Haige Chen²  Ming Cao²  Chaoyong Yang³  Weifeng Yu¹  Jie Tian¹ 

[1] Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine;Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine;Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine;The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University

关键词: μ-opioid receptor agonist;    AKT;    bladder cancer;    circulating tumor cell;    epithelial-mesenchymal transition;    microfluidic chip;    MOR;    PI3K;    Slug;   

DOI  :  10.1002/cac2.12408

学科分类：社会科学、人文和艺术（综合）

来源: Springer

【 摘 要 】

Background μ-opioid receptor agonists (MORAs) are indispensable for analgesia in bladder cancer (BC) patients, both during surgery and for chronic pain treatment. Whether MORAs affect BC progression and metastasis remains largely unknown. This study focused on the effects of MORAs on the formation of circulating tumor cells (CTCs) in BC and aimed to provide potential therapeutic targets, which would retain the pain-relieving effects of MORAs in BC patients without sacrificing their long-term prognosis.Methods Different preclinical models were used to identify the effects of MORAs on the progression of BC. A novel immunocapture microfluidic chip was utilized to analyze whether MORAs affected the number of CTCs in mouse models and clinical BC patients. Bioinformatic analyses, total transcriptome sequencing, and molecular biology methods were then used to investigate the underlying mechanisms in these models and in BC cell lines.Results Mouse models of hematogenous metastasis and in situ BC demonstrated that tumor metastasis was significantly increased after MORA treatment. A significant increase in the number of mesenchymal and/or epithelial CTCs was detected after MORA treatment in both the mouse models and clinical trial patients. Mechanistically, MORAs facilitated the formation of CTCs by activating the MOR/PI3K/AKT/Slug signaling pathway, hereby promoting the epithelial-mesenchymal transition (EMT) of BC cells, as knockdown of MOR, Slug or blockade of PI3K inhibited the EMT process and CTC formation.Conclusion MORAs promoted BC metastasis by facilitating CTC formation. The EMT-CTC axis could be targeted for preventive measures during MORA treatment to inhibit the associated tumor metastasis or recurrence in BC patients.

【 授权许可】

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