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
Xiaoqiang Wang
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorSong Zhang
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorDi Jin
Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorJiamei Luo
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorYumiao Shi
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorYiqi Zhang
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorLingling Wu
Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorYanling Song
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, Xiamen, Fujian, P. R. China
Search for more papers by this authorDiansan Su
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorZhiying Pan
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorHaige Chen
Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorCorresponding Author
Ming Cao
Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Correspondence
Jie Tian, and Weifeng Yu, Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected] and [email protected]
Chaoyong Yang, Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
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, Xiamen 361005, Fujian, P. R. China.
Email: [email protected]
Ming Cao, Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Chaoyong Yang
Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
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, Xiamen, Fujian, P. R. China
Correspondence
Jie Tian, and Weifeng Yu, Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected] and [email protected]
Chaoyong Yang, Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
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, Xiamen 361005, Fujian, P. R. China.
Email: [email protected]
Ming Cao, Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Weifeng Yu
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Correspondence
Jie Tian, and Weifeng Yu, Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected] and [email protected]
Chaoyong Yang, Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
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, Xiamen 361005, Fujian, P. R. China.
Email: [email protected]
Ming Cao, Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jie Tian
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Correspondence
Jie Tian, and Weifeng Yu, Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected] and [email protected]
Chaoyong Yang, Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
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, Xiamen 361005, Fujian, P. R. China.
Email: [email protected]
Ming Cao, Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected]
Search for more papers by this authorXiaoqiang Wang
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorSong Zhang
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorDi Jin
Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorJiamei Luo
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorYumiao Shi
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorYiqi Zhang
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorLingling Wu
Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorYanling Song
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, Xiamen, Fujian, P. R. China
Search for more papers by this authorDiansan Su
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorZhiying Pan
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorHaige Chen
Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Search for more papers by this authorCorresponding Author
Ming Cao
Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Correspondence
Jie Tian, and Weifeng Yu, Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected] and [email protected]
Chaoyong Yang, Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
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, Xiamen 361005, Fujian, P. R. China.
Email: [email protected]
Ming Cao, Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Chaoyong Yang
Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
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, Xiamen, Fujian, P. R. China
Correspondence
Jie Tian, and Weifeng Yu, Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected] and [email protected]
Chaoyong Yang, Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
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, Xiamen 361005, Fujian, P. R. China.
Email: [email protected]
Ming Cao, Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Weifeng Yu
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Correspondence
Jie Tian, and Weifeng Yu, Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected] and [email protected]
Chaoyong Yang, Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
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, Xiamen 361005, Fujian, P. R. China.
Email: [email protected]
Ming Cao, Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jie Tian
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
Correspondence
Jie Tian, and Weifeng Yu, Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected] and [email protected]
Chaoyong Yang, Institute of Molecular Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
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, Xiamen 361005, Fujian, P. R. China.
Email: [email protected]
Ming Cao, Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P. R. China.
Email: [email protected]
Search for more papers by this authorXiaoqiang Wang, Song Zhang and Di Jin contributed equally to this work.
Abstract
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.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| cac212408-sup-0001-SuppMat.docx3.5 MB | Supporting Information |
| cac212408-sup-0002-VideoS1.avi8.1 MB | Supporting Information |
| cac212408-sup-0003-VideoS2.avi10.4 MB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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