Tumor‐derived exosomal BCYRN1 activates WNT5A/VEGF‐C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer
Abstract Background Patients with lymph node (LN) metastatic bladder cancer (BCa) present with extremely poor prognosis. BCa‐derived exosomes function as crucial bioactive cargo carriers to mediate the signal transduction in tumor microenvironment triggering tumor metastasis. However, the mechanisms...
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| Format: | Article |
| Language: | English |
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Wiley
2021-07-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.497 |
| _version_ | 1818535475070107648 |
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| author | Hanhao Zheng Changhao Chen Yuming Luo Min Yu Wang He Mingjie An Bowen Gao Yao Kong Yiyao Ya Yan Lin Yuting Li Keji Xie Jian Huang Tianxin Lin |
| author_facet | Hanhao Zheng Changhao Chen Yuming Luo Min Yu Wang He Mingjie An Bowen Gao Yao Kong Yiyao Ya Yan Lin Yuting Li Keji Xie Jian Huang Tianxin Lin |
| author_sort | Hanhao Zheng |
| collection | DOAJ |
| description | Abstract Background Patients with lymph node (LN) metastatic bladder cancer (BCa) present with extremely poor prognosis. BCa‐derived exosomes function as crucial bioactive cargo carriers to mediate the signal transduction in tumor microenvironment triggering tumor metastasis. However, the mechanisms underlying exosome‐mediated LN metastasis in BCa are unclear. Methods We conducted the high‐throughput sequencing to explore the expression profile of long noncoding RNA (lncRNA) in urinary exosomes (urinary‐EXO) from patients with BCa and further evaluated the clinical relevance of exosomal lncRNA BCYRN1 in a larger 210‐case cohort. The functional role of exosomal BCYRN1 was evaluated through the migration and tube formation assays in vitro and the footpad‐popliteal LN metastasis model in vivo. RNA pull‐down assays, luciferase assays, and actinomycin assays were conducted to detect the regulatory mechanism of exosomal BCYRN1. Results LncRNA BCYRN1 was substantially upregulated in urinary‐EXO from patients with BCa, and associated with the LN metastasis of BCa. We demonstrated that exosomal BCYRN1 markedly promoted tube formation and migration of human lymphatic endothelial cells (HLECs) in vitro and lymphangiogenesis and LN metastasis of BCa in vivo. Mechanistically, BCYRN1 epigenetically upregulated WNT5A expression by inducing hnRNPA1‐associated H3K4 trimethylation in WNT5A promoter, which activated Wnt/β‐catenin signaling to facilitate the secretion of VEGF‐C in BCa. Moreover, exosomal BCYRN1 was transmitted to HLECs to stabilize the VEGFR3 mRNA and thus formed an hnRNPA1/WNT5A/VEGFR3 feedforward regulatory loop, ultimately promoting the lymphatic metastasis of BCa. Importantly, blocking VEGFR3 with specific inhibitor, SAR131675 significantly impaired exosomal BCYRN1‐induced the LN metastasis in vivo. Clinically, exosomal BCYRN1 was positively associated with the shorter survival of BCa patients and identified as a poor prognostic factor of patients. Conclusion Our results uncover a novel mechanism by which exosomal BCYRN1 synergistically enhances VEGF‐C/VEGFR3 signaling‐induced lymphatic metastasis of BCa, indicating that BCYRN1 may serve as an encouraging therapeutic target for patients with BCa. |
| first_indexed | 2024-12-11T18:25:22Z |
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| id | doaj.art-ba20936f42174ec5a239a9ce2ffa88d8 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-12-11T18:25:22Z |
| publishDate | 2021-07-01 |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-ba20936f42174ec5a239a9ce2ffa88d82022-12-22T00:55:06ZengWileyClinical and Translational Medicine2001-13262021-07-01117n/an/a10.1002/ctm2.497Tumor‐derived exosomal BCYRN1 activates WNT5A/VEGF‐C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancerHanhao Zheng0Changhao Chen1Yuming Luo2Min Yu3Wang He4Mingjie An5Bowen Gao6Yao Kong7Yiyao Ya8Yan Lin9Yuting Li10Keji Xie11Jian Huang12Tianxin Lin13Department of Urology Sun Yat‐sen Memorial Hospital Guangzhou Guangdong P. R. ChinaDepartment of Urology Sun Yat‐sen Memorial Hospital Guangzhou Guangdong P. R. ChinaDepartment of General Surgery Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou Guangdong P. R. ChinaDepartment of General Surgery Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou Guangdong P. R. ChinaDepartment of Urology Sun Yat‐sen Memorial Hospital Guangzhou Guangdong P. R. ChinaDepartment of Urology Sun Yat‐sen Memorial Hospital Guangzhou Guangdong P. R. ChinaDepartment of Pancreatobiliary Surgery Sun Yat‐sen Memorial Hospital Guangzhou Guangdong P. R. ChinaDepartment of General Surgery Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou Guangdong P. R. ChinaDepartment of Urology Guangzhou First People's Hospital School of Medicine South China University of Technology Guangzhou ChinaDepartment of Urology Sun Yat‐sen Memorial Hospital Guangzhou Guangdong P. R. ChinaDepartment of General Surgery Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou Guangdong P. R. ChinaDepartment of Urology Guangzhou First People's Hospital School of Medicine South China University of Technology Guangzhou ChinaDepartment of Urology Sun Yat‐sen Memorial Hospital Guangzhou Guangdong P. R. ChinaDepartment of Urology Sun Yat‐sen Memorial Hospital Guangzhou Guangdong P. R. ChinaAbstract Background Patients with lymph node (LN) metastatic bladder cancer (BCa) present with extremely poor prognosis. BCa‐derived exosomes function as crucial bioactive cargo carriers to mediate the signal transduction in tumor microenvironment triggering tumor metastasis. However, the mechanisms underlying exosome‐mediated LN metastasis in BCa are unclear. Methods We conducted the high‐throughput sequencing to explore the expression profile of long noncoding RNA (lncRNA) in urinary exosomes (urinary‐EXO) from patients with BCa and further evaluated the clinical relevance of exosomal lncRNA BCYRN1 in a larger 210‐case cohort. The functional role of exosomal BCYRN1 was evaluated through the migration and tube formation assays in vitro and the footpad‐popliteal LN metastasis model in vivo. RNA pull‐down assays, luciferase assays, and actinomycin assays were conducted to detect the regulatory mechanism of exosomal BCYRN1. Results LncRNA BCYRN1 was substantially upregulated in urinary‐EXO from patients with BCa, and associated with the LN metastasis of BCa. We demonstrated that exosomal BCYRN1 markedly promoted tube formation and migration of human lymphatic endothelial cells (HLECs) in vitro and lymphangiogenesis and LN metastasis of BCa in vivo. Mechanistically, BCYRN1 epigenetically upregulated WNT5A expression by inducing hnRNPA1‐associated H3K4 trimethylation in WNT5A promoter, which activated Wnt/β‐catenin signaling to facilitate the secretion of VEGF‐C in BCa. Moreover, exosomal BCYRN1 was transmitted to HLECs to stabilize the VEGFR3 mRNA and thus formed an hnRNPA1/WNT5A/VEGFR3 feedforward regulatory loop, ultimately promoting the lymphatic metastasis of BCa. Importantly, blocking VEGFR3 with specific inhibitor, SAR131675 significantly impaired exosomal BCYRN1‐induced the LN metastasis in vivo. Clinically, exosomal BCYRN1 was positively associated with the shorter survival of BCa patients and identified as a poor prognostic factor of patients. Conclusion Our results uncover a novel mechanism by which exosomal BCYRN1 synergistically enhances VEGF‐C/VEGFR3 signaling‐induced lymphatic metastasis of BCa, indicating that BCYRN1 may serve as an encouraging therapeutic target for patients with BCa.https://doi.org/10.1002/ctm2.497BCYRN1bladder cancerexosomeslymph node metastasisVEGF‐C/VEGFR3 signaling |
| spellingShingle | Hanhao Zheng Changhao Chen Yuming Luo Min Yu Wang He Mingjie An Bowen Gao Yao Kong Yiyao Ya Yan Lin Yuting Li Keji Xie Jian Huang Tianxin Lin Tumor‐derived exosomal BCYRN1 activates WNT5A/VEGF‐C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer Clinical and Translational Medicine BCYRN1 bladder cancer exosomes lymph node metastasis VEGF‐C/VEGFR3 signaling |
| title | Tumor‐derived exosomal BCYRN1 activates WNT5A/VEGF‐C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer |
| title_full | Tumor‐derived exosomal BCYRN1 activates WNT5A/VEGF‐C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer |
| title_fullStr | Tumor‐derived exosomal BCYRN1 activates WNT5A/VEGF‐C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer |
| title_full_unstemmed | Tumor‐derived exosomal BCYRN1 activates WNT5A/VEGF‐C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer |
| title_short | Tumor‐derived exosomal BCYRN1 activates WNT5A/VEGF‐C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer |
| title_sort | tumor derived exosomal bcyrn1 activates wnt5a vegf c vegfr3 feedforward loop to drive lymphatic metastasis of bladder cancer |
| topic | BCYRN1 bladder cancer exosomes lymph node metastasis VEGF‐C/VEGFR3 signaling |
| url | https://doi.org/10.1002/ctm2.497 |
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