circEHBP1 promotes lymphangiogenesis and lymphatic metastasis of bladder cancer via miR-130a-3p/TGFβR1/VEGF-D signaling
Autor: | Bowen Gao, Jian Huang, Changhao Chen, Jiang Zhu, Yue Zhao, Zhihua Li, Hanhao Zheng, Yuming Luo, Yuting Li, Le Ai, Hao Huang, Yao Kong |
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Rok vydání: | 2021 |
Předmět: |
Male
Receptor Transforming Growth Factor-beta Type I Vascular Endothelial Growth Factor D Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Line Tumor Drug Discovery Genetics Animals Humans Medicine Secretion Lymphangiogenesis Receptor 3' Untranslated Regions Molecular Biology Neoplasm Staging 030304 developmental biology Pharmacology 0303 health sciences Bladder cancer biology business.industry RNA Circular Transforming growth factor beta medicine.disease Up-Regulation Gene Expression Regulation Neoplastic MicroRNAs Urinary Bladder Neoplasms Vascular endothelial growth factor C Lymphatic Metastasis 030220 oncology & carcinogenesis Cancer research biology.protein Molecular Medicine Female Signal transduction business Neoplasm Transplantation |
Zdroj: | Molecular Therapy. 29:1838-1852 |
ISSN: | 1525-0016 |
Popis: | Lymphatic metastasis constitutes a leading cause of recurrence and mortality in bladder cancer. Accumulating evidence indicates that lymphangiogenesis is indispensable to trigger lymphatic metastasis. However, the specific mechanism is poorly understood. In the present study, we revealed a pathway involved in lymphatic metastasis of bladder cancer, in which a circular RNA (circRNA) facilitated lymphangiogenesis in a vascular endothelial growth factor C (VEGF-C)-independent manner. Novel circRNA circEHBP1 was markedly upregulated in bladder cancer and correlated positively with lymphatic metastasis and poor prognosis of patients with bladder cancer. circEHBP1 upregulated transforming growth factor beta receptor 1 (TGFBR1) expression through physically binding to miR-130a-3p and antagonizing the suppression effect of miR-130a-3p on the 3' UTR region of TGFBR1. Subsequently, circEHBP1-mediated TGFβR1 overexpression activated the TGF-β/SMAD3 signaling pathway, thereby promoting the secretion of VEGF-D and driving lymphangiogenesis and lymphatic metastasis in bladder cancer. Importantly, administration of VEGF-D neutralizing antibodies remarkably blocked circEHBP1-induced lymphangiogenesis and lymphatic metastasis in vivo. Our findings highlighted that the circEHBP1/miR-130a-3p/TGFβR1/VEGF-D axis contributes to lymphangiogenesis and lymphatic metastasis of bladder cancer independent of VEGF-C, which might lead to the development of circEHBP1 as a potential biomarker and promising therapeutic target for lymphatic metastasis in bladder cancer. |
Databáze: | OpenAIRE |
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