Journal
MOLECULAR ONCOLOGY
Volume 16, Issue 6, Pages 1329-1346Publisher
WILEY
DOI: 10.1002/1878-0261.13192
Keywords
bladder cancer; cellular senescence; gemcitabine resistance; miR-99a-5p; SMARCD1
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Funding
- Japan Society for the Promotion of Science (KAKENHI) [19 K09715, 20 K18146, 21 K09404, 21 K09430]
- Takeda Science Foundation in Japan
- Facility of Laboratory Animal Science Research Support Center Institute for Research Promotion Kagoshima University
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MiR-99a-5p induces cellular senescence in gemcitabine-resistant bladder cancer cells by targeting SMARCD1, thereby inhibiting cell growth and restoring sensitivity to gemcitabine.
Patients with advanced bladder cancer are generally treated with a combination of chemotherapeutics, including gemcitabine, but the effect is limited due to acquisition of drug resistance. Thus, in this study, we investigated the mechanism of gemcitabine resistance. First, gemcitabine-resistant cells were established and resistance confirmed in vitro and in vivo. Small RNA sequencing analyses were performed to search for miRNAs involved in gemcitabine resistance. miR-99a-5p, selected as a candidate miRNA, was downregulated compared to its parental cells. In gain-of-function studies, miR-99a-5p inhibited cell viabilities and restored sensitivity to gemcitabine. RNA sequencing analysis was performed to find the target gene of miR-99a-5p. SMARCD1 was selected as a candidate gene. Dual-luciferase reporter assays showed that miR-99a-5p directly regulated SMARCD1. Loss-of-function studies conducted with si-RNAs revealed suppression of cell functions and restoration of gemcitabine sensitivity. miR-99a-5p overexpression and SMARCD1 knockdown also suppressed gemcitabine-resistant cells in vivo. Furthermore, beta-galactosidase staining showed that miR-99a-5p induction and SMARCD1 suppression contributed to cellular senescence. In summary, tumor-suppressive miR-99a-5p induced cellular senescence in gemcitabine-resistant bladder cancer cells by targeting SMARCD1.
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