microRNA-99a-5p induces cellular senescence in gemcitabine-resistant bladder cancer by targeting SMARCD1

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Advanced bladder cancer treatment often involves gemcitabine chemotherapy.
• Acquisition of drug resistance limits the efficacy of gemcitabine.
• Understanding gemcitabine resistance mechanisms is crucial for developing new therapies.

Purpose of the Study:

• To investigate the molecular mechanisms underlying gemcitabine resistance in bladder cancer.
• To identify key microRNAs (miRNAs) and their target genes involved in this resistance.
• To explore the potential of targeting these molecules for therapeutic intervention.

Main Methods:

• Establishment and validation of gemcitabine-resistant bladder cancer cell lines in vitro and in vivo.
• Small RNA sequencing to identify differentially expressed miRNAs.
• Gain-of-function and loss-of-function studies for miR-99a-5p and its target gene.
• RNA sequencing and dual-luciferase reporter assays to identify and validate gene targets.
• Assessment of cellular senescence via β-galactosidase staining.

Main Results:

• miR-99a-5p was significantly downregulated in gemcitabine-resistant bladder cancer cells.
• Overexpression of miR-99a-5p inhibited cell viability and restored sensitivity to gemcitabine.
• SMARCD1 was identified as a direct target gene of miR-99a-5p.
• miR-99a-5p induction and SMARCD1 suppression promoted cellular senescence and suppressed tumor growth in vivo.

Conclusions:

• The tumor-suppressive miR-99a-5p plays a critical role in overcoming gemcitabine resistance.
• miR-99a-5p induces cellular senescence in gemcitabine-resistant bladder cancer cells by targeting SMARCD1.
• Targeting the miR-99a-5p/SMARCD1 axis represents a promising therapeutic strategy for advanced bladder cancer.