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Updated: Jul 16, 2025
An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
Targeting microRNA-145-mediated progressive phenotypes of early bladder cancer in a molecularly defined in vivo model
Kazuki Heishima1,2,3, Nobuhiko Sugito1, Chikara Abe4
1The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Gifu, Japan.
Abstract:
A progressive subclass of early-stage non-muscle-invasive bladder cancer (NMIBC) frequently recurs and progress into invasive carcinoma, thus decreasing the overall survival rate of NMIBC. However, therapeutic development for progressive NMIBC has been challenging due to the lack of molecularly validated in vivo models and agents targeting its genetic vulnerability. We herein molecularly characterized an interventional model of progressive NMIBC and revealed the principal functions and therapeutic potential of microRNA-145 (miR-145) in early bladder tumorigenesis. N-butyl-N-(4-hydroxybutyl)nitrosamine-induced premalignant lesions (BiPLs) in rats exhibited downregulated expression of miR-145 as well as highly similar mutation/expression profiles to those of the human progressive NMIBC subclass with the worst prognosis. The expression patterns of miR-145 inversely correlated with those of BC-related oncogenes in BiPLs. We also demonstrated that miR-145 dominantly regulated interferon pathways and c-Myc expression, which play a crucial role in the pathogenesis of progressive NMIBC. Furthermore, we demonstrated that miR-145 replacement with a novel miR-145-based intravesical agent (miR-145S1) significantly inhibited the progression of BiPLs in vivo. These results provide insights into the essential role of miR-145 as the earliest-acting oncogenic driver of bladder tumorigenesis as well as a validated interventional model and novel miR-145-based nucleic acid therapeutic agent for progressive NMIBC.
Insights
MicroRNA-145 (miR-145) is crucial in early bladder cancer. Restoring miR-145 in a novel rat model significantly inhibited tumor progression, offering a new therapeutic strategy for non-muscle-invasive bladder cancer (NMIBC).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Progressive non-muscle-invasive bladder cancer (NMIBC) frequently recurs and progresses to invasive carcinoma, impacting survival rates.
- Therapeutic development for progressive NMIBC is hindered by a lack of validated in vivo models and targeted agents.
- Understanding the molecular drivers of early bladder tumorigenesis is critical for effective intervention.
Purpose of the Study:
- To molecularly characterize an interventional model of progressive NMIBC.
- To investigate the role and therapeutic potential of microRNA-145 (miR-145) in early bladder cancer.
- To evaluate a novel miR-145-based therapeutic agent for progressive NMIBC.
Main Methods:
- Development and molecular characterization of N-butyl-N-(4-hydroxybutyl)nitrosamine-induced premalignant lesions (BiPLs) in rats.
- Analysis of miR-145 expression patterns and correlation with oncogenes in BiPLs.
- In vivo evaluation of a novel intravesical miR-145-based agent (miR-145S1) for its efficacy in inhibiting tumor progression.
Main Results:
- BiPLs exhibited downregulated miR-145 and molecular profiles similar to human progressive NMIBC with poor prognosis.
- miR-145 inversely correlated with bladder cancer-related oncogenes and regulated interferon pathways and c-Myc expression.
- Intravesical administration of miR-145S1 significantly inhibited BiPL progression in vivo.
Conclusions:
- miR-145 plays an essential role as an early oncogenic driver in bladder tumorigenesis.
- The validated rat model provides a platform for studying progressive NMIBC.
- The novel miR-145-based agent (miR-145S1) demonstrates therapeutic potential for progressive NMIBC.
