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Published on: March 14, 2019
MicroRNA-34a-5p: A pivotal therapeutic target in gallbladder cancer
Takashi Oda1, Koichiro Tsutsumi2, Taisuke Obata1
1Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan.
Abstract:
Gallbladder cancer incidence has been increasing globally, and it remains challenging to expect long prognosis with the current systemic chemotherapy. We identified a novel nucleic acid-mediated therapeutic target against gallbladder cancer by using innovative organoid-based gallbladder cancer models generated from KrasLSL-G12D/+; Trp53f/f mice. Using comprehensive microRNA expression analyses and a bioinformatics approach, we identified significant microRNA-34a-5p downregulation in both murine gallbladder cancer organoids and resected human gallbladder cancer specimens. In three different human gallbladder cancer cell lines, forced microRNA-34a-5p expression inhibited cell proliferation and induced cell-cycle arrest at the G1 phase by suppressing direct target (CDK6) expression. Furthermore, comprehensive RNA sequencing revealed the significant enrichment of gene sets related to the cell-cycle regulators after microRNA-34a-5p expression in gallbladder cancer cells. In a murine xenograft model, locally injected microRNA-34a-5p mimics significantly inhibited gallbladder cancer progression and downregulated CDK6 expression. These results provide a rationale for promising therapeutics against gallbladder cancer by microRNA-34a-5p injection, as well as a strategy to explore therapeutic targets against cancers using organoid-based models, especially for those lacking useful genetically engineered murine models, such as gallbladder cancer.
Insights
Researchers discovered that microRNA-34a-5p downregulation is common in gallbladder cancer. Restoring microRNA-34a-5p levels inhibited cancer cell growth by targeting CDK6, offering a potential new therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gallbladder cancer incidence is rising globally, posing a significant therapeutic challenge.
- Current systemic chemotherapy offers limited long-term prognosis for patients.
- Novel therapeutic targets are urgently needed for effective gallbladder cancer treatment.
Purpose of the Study:
- To identify novel nucleic acid-mediated therapeutic targets for gallbladder cancer.
- To investigate the role of microRNA-34a-5p in gallbladder cancer pathogenesis and progression.
- To evaluate the therapeutic potential of microRNA-34a-5p in preclinical models.
Main Methods:
- Generation of innovative organoid-based gallbladder cancer models from Kras/Trp53 mutant mice.
- Comprehensive microRNA expression analysis and bioinformatics approach.
- In vitro studies using human gallbladder cancer cell lines and in vivo xenograft models.
Main Results:
- Significant downregulation of microRNA-34a-5p was identified in murine organoids and human gallbladder cancer specimens.
- Forced expression of microRNA-34a-5p inhibited cell proliferation and induced G1 cell-cycle arrest by suppressing CDK6.
- MicroRNA-34a-5p mimics significantly inhibited tumor progression and downregulated CDK6 in a murine xenograft model.
Conclusions:
- MicroRNA-34a-5p represents a promising therapeutic target for gallbladder cancer.
- MicroRNA-34a-5p injection demonstrates potential as a novel therapeutic strategy.
- Organoid-based models are valuable for exploring therapeutic targets in cancers lacking established murine models.
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