Dicer ablation promotes a mesenchymal and invasive phenotype in bladder cancer cells
Alan P Lombard1, Rebecca M Lim1, Rachel M Nakagawa1
1Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA.
Abstract:
Dicer expression is frequently altered in cancer and affects a wide array of cellular functions acting as an oncogene or tumor suppressor in varying contexts. It has been shown that Dicer expression is also deregulated in urothelial cell carcinoma of the bladder (UCCB) but the nature of this deregulation differs between reports. The aim of the present study was to gain a better understanding of the role of Dicer in bladder cancer to help determine its contribution to the disease. The results showed that Dicer transcript levels were decreased in UCCB tumor tissues as compared to normal tissues, suggesting that Dicer is a tumor suppressor. However, consistent with previous results, we demonstrated that knockdown of Dicer decreases cell viability and increases the induction of apoptosis, suggesting that Dicer is an oncogene. To resolve this discrepancy, we assessed the effects of decreased Dicer expression on epithelial-to‑mesenchymal transition, migration and invasion. We showed that decreased Dicer levels promoted a mesenchymal phenotype and increased migration. Additionally, the results showed that Dicer protein ablation leads to increased cell invasion, higher levels of matrix metalloproteinase-2, and decreased levels of key miRNAs shown to inhibit invasion. The results of this study suggest that decreased Dicer levels may portend a more malignant phenotype.
Insights
Decreased Dicer expression in bladder cancer promotes tumor cell invasion and migration, suggesting a role in disease progression. This finding helps clarify Dicer
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Dicer enzyme expression is altered in various cancers, with conflicting roles as an oncogene or tumor suppressor.
- Dicer deregulation in urothelial cell carcinoma of the bladder (UCCB) has been reported, but its precise function remains unclear.
Purpose of the Study:
- To investigate the role of Dicer in bladder cancer progression.
- To resolve discrepancies regarding Dicer's function in urothelial cell carcinoma of the bladder.
Main Methods:
- Quantitative analysis of Dicer transcript levels in UCCB tissues versus normal tissues.
- Assessment of cell viability, apoptosis, epithelial-to-mesenchymal transition (EMT), migration, and invasion upon Dicer modulation.
- Measurement of matrix metalloproteinase-2 (MMP-2) and key microRNA (miRNA) levels.
Main Results:
- Dicer transcript levels were reduced in UCCB tumors compared to normal tissues.
- Dicer knockdown decreased cell viability and increased apoptosis, suggesting an oncogenic role.
- Reduced Dicer expression promoted a mesenchymal phenotype, increased migration, and enhanced cell invasion.
- Dicer ablation correlated with increased MMP-2 and decreased levels of invasion-inhibiting miRNAs.
Conclusions:
- Decreased Dicer expression in bladder cancer is associated with increased malignancy.
- Reduced Dicer levels promote invasion and migration, potentially through MMP-2 and miRNA regulation.
- Dicer's role in UCCB appears context-dependent, with decreased expression linked to a more aggressive phenotype.
