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Oncogenic miRNA-182-5p targets Smad4 and RECK in human bladder cancer
Hiroshi Hirata1, Koji Ueno, Varahram Shahryari
1Department of Urology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
Abstract:
Onco-miR-182-5p has been reported to be over-expressed in bladder cancer (BC) tissues however a detailed functional analysis of miR-182-5p has not been carried out in BC. Therefore the purpose of this study was to: 1. conduct a functional analysis of miR-182-5p in bladder cancer, 2. assess its usefulness as a tumor marker, 3. identify miR-182-5p target genes in BC. Initially we found that miR-182-5p expression was significantly higher in bladder cancer compared to normal tissues and high miR-182-5p expression was associated with shorter overall survival in BC patients. To study the functional significance of miR-182-5p, we over-expressed miR-182-5p with miR-182-5p precursor and observed that cell proliferation, migration and invasion abilities were increased in BC cells. However cell apoptosis was inhibited by miR-182-5p. We also identified Smad4 and RECK as potential target genes of miR-182-5p using several algorithms. 3'UTR luciferase activity of these target genes was significantly decreased and protein expression of these target genes was significantly up-regulated in miR-182-5p inhibitor transfected bladder cancer cells. MiR-182-5p also increased nuclear beta-catenin expression and while Smad4 repressed nuclear beta-catenin expression. In conclusion, our data suggests that miR-182-5p plays an important role as an oncogene by knocking down RECK and Smad4, resulting in activation of the Wnt-beta-catenin signaling pathway in bladder cancer.
Insights
Oncogenic microRNA-182-5p promotes bladder cancer progression by inhibiting tumor suppressor genes RECK and Smad4, activating the Wnt-beta-catenin pathway. High miR-182-5p expression correlates with poorer survival in bladder cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MicroRNA-182-5p (miR-182-5p) is overexpressed in bladder cancer (BC).
- Detailed functional analysis of miR-182-5p in BC is lacking.
- Investigating miR-182-5p's role is crucial for understanding BC pathogenesis.
Purpose of the Study:
- To functionally analyze miR-182-5p in bladder cancer.
- To evaluate miR-182-5p as a potential tumor marker.
- To identify miR-182-5p target genes in BC.
Main Methods:
- Expression analysis of miR-182-5p in BC tissues.
- Overexpression and inhibition of miR-182-5p in BC cell lines.
- Bioinformatic prediction and luciferase reporter assays for target gene validation.
- Western blot analysis for protein expression and nuclear translocation studies.
Main Results:
- miR-182-5p was significantly upregulated in BC tissues and associated with shorter overall survival.
- Overexpression of miR-182-5p enhanced BC cell proliferation, migration, and invasion while inhibiting apoptosis.
- Smad4 and RECK were identified as direct targets, with their inhibition by miR-182-5p leading to Wnt-beta-catenin pathway activation.
Conclusions:
- miR-182-5p acts as an oncogene in bladder cancer.
- Downregulation of RECK and Smad4 by miR-182-5p contributes to BC progression.
- miR-182-5p is a potential therapeutic target and prognostic biomarker for bladder cancer.
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