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MicroRNA-126 inhibits invasion in bladder cancer via regulation of ADAM9
A Y Jia1, M Castillo-Martin2, D M Bonal2
1Department of Pathology and Cell Biology, Columbia University, 1130 St Nicholas Avenue, New York, NY 10032, USA.
Background:
The miRNA deregulation is commonly observed in human malignancies, where they act as tumour suppressors or oncogenes. Despite the association of several miRNAs with bladder cancer, little is known about the miRNAs that contribute to bladder cancer progression from non-muscle invasive (NMI) to muscle-invasive (MI) disease.
Methods:
We first profiled the expression of miRNAs and mRNAs in a cohort of urothelial carcinomas and further characterised the role of miR-126 in invasion, as it emerged as the most downregulated miRNA between MI and NMI tumours.
Results:
We found that restoration of miR-126 levels attenuated the invasive potential of bladder cancer cells. Mechanistically, we identified the role of miR-126 in invasion through its ability to target ADAM9. Notably, a significant inverse correlation between miR-126 and ADAM9 expression was observed, where ADAM9 was upregulated in MI bladder cancer cells. While knockdown of ADAM9 attenuated the invasiveness of cells with low miR-126 levels, experimental upregulation of ADAM9 recapitulated the invasive phenotype. Furthermore, ADAM9 expression assessed by immunohistochemistry significantly correlated with poor prognosis in patients with urothelial carcinoma.
Conclusions:
In this study we describe the role of miR-126 in bladder cancer progression, identifying miR-126 and ADAM9 as potential clinical biomarkers of disease aggressiveness.
Insights
MicroRNA-126 (miR-126) downregulation promotes bladder cancer invasion by upregulating ADAM9. Restoring miR-126 or inhibiting ADAM9 may offer therapeutic strategies for aggressive bladder cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MicroRNA (miRNA) deregulation is implicated in various cancers, acting as tumor suppressors or oncogenes.
- While some miRNAs are linked to bladder cancer, their specific roles in progression from non-muscle-invasive (NMI) to muscle-invasive (MI) disease remain unclear.
Purpose of the Study:
- To investigate the role of specific miRNAs, particularly miR-126, in bladder cancer progression from NMI to MI disease.
- To elucidate the molecular mechanisms by which miR-126 influences bladder cancer cell invasion.
Main Methods:
- Profiling of miRNA and mRNA expression in urothelial carcinomas.
- Functional assays to assess the impact of miR-126 restoration on bladder cancer cell invasion.
- Investigating the regulatory relationship between miR-126 and its target gene ADAM9.
Main Results:
- miR-126 was significantly downregulated in muscle-invasive (MI) compared to non-muscle-invasive (NMI) bladder tumors.
- Restoration of miR-126 levels reduced bladder cancer cell invasiveness.
- ADAM9 was identified as a direct target of miR-126, with its expression inversely correlated with miR-126 and upregulated in MI tumors.
- Modulating ADAM9 levels mimicked or reversed the invasive phenotype, and high ADAM9 expression correlated with poor patient prognosis.
Conclusions:
- miR-126 plays a crucial role in suppressing bladder cancer cell invasion.
- The miR-126/ADAM9 axis is a key mechanism driving bladder cancer progression.
- Both miR-126 and ADAM9 represent potential biomarkers for assessing bladder cancer aggressiveness and patient prognosis.
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