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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Glucocorticoid receptor beta increases migration of human bladder cancer cells
Lucien McBeth1, Assumpta C Nwaneri1, Maria Grabnar1
1Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA.
Abstract:
Bladder cancer is observed worldwide having been associated with a host of environmental and lifestyle risk factors. Recent investigations on anti-inflammatory glucocorticoid signaling point to a pathway that may impact bladder cancer. Here we show an inverse effect on the glucocorticoid receptor (GR) isoform signaling that may lead to bladder cancer. We found similar GRα expression levels in the transitional uroepithelial cancer cell lines T24 and UMUC-3. However, the T24 cells showed a significant (p < 0.05) increased expression of GRβ compared to UMUC-3, which also correlated with higher migration rates. Knockdown of GRβ in the T24 cells resulted in a decreased migration rate. Mutational analysis of the 3' untranslated region (UTR) of human GRβ revealed that miR144 might positively regulate expression. Indeed, overexpression of miR144 increased GRβ by 3.8 fold. In addition, miR144 and GRβ were upregulated during migration. We used a peptide nucleic acid conjugated to a cell penetrating-peptide (Sweet-P) to block the binding site for miR144 in the 3'UTR of GRβ. Sweet-P effectively prevented miR144 actions and decreased GRβ expression, as well as the migration of the T24 human bladder cancer cells. Therefore, GRβ may have a significant role in bladder cancer, and possibly serve as a therapeutic target for the disease.
Insights
Glucocorticoid receptor beta (GRβ) may drive bladder cancer progression. Inhibiting its interaction with miR144 using Sweet-P reduced cancer cell migration, suggesting GRβ as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Bladder cancer is a global health concern linked to environmental and lifestyle factors.
- Glucocorticoid receptor (GR) signaling is implicated in cancer, with distinct roles for its isoforms.
Purpose of the Study:
- To investigate the role of glucocorticoid receptor (GR) isoforms, specifically GRβ, in bladder cancer.
- To explore the regulatory mechanism of GRβ expression involving miR144 and its impact on cancer cell migration.
Main Methods:
- Compared GRα and GRβ expression in bladder cancer cell lines (T24 and UMUC-3).
- Assessed the effect of GRβ knockdown on cell migration.
- Investigated the regulatory role of miR144 on GRβ expression using overexpression and mutational analysis.
- Utilized a peptide nucleic acid (Sweet-P) to inhibit miR144 binding to GRβ 3'UTR.
Main Results:
- T24 cells exhibited higher GRβ expression and migration rates compared to UMUC-3 cells.
- GRβ knockdown significantly decreased T24 cell migration.
- miR144 positively regulated GRβ expression, and both were upregulated during migration.
- Sweet-P treatment reduced GRβ expression and bladder cancer cell migration.
Conclusions:
- GRβ plays a significant role in bladder cancer cell migration.
- miR144 positively regulates GRβ expression, contributing to bladder cancer progression.
- Targeting the miR144-GRβ interaction with agents like Sweet-P shows therapeutic potential for bladder cancer.
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