Glucocorticoid receptor beta increases migration of human bladder cancer cells

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.

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

“…GR␤, however, has a truncated helix 12 and is missing the ligand binding pocket known to bind to GCs (3). The known function of GR␤ is to act as a dominant-negative antagonist to GR␣ (3,5,(7)(8)(9). We have previously shown that GR␤ mRNA increased from fasting and refeeding in the livers of mice (8).…”

Long non-coding RNA polymorphisms on 8q24 are associated with the prognosis of gastric cancer in a Chinese population

“…GRβ lacks the ligand-binding domain for glucocorticoids (Hinds et al, 2010) and has been indicated to inhibit GRa (Leung et al, 1997;Hinds et al, 2010;Kubin et al, 2016). GRβ has been demonstrated to be involved in the migration of bladder cancer and brain cancer (Mcbeth et al, 2016;Ying et al, 2013), and some other studies have also reported that GRβ levels are elevated in inflammatory diseases and cancers, leading to increased progression (Zhu et al, 2007;Marino et al, 2016;Psarra et al, 2005). Hence, we hypothesise that the poor prognosis of patients with the rs12682421 A allele may be associated with a higher GRβ expression.…”

Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes

“…27,28 Furthermore, this isoform was found to participate in the molecular pathways of glioma formation as well as in the migration of bladder cancer cells. [29][30][31] In addition to in vitro and animal experiments, studies in humans have shown that hGRβ expression levels are associated with glucocorticoid resistance in severa l inflammatory diseases (ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, asthma), hematologic malignancies (acute lymphoblastic leukemia, chronic lymphocytic leukemia) as well as in many mood disorders (major depression, schizophrenia). 18,32 In contradistinction to hGRβ, the hGRα isoform is ubiquitously expressed in every tissue except the SCN Figure 1.…”