Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Sci Rep ; 11(1): 13171, 2021 06 23.
Article in English | MEDLINE | ID: mdl-34162983

ABSTRACT

Bladder outlet obstruction (BOO) often results in lower urinary tract symptoms (LUTSs) and negatively affects quality of life. Here, we evaluated gene expression patterns in the urinary bladder during tissue remodeling due to BOO. We divided BOO model rats into two groups according to the degree of hypertrophy of smooth muscle in the bladder. The strong muscular hypertrophy group, which exhibited markedly increased bladder smooth muscle proportion and HIF1α mRNA levels compared with the control group, was considered a model for the termination of hypertrophy, whereas the mild muscular hypertrophy group was considered a model of the initiation of hypertrophy. Some genes related to urinary function showed different expression patterns between the two groups. Furthermore, we found that several genes, including D-box binding PAR bZIP transcription factor (DBP), were upregulated only in the mild muscular hypertrophy group. DBP expression levels were increased in bladder smooth muscle cells in response to hypoxic stress. DBP associated with enhancer and promoter regions of NOS3 gene locus and upregulated NOS3 gene expression under hypoxic conditions. These findings suggested that the regulatory systems of gene expression were altered during tissue remodeling following BOO. Furthermore, circadian clock components might be involved in control of urinary function via transcriptional gene regulation in response to hypoxic stimuli.


Subject(s)
Gene Expression Profiling , Urinary Bladder Neck Obstruction/genetics , Animals , Cell Hypoxia , Cells, Cultured , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Disease Models, Animal , Female , Gene Expression Regulation , Hypertrophy , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Muscle, Smooth/metabolism , Muscle, Smooth/pathology , Nitric Oxide Synthase Type III/biosynthesis , Nitric Oxide Synthase Type III/genetics , RNA-Seq , Rats , Rats, Sprague-Dawley , Transcription Factors/biosynthesis , Transcription Factors/genetics , Urinary Bladder Neck Obstruction/metabolism
2.
Article in English | MEDLINE | ID: mdl-30076933

ABSTRACT

The androgen receptor (AR) promotes growth of prostate cancer cells by controlling the expression of target genes. This study showed that MRG domain binding protein (MRGBP) accelerated AR-mediated transactivation. We first showed that MRGBP promoted growth of AR-positive prostate cancer cells. MRGBP increased the expression of certain AR target genes, including KLK3 and TMPRSS2, and it associated with AR binding regions of these genes during androgen treatment. Furthermore, MRGBP interacted with MRG15 and TIP60 in prostate cancer cells. Androgen-stimulated AR enhanced histone H3K4me1 or H3K4me3 levels at AR binding regions. MRGBP was recruited to active gene regions through its binding with H3K4me1/3 by MRG15. Then, MRGBP promoted recruitment of TIP60 and acetylation of histone variant H2A.Z at the location of AR binding. Accordingly, AR occupancy of the AR binding regions was increased by MRGBP. Together, these results suggest that MRGBP promotes activation of AR-associated enhancer and promoter regions through an epigenetic mechanism.

3.
Cancer Lett ; 431: 182-189, 2018 09 01.
Article in English | MEDLINE | ID: mdl-29778569

ABSTRACT

Renal cell carcinoma (RCC) is the most common malignancy of kidney and remains largely intractable once it recurs after resection. mTOR inhibitors have been one of the mainstays used against recurrent RCC; however, there has been a major problem of the resistance to mTOR inhibitors, and thus new combination treatments with mTOR inhibitors are required. We here retrospectively showed that regular use of antilipidemic drug statins could provide a longer progression free survival (PFS) in RCC patients prescribed with an mTOR inhibitor everolimus than without statins (median PFS, 7.5 months vs. 3.2 months, respectively; hazard ratio, 0.52; 95% CI, 0.22-1.11). In order to give a rationale for this finding, we used RCC cell lines and showed the combinatorial effects of an mTOR inhibitor with statins induced a robust activation of retinoblastoma protein, whose mechanisms were involved in statins-mediated hindrance of KRAS or Rac1 protein prenylation. Finally, statins treatment also enhanced the efficacy of an mTOR inhibitor in RCC xenograft models. Thus, we provide molecular and (pre)clinical data showing that statins use could be a drug repositioning for RCC patients to enhance the efficacy of mTOR inhibitors.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Enzyme Inhibitors/therapeutic use , Everolimus/therapeutic use , Kidney Neoplasms/drug therapy , Mevalonic Acid/metabolism , Retinoblastoma Binding Proteins/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , Ubiquitin-Protein Ligases/metabolism , Animals , Apoptosis , Carcinoma, Renal Cell/genetics , Cell Line, Tumor , Cell Survival , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Kidney Neoplasms/genetics , Mice , Mice, SCID , Prenylation , Progression-Free Survival , RNA, Small Interfering/metabolism , Retinoblastoma Binding Proteins/genetics , Retrospective Studies , Treatment Outcome , Ubiquitin-Protein Ligases/genetics
4.
Biochem Biophys Res Commun ; 485(2): 267-271, 2017 04 01.
Article in English | MEDLINE | ID: mdl-28235487

ABSTRACT

Renal cell carcinoma (RCC) is the most common type of kidney cancer. However, the mechanisms underlying the progression of the disease are not well understood. The data in this report suggest that canopy FGF signaling regulator 2 (CNPY2) is a promoter of RCC progression. We found that CNPY2 significantly promoted growth of RCC cells and upregulated TP53 gene expression. Although TP53 is widely known as a tumor suppressor, in RCC TP53 promoted tumor cell growth. A typical p53 target gene, CDKN1A, was upregulated by both p53 and CNPY2 in RCC cells, suggesting that CNPY2 increased the expression level of TP53. Consistent with these results, CNPY2 and TP53 expression levels were positively correlated in RCC patients. These findings suggested that CNPY2 promoted cancer cell growth in RCC through regulating TP53 gene expression.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Carcinoma, Renal Cell/genetics , Cell Proliferation , Down-Regulation , Kidney Neoplasms/genetics , Kidney/pathology , Tumor Suppressor Protein p53/genetics , Adaptor Proteins, Signal Transducing/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Genes, p53 , Humans , Kidney/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Tumor Suppressor Protein p53/metabolism
5.
Mol Cancer Ther ; 15(9): 2066-75, 2016 09.
Article in English | MEDLINE | ID: mdl-27406983

ABSTRACT

The prognosis of muscle-invasive bladder cancer with metastasis is poor. There have been no therapeutic improvements for many years, and an innovative therapy for muscle-invasive bladder cancer has been awaited to replace the conventional cytotoxic chemotherapy. Here, we show a candidate method for the treatment of bladder cancer. The combined treatment with a novel histone deacetylase (HDAC) inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth and markedly induced apoptosis through the caspase-dependent pathway in high-grade bladder cancer cells. Furthermore, the combined treatment induced expression of death receptor 5 (DR5). We identified that knockdown of DR5 by small interfering RNA (siRNA) significantly suppressed apoptosis by the combined treatment. Therefore, we conjectured that the apoptosis induced by OBP-801 and celecoxib is at least partially dependent on DR5. However, it was interesting that the combined treatment drastically suppressed expression of DR5 ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). These data suggest that there is no involvement of TRAIL in the induction of apoptosis by the combination, regardless of the dependence of DR5. Moreover, xenograft studies using human bladder cancer cells showed that the combined therapy suppressed tumor growth by upregulating expressions of DR5 and Bim. The inhibition of tumor growth was significantly more potent than that of each agent alone, without significant weight loss. This combination therapy provided a greater benefit than monotherapy in vitro and in vivo These data show that the combination therapy with OBP-801 and celecoxib is a potential novel therapeutic strategy for patients with muscle-invasive bladder cancer. Mol Cancer Ther; 15(9); 2066-75. ©2016 AACR.


Subject(s)
Apoptosis/drug effects , Celecoxib/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Peptides, Cyclic/pharmacology , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Signal Transduction/drug effects , Urinary Bladder Neoplasms/metabolism , Animals , Bcl-2-Like Protein 11/metabolism , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Drug Synergism , Female , Humans , Mice , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/metabolism , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Xenograft Model Antitumor Assays
SELECTION OF CITATIONS
SEARCH DETAIL
...