scholarly journals Fragile Gene WWOX Guides TFAP2A/TFAP2C-Dependent Actions Against Tumor Progression in Grade II Bladder Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Damian Kołat ◽  
Żaneta Kałuzińska ◽  
Elżbieta Płuciennik
Keyword(s):  
Bladder Cancer ◽  
Transcription Factors ◽  
Matrix Metalloproteinase ◽  
Tumor Cell ◽  
Cell Viability ◽  
Migration Rate ◽  
Matrix Metalloproteinase 2 ◽  
Biological Processes ◽  
Bladder Carcinogenesis ◽  
Grade Ii

IntroductionThe presence of common fragile sites is associated with no-accidental chromosomal instability which occurs prior to carcinogenesis. The WWOX gene spans the second most active fragile site: FRA16D. Chromosomal breakage at this site is more common in bladder cancer patients who are tobacco smokers which suggests the importance of WWOX gene loss regarding bladder carcinogenesis. Tryptophan domains of WWOX are known to recognize motifs of other proteins such as AP-2α and AP-2γ allowing protein-protein interactions. While the roles of both AP-2 transcription factors are important for bladder carcinogenesis, their nature is different. Based on the literature, AP-2γ appears to be oncogenic, whereas AP-2α mainly exhibits tumor suppressor character. Presumably, the interaction between WWOX and both transcription factors regulates thousands of genes, hence the aim of the present study was to determine WWOX, AP-2α, and AP-2γ function in modulating biological processes of bladder cancer.MethodsRT-112 cell line (grade II bladder cancer) was subjected to two stable lentiviral transductions. Overall, this resulted in six variants to investigate distinct WWOX, AP-2α, or AP-2γ function as well as WWOX in collaboration with a particular transcription factor. Cellular models were examined with immunocytochemical staining and in terms of differences in biological processes using assays investigating cell viability, proliferation, apoptosis, adhesion, clonogenicity, migration, activity of metalloproteinases and 3D culture growth.ResultsWWOX overexpression increased apoptosis but decreased cell viability, migration and large spatial colonies. AP-2α overexpression decreased tumor cell viability, migratory potential, matrix metalloproteinase-2 activity and clonogenicity. AP-2γ overexpression decreased matrix metalloproteinase-2 activity but increased wound healing, adhesion, clonogenicity and spatial colony formation. WWOX and AP-2α overexpression induced apoptosis but decreased cell viability, adhesion, matrix metalloproteinase-2 activity, overall number of cultured colonies and migration rate. WWOX and AP-2γ overexpression decreased tumor cell viability, proliferation potential, adhesion, clonogenicity and the ability to create spatial structures, but also increased apoptosis or migration rate.ConclusionCo-overexpression of WWOX with AP-2α or WWOX with AP-2γ resulted in a net anti-tumor effect. However, considering this research findings and the difference between AP-2α and AP-2γ, we suggest that this similarity is due to a divergent behavior of WWOX.

scholarly journals Prognostic values of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression in bladder cancer

Cancer ◽  
1998 ◽  
Vol 82 (7) ◽  
pp. 1359-1366 ◽  
Author(s):  
Hiro-omi Kanayama ◽  
Kin-ya Yokota ◽  
Yasushi Kurokawa ◽  
Yoshihide Murakami ◽  
Masaaki Nishitani ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Matrix Metalloproteinase ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Tissue Inhibitor

Compound A inhibits bladder cancer growth predominantly via glucocorticoid receptor transrepression.

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Bladder Cancer ◽  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Cancer Growth ◽  
Vascular Endothelial ◽  
Nuclear Factor ◽  
Hairpin Rna ◽  
Compound A ◽  
Endothelial Growth Factor ◽  
Metalloproteinase 9

Recent evidence indicates that glucocorticoids (GCs) suppress bladder cancer cell invasion throughthe GC receptor (GR) pathway, whereas androgen-mediated androgen receptor (AR) signals inducebladder tumor progression. In this study, we assessed the effects of 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride (compound A [CpdA]), which was shown to function asnot only a GR modulator but also an AR antagonist, on the growth of bladder cancer. In GR/ARpositivecells, CpdA strongly inhibited cell proliferation and colony formation as well as increasedG1 phase-arrested cell population and apoptosis. Specifically, CpdA at 1?Mdecreased cell viabilityof TCCSUP/UMUC3-control-short hairpin RNA (shRNA), TCCSUP/UMUC3-GR-shRNA, and TCCSUP/UMUC3-AR-shRNA by 50%/67%, 25%/26%, and 38%/58%, respectively. CpdA also inhibited cellmigration and invasion of GR/AR-positive (up to 61% decrease) and GR-positive/AR-silencing (upto 51% decrease) lines and, less strongly, those of GR-silencing/AR-positive lines (up to 35%decrease). Additionally, in UMUC3-control xenograft-bearing male mice, CpdA more stronglysuppressed tumor growth than dexamethasone or hydroxyflutamide. In reporter gene assays,CpdA failed to induce GR transactivation, whereas it antagonized dihydrotestosterone-enhancedAR transactivation. In contrast, CpdA reduced nuclear factor (NF)-?B and activator protein 1transcriptional activities, indicating induction of GR-mediated transrepression. Correspondingly,the expression of NF-?B-related molecules, matrix metalloproteinase-2, matrix metalloproteinase-9, interleukin-6, and vascular endothelial growth factor, was significantly down-regulatedby CpdA in control lines but not in GR-silencing cells. Moreover, coimmunoprecipitation showedthat CpdA promoted the interactions between GR and NF-?B. Thus, CpdA likely inhibits bladdercancer growth predominantly via inducing GR transrepression and at least partially mediatedthrough the AR pathway, suggesting its effects more beneficial than GCs/pure GR ligands or ARantagonists. (Molecular Endocrinology 29: 1486–1497, 2015)

scholarly journals Function of α3β1–Tetraspanin Protein Complexes in Tumor Cell Invasion. Evidence for the Role of the Complexes in Production of Matrix Metalloproteinase 2 (Mmp-2)

1999 ◽  
Vol 146 (6) ◽  
pp. 1375-1389 ◽  
Author(s):  
Tsuyoshi Sugiura ◽  
Fedor Berditchevski
Keyword(s):  
Monoclonal Antibodies ◽  
Matrix Metalloproteinase ◽  
Tumor Cell ◽  
Protein Complexes ◽  
Video Recording ◽  
Specific Inhibitor ◽  
Matrix Metalloproteinase 2 ◽  
Integrin Subunit ◽  
Protein Tyrosine ◽  
Tumor Cell Migration

Tumor cell migration through the three- dimensional extracellular matrix (ECM) environment is an important part of the metastatic process. We have analyzed a role played by the integrin–tetraspanin protein complexes in invasive migration by culturing MDA-MB-231 cells within Matrigel. Using time-lapse video recording, we demonstrated that the Matrigel-embedded cells remain round and exhibit only limited ability for migration by extending short, highly dynamic pseudopodia. The α3β1–tetraspanin protein complexes were clustered on the thin microvilli-like protrusions extending from both the main cell body and pseudopodia. Ligation of the α3β1–tetraspanin protein complexes with monoclonal antibodies specifically stimulates production of matrix metalloproteinase 2 (MMP-2) and induces formation of long invasive protrusions within Matrigel. Accordingly, treatment with the monoclonal antibodies to various tetraspanin proteins and to the α3 integrin subunit increases invasive potential of the MDA-MB-231 cells in the Matrigel-penetration assay. A specific inhibitor of phosphoinositide 3-kinase (PI3K), LY294002, negated the effect of the monoclonal antibodies on the morphology of the Matrigel-embedded cells and on production of MMP-2. Interestingly, broad-spectrum inhibitors of protein tyrosine kinases (genistein) and protein tyrosine phosphatases (orthovanadate), and actin filament stabilizing compound (jasplakinolide), also block protrusive activity of the Matrigel-embedded cells but have no effect on the production of MMP-2. These results indicate that α3β1–tetraspanin protein complexes may control invasive migration of tumor cells by using at least two PI3K-dependent signaling mechanisms: through rearrangement of the actin cytoskeleton and by modulating the MMP-2 production.

scholarly journals Effects of Dendrobium Polysaccharides on the Functions of Human Skin Fibroblasts and Expression of Matrix Metalloproteinase-2 under High-Glucose Conditions

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Yajia Li ◽  
Ziqin Cao ◽  
Qiangxiang Li ◽  
Chenxu Wang ◽  
Zhuo Zhou
Keyword(s):  
Matrix Metalloproteinase ◽  
Cell Viability ◽  
Human Skin ◽  
High Glucose ◽  
Quantitative Polymerase Chain Reaction ◽  
Skin Fibroblasts ◽  
Matrix Metalloproteinase 2 ◽  
Protective Effects ◽  
Human Skin Fibroblasts ◽  
Apoptosis Rate

The effects of Dendrobium polysaccharides (PDC) on the functions of human skin fibroblasts (HSFs) and expression of matrix metalloproteinase-2 under high-glucose conditions and exploration of the underlying mechanism remain unclear. We used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis and flow cytometry to evaluate the cell viability and apoptosis. The collagen levels were determined by the Sircol™ Collagen Assay. Real-time quantitative polymerase chain reaction (RT-PCR) was used to detect the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase inhibitor (TIMP-2) mRNA. We found the following: (1) under the high-glucose condition, the HSF cell viability, the expression of TIMP-2 mRNA, and the collagen levels were reduced, while the apoptosis rate and the expression of MMP-2 mRNA increased ( P < 0.05 ). (2) In the high-glucose + PDC group, the PDC reversed the changes in the collagen level, viability, and apoptosis rate of the HSF cells caused by high glucose, with the expression of protein and TIMP-2 mRNA increased and the level of MMP-2 mRNA decreased ( P < 0.05 ). This is the first time attempting to reveal that PDC can exhibit protective effects on HSF under high-glucose conditions, which may be related to the upregulation of the TIMP-2 expression and inhibition of the MMP-2 expression.

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