PDE4B Induces Epithelial-to-Mesenchymal Transition in Bladder Cancer Cells and Is Transcriptionally Suppressed by CBX7

Urinary bladder cancer (UBC) is a common malignant tumor with high incidence. Advances in the diagnosis and treatment of this disease demand the identification of novel therapeutic targets. Multiple studies demonstrated that PDE4B level was upregulated in malignancies and high PDE4B expression was correlated with poor outcomes. Herein, we identified that PDE4B was a potential therapeutic target in UBC. We confirmed that PDE4B expression was correlated with aggressive clinicopathological characteristics and unfavorable prognosis. Functional studies demonstrated that ectopic expression of PDE4B promoted UBC cells proliferation, migration and invasion, whereas PDE4B depletion suppressed cancer cell aggressiveness. We also identified CBX7 as a regulator of PDE4B to suppress the expression of PDE4B at the transcription level in a PRC1-dependent manner. Moreover, our results indicated that PDE4B induced epithelial-to-mesenchymal transition (EMT) in UBC cells via β-catenin pathway, whereas inhibition of PDE4B by its small molecule inhibitor, rolipram, effectively reversed the PDE4B overexpression-induced effects. To sum up, our results indicated that PDE4B acts as an oncogene by promoting UBC cell migration and invasion via β-catenin/EMT pathway.

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MiR-301b promotes the proliferation, mobility, and epithelial-to-mesenchymal transition of bladder cancer cells by targeting EGR1

Biochemistry and Cell Biology ◽

10.1139/bcb-2016-0232 ◽

2017 ◽

Vol 95 (5) ◽

pp. 571-577 ◽

Cited By ~ 16

Author(s):

Lei Yan ◽

Yan Wang ◽

Jun Liang ◽

Zhixin Liu ◽

Xiaodong Sun ◽

...

Keyword(s):

Bladder Cancer ◽

Epithelial To Mesenchymal Transition ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Luciferase Reporter Gene ◽

Mesenchymal Transition ◽

Normal Tissues ◽

Early Growth Response Gene ◽

Bladder Cancer Cells ◽

Related Proteins

We investigated the role of miR-301b in the modulation of the proliferation, migration, and invasion of bladder cancer (BLCA) cells. The expression of miR-301b and EGR1 (early growth response gene 1) mRNA were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). A dual-luciferase reporter gene system was used to identify the target relationship between miR-301b and EGR1. Cell proliferation, cell cycle, and apoptosis were analyzed by MTT assay, colony-forming assay, and flow cytometry, respectively. Cell motility and invasiveness were assessed by wound healing and Transwell assays. The expression of proteins involved in epithelial-to-mesenchymal transition (EMT) and EGR1 were determined by Western blot. Our results showed that miR-301b was up-regulated while EGR1 was down-regulated in BLCA tissues compared with adjacent normal tissues. The proliferation, migration, and invasiveness of T24 cells (a kind of human BLCA cell) were suppressed by decreasing miR-301b expression or increasing EGR1 expression. In addition, miR-301b promoted EMT signaling by influencing the expression of related proteins. In conclusion, miR-301b promotes the proliferation, migration, and aggressiveness of human BLCA cells by inhibiting the expression of EGR1.

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Repurposing Penfluridol in Combination with Temozolomide for the Treatment of Glioblastoma

Cancers ◽

10.3390/cancers11091310 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1310 ◽

Cited By ~ 3

Author(s):

Kim ◽

Chong ◽

Ryu ◽

Park ◽

Yu ◽

...

Keyword(s):

Treatment Group ◽

Antitumor Effect ◽

Epithelial To Mesenchymal Transition ◽

Treatment Strategies ◽

Antipsychotic Agent ◽

Therapeutic Modality ◽

Migration And Invasion ◽

Dependent Manner ◽

Mesenchymal Transition

Despite the presence of aggressive treatment strategies, glioblastoma remains intractable, warranting a novel therapeutic modality. An oral antipsychotic agent, penflurido (PFD), used for schizophrenia treatment, has shown an antitumor effect on various types of cancer cells. As glioma sphere-forming cells (GSCs) are known to mediate drug resistance in glioblastoma, and considering that antipsychotics can easily penetrate the blood-brain barrier, we investigated the antitumor effect of PFD on patient-derived GSCs. Using five GSCs, we found that PFD exerts an antiproliferative effect in a time- and dose-dependent manner. At IC50, spheroid size and second-generation spheroid formation were significantly suppressed. Stemness factors, SOX2 and OCT4, were decreased. PFD treatment reduced cancer cell migration and invasion by reducing the Integrin α6 and uPAR levels and suppression of the expression of epithelial-to-mesenchymal transition (EMT) factors, vimentin and Zeb1. GLI1 was found to be involved in PFD-induced EMT inhibition. Furthermore, combinatorial treatment of PFD with temozolomide (TMZ) significantly suppressed tumor growth and prolonged survival in vivo. Immunostaining revealed decreased expression of GLI1, SOX2, and vimentin in the PFD treatment group but not in the TMZ-only treatment group. Therefore, PFD can be effectively repurposed for the treatment of glioblastoma by combining it with TMZ.

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Taraxasterol inhibits TGF-β1-induced epithelial-to-mesenchymal transition in papillary thyroid cancer cells through regulating the Wnt/β-catenin signaling

Human & Experimental Toxicology ◽

10.1177/09603271211023792 ◽

2021 ◽

pp. 096032712110237

Author(s):

J Zhu ◽

X Li ◽

S Zhang ◽

J Liu ◽

X Yao ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Epithelial To Mesenchymal Transition ◽

Suppressive Effect ◽

Migration And Invasion ◽

Dependent Manner ◽

Papillary Thyroid ◽

Concentration Dependent Manner ◽

Mesenchymal Transition ◽

Tgf Β1

Taraxasterol (TAR) is a kind of active compound extracted from dandelion and its molecular structure resembles steroid hormones. Recently, TAR has been reported to show an anti-tumor activity. However, the specific role of TAR in papillary thyroid cancer (PTC) has not been clarified. In this study, we investigated the effect of TAR on PTC cell migration, invasion and epithelial-to-mesenchymal transition (EMT) induced by TGF-β1. PTC cells were exposed to TGF-β1 (5 ng/mL) and then treated with different concentrations of TAR. We found that TAR showed no obvious cytotoxicity below 10 μg/mL but notably reduced migration and invasion of TGF-β1-treated PTC cells. Moreover, TAR treatment decreased MMP-2 and MMP-9 levels, and obviously affected the expression of EMT markers. We also observed that Wnt3a and β-catenin levels were significantly increased in TGF-β1-treated PTC cells while TAR inhibited these effects in a concentration-dependent manner. Additionally, activation of the Wnt pathway by LiCl attenuated the suppressive effect of TAR on TGF-β1-induced migration, invasion and EMT in PTC cells. Taken together, we highlighted that TAR could significantly suppress TGF-β1-regulated migration and invasion by reversing the EMT process via the Wnt/β-catenin pathway, suggesting that TAR may be a potential anti-cancer agent for PTC treatment.

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CBX7 suppresses urinary bladder cancer progression via modulating AKR1B10–ERK signaling

Cell Death and Disease ◽

10.1038/s41419-021-03819-0 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Zhengnan Huang ◽

Yilin Yan ◽

Zhen Zhu ◽

Jiakuan Liu ◽

Xiao He ◽

...

Keyword(s):

Bladder Cancer ◽

Urinary Bladder ◽

Cancer Cell ◽

Cancer Progression ◽

Ectopic Expression ◽

Tumor Development ◽

Urinary Bladder Cancer ◽

Promoter Hypermethylation ◽

Erk Signaling ◽

Dependent Manner

AbstractThe chromobox (CBX) proteins mediate epigenetic gene silencing and have been implicated in the cancer development. By analyzing eight CBX family members in TCGA dataset, we found that chromobox 7 (CBX7) was the most strikingly downregulated CBX family member in urinary bladder cancer (UBC), as compared to normal tissues. Though dysregulation of CBX7 has been reported in multiple cancers, its specific role and clinical relevance in UBC remain unclear. Herein, we found that frequent downregulation of CBX7 in UBC specimens, which was due to its promoter hypermethylation, was correlated with poor prognosis. The ectopic expression of CBX7 suppressed UBC cell proliferation, migration, invasion, and cancer stemness, whereas CBX7 depletion promoted cancer cell aggressiveness. Importantly, CBX7 overexpression in UBC cells inhibited tumorigenicity, whereas CBX7 depletion promoted the tumor development, indicating its tumor-suppressive role in UBC. Using RNA-seq and chromosome immunoprecipitation (ChIP) assays, we identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of CBX7, which was negatively modulated by CBX7 in a PRC1-dependent manner and involved in stimulating ERK signaling. Consistently, AKR1B10 overexpression induced cancer cell aggressiveness, whereas suppression of AKR1B10 by siRNA or its small molecular inhibitor, oleanolic acid, reversed the CBX7 deficiency-induced cellular effects. AKR1B10 overexpression was negatively associated with CBX7 downregulation and predicted poor clinical outcomes in UBC patients. Taken together, our results indicate that CBX7 functions as a tumor suppressor to downregulate AKR1B10 and further inactivates ERK signaling. This CBX7/AKR1B10/ERK signaling axis may provide a new therapeutic strategy against UBC.

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Hic-5 promotes invadopodia formation and invasion during TGF-β–induced epithelial–mesenchymal transition

The Journal of Cell Biology ◽

10.1083/jcb.201108143 ◽

2012 ◽

Vol 197 (3) ◽

pp. 421-437 ◽

Cited By ~ 99

Author(s):

Jeanine Pignatelli ◽

David A. Tumbarello ◽

Ronald P. Schmidt ◽

Christopher E. Turner

Keyword(s):

Cell Migration ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Ectopic Expression ◽

Migration And Invasion ◽

Dependent Manner ◽

Matrix Degradation ◽

Mesenchymal Transition ◽

Cell Migration And Invasion ◽

Invadopodia Formation

Transforming growth factor β (TGF-β)–stimulated epithelial–mesenchymal transition (EMT) is an important developmental process that has also been implicated in increased cell invasion and metastatic potential of cancer cells. Expression of the focal adhesion protein Hic-5 has been shown to be up-regulated in epithelial cells in response to TGF-β. Herein, we demonstrate that TGF-β–induced Hic-5 up-regulation or ectopic expression of Hic-5 in normal MCF10A cells promoted increased extracellular matrix degradation and invasion through the formation of invadopodia. Hic-5 was tyrosine phosphorylated in an Src-dependent manner after TGF-β stimulation, and inhibition of Src activity or overexpression of a Y38/60F nonphosphorylatable mutant of Hic-5 inhibited matrix degradation and invasion. RhoC, but not RhoA, was also required for TGF-β– and Hic-5–induced matrix degradation. Hic-5 also induced matrix degradation, cell migration, and invasion in the absence of TGF-β via Rac1 regulation of p38 MAPK. These data identify Hic-5 as a critical mediator of TGF-β–stimulated invadopodia formation, cell migration, and invasion.

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Desloratadine, a Novel Antigrowth Reagent for Bladder Cancer

Technology in Cancer Research & Treatment ◽

10.1177/1533033820926591 ◽

2020 ◽

Vol 19 ◽

pp. 153303382092659 ◽

Cited By ~ 1

Author(s):

Jianfeng Ma ◽

Jinchun Qi ◽

Shoubin Li ◽

Chaohua Zhang ◽

Haijiang Wang ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Growth ◽

Anticancer Activity ◽

Interleukin 6 ◽

Migration And Invasion ◽

Dependent Manner ◽

Induce Cell Cycle Arrest ◽

Mesenchymal Transition ◽

E Cadherin

Desloratadine, a potent antagonist for human histamine H1 receptor, has been revealed to exhibit antihistaminic activity and anti-inflammatory activity. However, it is not yet known whether desloratadine has any effect on the biological behaviors of tumor cells. In this study, we aimed to investigate the effects of desloratadine on cell growth and invasion in bladder cancer EJ and SW780 cells in vitro. We observed that desloratadine inhibited cell viability of EJ and SW780 cells in a dose- and time-dependent manner. Desloratadine treatment was also revealed to suppress colony-formation ability and induce cell cycle arrest at G1 phase in EJ cells. Desloratadine promoted cell apoptosis via modulating the expression of Bcl-2, Bax, cleaved caspase 3, and cleaved caspase 9 in EJ and SW780 cells. Western blot resulted showed that desloratadine also impaired the expression of autophagy-related proteins, such as Beclin 1, P62, and LC3I/II in EJ and SW780 cells; while autophagy inhibitor LY294002 reversed the effects of desloratadine on these proteins. Moreover, desloratadine remarkably attenuated cell migration and invasion. Furthermore, we illustrated that desloratadine downregulated the expression of N-cadherin, Vimentin, Snail1, and Snail2, while upregulated the expression of E-cadherin in EJ and SW780 cells in vitro. The level of interleukin 6 was reduced in desloratadine-treated cells, while upregulation of interleukin 6 significantly abolished the anticancer activity of desloratadine in cell invasion and Bcl-2, Bax, Beclin1, LC3-I/II, N-cadherin, and E-cadherin expression in EJ cells. Taken together, our data suggest a potential anticancer activity of desloratadine on cell growth and invasion for bladder cancer, which may be mediated by diminishing the epithelial-to-mesenchymal transition and interleukin 6.

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SENP3 Promotes Bladder Cancer Proliferation and EMT Transformation by Affecting the Expression of PYCR1 via DeSUMOylation of STAT3

10.21203/rs.3.rs-875422/v1 ◽

2021 ◽

Author(s):

Zhuo Li ◽

Jian Liu ◽

Huifeng Fu ◽

Yuanwei Li ◽

Qaing Lu ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Progression ◽

Protein Level ◽

Epithelial To Mesenchymal Transition ◽

Migration And Invasion ◽

Cancer Proliferation ◽

Mesenchymal Transition ◽

Activity Factor ◽

Carcinogenic Effects

Abstract Abnormal activation of signal transducer and activator of transcription 3 (STAT3) has been found in various types of human cancers, including bladder cancer (BC). In our study, we examined the regulation of STAT3 post-translational modifications (PTMs) and found that SENP3 is high in bladder cancer. SENP3 and STAT3 were highly expressed in BC tissues when compared with tissue adjacent to carcinoma. SENP3 induced STAT3 protein level and p-STAT3 translocating into nuclear through deSUMOylation of STAT3. Further, nuclear STAT3, as a transcriptional activity factor, promoted pyrroline-5-carboxylate reductase 1 PYCR1 gene and protein level by interacting with the promoter of (PYCR1). Next, we found that knockdown of PYCR1 inhibited Epithelial to mesenchymal transition of bladder cancer, and simultaneously mitigated the carcinogenic effects of STAT3. In vitro, STAT3 knockdown in bladder cancer cells inhibited cell proliferation, migration, and invasion. In contrast, SENP3 overexpression reversed these effects. In all, results lend novel insights into the regulation of STAT3, which has key roles in bladder cancer progression.

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Sirtuins’ Deregulation in Bladder Cancer: SIRT7 Is Implicated in Tumor Progression through Epithelial to Mesenchymal Transition Promotion

Cancers ◽

10.3390/cancers12051066 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1066 ◽

Cited By ~ 2

Author(s):

Sara Monteiro-Reis ◽

Ana Lameirinhas ◽

Vera Miranda-Gonçalves ◽

Diana Felizardo ◽

Paula C. Dias ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Biology ◽

Epithelial To Mesenchymal Transition ◽

Cohort Analysis ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Age Related ◽

Normal Bladder ◽

E Cadherin

Sirtuins are emerging players in cancer biology and other age-related disorders, and their putative role in bladder cancer (BlCa) remains elusive. Further understanding of disease biology may allow for generation of more effective pathway-based biomarkers and targeted therapies. Herein, we aimed to illuminate the role of sirtuins’ family in BlCa and evaluate their potential as disease biomarkers and therapeutic targets. SIRT1-7 transcripts and protein levels were evaluated in a series of primary BlCa and normal bladder mucosa tissues. SIRT7 knockdown was performed through lentiviral transduction in MGHU3, 5637 and J82 cells and its functional role was assessed. SIRT1, 2, 4 and 5 expression levels were significantly lower in BlCa, whereas SIRT6 and 7 were overexpressed, and these results were corroborated by TCGA cohort analysis. SIRT7 transcript levels were significantly decreased in muscle-invasive vs. papillary BlCa. In vitro studies showed that SIRT7 downregulation promoted cells migration and invasion. Accordingly, increased EMT markers expression and decreased E-Cadherin (CDH1) was observed in those BlCa cells. Moreover, increased EZH2 expression and H3K27me3 deposition in E-Cadherin promoter was found in sh-SIRT7 cells. We demonstrated that sirtuins are globally deregulated in BlCa, and specifically SIRT7 downregulation is implicated in EMT, fostering BlCa invasiveness through EZH2-CDH1 axis.

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The dark-side of the outside: how extracellular heat shock proteins promote cancer

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03764-3 ◽

2021 ◽

Author(s):

Laura Seclì ◽

Federica Fusella ◽

Lidia Avalle ◽

Mara Brancaccio

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Epithelial To Mesenchymal Transition ◽

Dark Side ◽

Migration And Invasion ◽

Protein Activity ◽

Tumour Immunity ◽

Mesenchymal Transition ◽

Cancer Hallmarks ◽

Shock Proteins

AbstractIn addition to exerting several essential house-keeping activities in the cell, heat shock proteins (HSPs) are crucial players in a well-structured molecular program activated in response to stressful challenges. Among the different activities carried out by HSPs during emergency, they reach the extracellular milieu, from where they scout the surroundings, regulate extracellular protein activity and send autocrine and paracrine signals. Cancer cells permanently experience stress conditions due to their altered equilibrium and behaviour, and constantly secrete heat shock proteins as a result. Other than supporting anti-tumour immunity, extracellular heat shock proteins (eHSPs), can also exacerbate cancer cell growth and malignancy by sustaining different cancer hallmarks. eHSPs are implicated in extracellular matrix remodelling, resistance to apoptosis, promotion of cell migration and invasion, induction of epithelial to mesenchymal transition, angiogenesis and activation of stromal cells, supporting ultimately, metastasis dissemination. A broader understanding of eHSP activity and contribution to tumour development and progression is leading to new opportunities in the diagnosis and treatment of cancer.

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Study of LBHD1 Expression with Invasion and Migration of Bladder Cancer

Open Life Sciences ◽

10.1515/biol-2019-0049 ◽

2019 ◽

Vol 14 (1) ◽

pp. 440-447

Author(s):

Chunhui Dong ◽

Yihui Liu ◽

Guiping Yu ◽

Xu Li ◽

Ling Chen

Keyword(s):

Cell Proliferation ◽

Bladder Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Tumor Antigens ◽

Urinary Bladder Cancer ◽

Migration And Invasion ◽

Cell Migration And Invasion ◽

Invasion And Migration ◽

Bladder Cancer Cells

AbstractLBHD1 (C11ORF48) is one of the ten potential tumor antigens identified by immunoscreening the urinary bladder cancer cDNA library in our previous study. We suspect that its expression is associated with human bladder cancer. However, the exact correlation remains unclear. To address the potential functional relationship between LBHD1 and bladder cancer, we examined the LBHD1 expression at the mRNA and protein level in 5 different bladder cancer cell lines: J82, T24, 253J, 5637, and BLZ-211. LBHD1 high and low expressing cells were used to investigate the migration, invasion, and proliferation of bladder cancer cells following transfection of LBHD1 with siRNA and plasmids, respectively. Our experiment showed that the degree of gene expression was positively related to the migration and invasion of the cancer cells while it had little effect on cell proliferation. Knocking down LBHD1 expression with LBHD1 siRNA significantly attenuated cell migration and invasion in cultured bladder cancer cells, and overexpressing LBHD1 with LBHD1 cDNA plasmids exacerbated cell migration and invasion. Nevertheless, a difference in cell proliferation after transfection of LBHD1 siRNA and LBHD1 cDNA plasmids was not found. Our findings suggest that LBHD1 might play a role in cell migration and invasion.

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