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

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.

scholarly journals Differential Gene Expression in Bladder Tumors from Workers Occupationally Exposed to Arylamines

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Ramya T. Kolli ◽  
Zongli Xu ◽  
Vijayalakshmi Panduri ◽  
Jack A. Taylor
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Occupational Exposure ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Occupational Exposures ◽  
Bladder Tumors ◽  
Mesenchymal Transition ◽  
Custom Panel

Occupational exposure to the arylamines benzidine and β-naphthylamine increase bladder cancer risk up to 100-fold, making them some of the most powerful human carcinogens. We hypothesize that tumors arising in people with occupational exposures have different patterns of gene expression than histologically similar tumors from people without such exposures. In a case-case study, we compare gene expression in 22 formalin-fixed paraffin-embedded (FFPE) bladder tumors from men with high-level occupational exposure to arylamines to that in 26 FFPE bladder tumors from men without such exposure. Gene expression analysis was performed on the NanoString nCounter system using a PanCancer Progression Panel comprised of 740 cancer progression-related genes and a custom panel of 69 arylamine- and bladder cancer-related genes which were chosen from in vitro studies. Although fold differences were small, there was evidence of differential expression by exposure status for 17 genes from the Progression Panel and 4 genes from the custom panel. In total, 10 genes showed dose-response association at a p < 0.01 , of which 4 genes (CD46, NR4A1, BAX, and YWHAZ) passed a false discovery rate (FDR) q value cutoff of 0.05 but were not significant after Bonferroni correction. Overall, we find limited evidence for differentially expressed genes in pathways related to DNA damage signaling and epithelial-to-mesenchymal transition (EMT).

scholarly journals Mitofusin-2 modulates the epithelial to mesenchymal transition in thyroid cancer progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mi-Hyeon You ◽  
Min Ji Jeon ◽  
Seong ryeong Kim ◽  
Woo Kyung Lee ◽  
Sheue-yann Cheng ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Cancer Cell Lines ◽  
Migration And Invasion ◽  
Mitofusin 2 ◽  
Mesenchymal Transition

AbstractHere, we investigated the potential roles of Mitofusin-2 (MFN2) in thyroid cancer progression. MFN2 regulates mitochondrial fusion/division in cells and plays an important role in various aspects of cell metabolism. MFN2 might involve in cell cycle regulation, apoptosis, and differentiation, and it might play a role as a tumor suppressor in carcinogenesis. We evaluated the prognostic impacts of MFN2 expression in thyroid cancer by analyzing TCGA data. In vitro and in vivo, MFN2 was knocked out using CRISPR/Cas9 or siRNA, and MFN2 was stably overexpressed in two thyroid cancer cell lines (Cal62 and HTH83). TCGA analysis revealed that MFN2 expression was lower in thyroid cancer than in normal tissues and significantly associated with a degree of differentiation, RAS mutations, and less lymph node metastasis. MFN2 expression was significantly correlated with cell adhesion molecules and epithelial to mesenchymal transition (EMT) in a gene-set enrichment assay. MFN2 knock-out (KO) in Cal62 and HTH83 cells using CRISPR/Cas9 or siRNA significantly promoted cell migration and invasion in vitro. The same trends were observed in MFN2 KO mouse embryonic fibroblasts (MEFs) compared to those in the controls (MFN2 WT MEFs). Conversely, MFN2 overexpression in cancer cell lines greatly inhibited cell migration and invasion. However, there was no difference in colony formation and proliferation in Cal62 and HTH83 cells after modulating MFN2, although there were significant differences between MFN KO and WT MEFs. EMT-associated protein expression was induced after MFN2 KO in both cancer cell lines. The mechanistic results suggest that MFN2 might modulate EMT through inducing the AKT signaling pathway. EMT-associated changes in protein expression were also confirmed by modulating MFN2 in xenograft tumors. Thus, MFN2 acts as a tumor suppressor in thyroid cancer progression and metastasis by modulating EMT.

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

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1066 ◽  
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.

scholarly journals Sp1-Induced Upregulation of LBX2-AS1 Aggravates The Progression of Glioblastoma By Targeting The miR-491-5p/LIF Axis

2021 ◽  
Author(s):  
Wentao Li ◽  
Ismatullah Soufiany ◽  
Xiao Lyu ◽  
Lin Zhao ◽  
Chenfei Lu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Regulatory Effects

Abstract Background: Mounting evidences have shown the importance of lncRNAs in tumorigenesis and cancer progression. LBX2-AS1 is an oncogenic lncRNA that has been found abnormally expressed in gastric cancer and lung cancer samples. Nevertheless, the biological function of LBX2-AS1 in glioblastoma (GBM) and potential molecular mechanism are largely unclear. Methods: Relative levels of LBX2-AS1 in GBM samples and cell lines were detected by qRT-PCR and FISH. In vivo and in vitro regulatory effects of LBX2-AS1 on cell proliferation, epithelial-to-mesenchymal transition (EMT) and angiogenesis in GBM were examined through xenograft models and functional experiments, respectively. The interaction between Sp1 and LBX2-AS1 was assessed by ChIP. Through bioinformatic analyses, dual-luciferase reporter assay, RIP and Western blot, the regulation of LBX2-AS1 and miR-491-5p on the target gene leukemia Inhibitory factor (LIF) was identified. Results: LBX2-AS1 was upregulated in GBM samples and cell lines, and its transcription was promoted by binding to the transcription factor Sp1. As a lncRNA mainly distributed in the cytoplasm, LBX2-AS1 upregulated LIF, and activated the LIF/STAT3 signaling by exerting the miRNA sponge effect on miR-491-5p, thus promoting cell proliferation, EMT and angiogenesis in GBM. Besides, LBX2-AS1 was unfavorable to the progression of glioma and the survival. Conclusion: Upregulated by Sp1, LBX2-AS1 promotes the progression of GBM by targeting the miR-491-5p/LIF axis. It is suggested that LBX2-AS1 may be a novel diagnostic biomarker and therapeutic target of GBM.

scholarly journals Circular RNA CircPPP1CB Suppresses Tumorigenesis by Interacting With the MiR-1307-3p/SMG1 Axis in Human Bladder Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Feifan Wang ◽  
Yan Zhang ◽  
Xuejian Zhou ◽  
Xianwu Chen ◽  
Jiayong Xiang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Human Cancer ◽  
Circular Rna ◽  
Human Bladder Cancer ◽  
Human Bladder ◽  
Mesenchymal Transition ◽  
Circular Structure

Circular RNA (circRNA) is a newly discovered endogenous non-coding RNA (ncRNA), which is characterized with a closed circular structure. A growing body of evidence has verified the vital roles of circRNAs in human cancer. In this research, we selected circPPP1CB as a study object by circRNA sequencing and quantitative real-time PCR (qRT-PCR) validation in human bladder cancer (BC). CircPPP1CB is downregulated in BC and is negatively correlated with clinical stages and histological grades. Functionally, circPPP1CB modulated cell growth, metastasis, and epithelial-to-mesenchymal transition (EMT) process in vitro and in vivo. Mechanically, we performed various experiments to verify the circPPP1CB/miR-1307-3p/SMG1 regulatory axis. Taken together, our results demonstrated that circPPP1CB participates in tumor growth, metastasis, and EMT process by interacting with the miR-1307-3p/SMG1 axis, and that circPPP1CB might be a novel therapeutic target and diagnostic biomarker in human BC.

scholarly journals TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis

2017 ◽  
Vol 24 (11) ◽  
pp. 565-578 ◽  
Author(s):  
Hongqiang Wang ◽  
Rui Zhou ◽  
Li Sun ◽  
Jianling Xia ◽  
Xuchun Yang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Topoisomerase I ◽  
Target Genes ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Migration And Invasion ◽  
Glucose Transporter 1 ◽  
Mesenchymal Transition

Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I (TOP1MT) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT knockdown significantly promoted GC migration and invasion in vitro and in vivo. Importantly, TOP1MT silencing increased glucose consumption, lactate production, glucose transporter 1 expression and the epithelial-mesenchymal transition (EMT) in GC. Additionally, regulation of glucose metabolism induced by TOP1MT was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low TOP1MT expression was associated with lymph node metastasis, recurrence and high mortality rates. TOP1MT deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression.

(S,R)3-(4-Hydroxyphenyl)-4,5-Dihydro-5-Isoxazole Acetic Acid Methyl Ester Inhibits Epithelial-to-Mesenchymal Transition through TGF-β/Smad4 Axis in Nasopharyngeal Carcinoma

2021 ◽  
Vol 21 ◽  
Author(s):  
Qibing Chen ◽  
Yan Wang ◽  
Fen Li ◽  
Xiang Cheng ◽  
Yu Xiao ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Nasopharyngeal Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Immunofluorescence Assay ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Background: Macrophage migration inhibitory factor (MIF), originally reported as an inflammation regulating molecule, is elevated in various cancer cells, which may promote carcinogenesis. Meanwhile, ISO-1 is a potent small molecular inhibitor of MIF, which has not been investigated in nasopharyngeal carcinoma (NPC); hence the impact of ISO-1 on NPC cells remains to be illustrated. Objective: This study intended to explore the biological function of ISO-1 in NPC cells in vitro and prove a possibility of ISO-1 being a novel agent in NPC treatments. Methods: Gene expression of MIF in Head and Neck squamous cell carcinoma were obtained from The Cancer Genome Atlas (TCGA) database. Nasal pharyngeal tissues were collected from adult patients undergoing nasopharyngeal biopsy for MIF level detection. Proliferation of NPC cell lines 5-8B and 6-10B was studied using Cell Counting Kit-8 (CCK-8) assay and plate-colony-formation assay, apoptosis was determined by flow cytometry and TUNEL staining, migration and invasion capacities were measured by wound-healing assay and transwell assay, all to explore the function of ISO-1 in NPC cells in vitro. Epithelial-to-mesenchymal transition (EMT) level of NPC cells was determined by Western blot analysis and immunofluorescence assay. Results: Transcript level of MIF was significantly higher in head and neck squamous cell carcinoma. Protein MIF was overexpressed in human NPC tissues compared to non-cancerous ones, and its expression could be compromised by ISO-1 in vitro. 100μM ISO-1 significantly hindered NPC cells migration and invasion capacities in vitro but acted relatively poorly on proliferation and apoptosis. Immunofluorescence assay and Western blotting implied a down-regulated EMT level through TGF-β/Smad4 axis in ISO-1 treated NPC cells compared to the vehicle. Conclusion: This study indicated that MIF antagonist ISO-1 holds impact on NPC progression by influencing the migration and invasion of NPC cells ISO-1 inhibits the EMT process of NPC cells through TGF-β/Smad4 axis, supporting that prudent application of ISO-1 may be a potential adjuvant treatment for NPC.

scholarly journals CSN8 is a key regulator in hypoxia-induced epithelial–mesenchymal transition and dormancy of colorectal cancer cells

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Songwen Ju ◽  
Feng Wang ◽  
Yirong Wang ◽  
Songguang Ju
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Treatment Conditions ◽  
Colorectal Cancer Cells

AbstractHypoxic stress plays a pivotal role in cancer progression; however, how hypoxia drives tumors to become more aggressive or metastatic and adaptive to adverse environmental stress is still poorly understood. In this study, we revealed that CSN8 might be a key regulatory switch controlling hypoxia-induced malignant tumor progression. We demonstrated that the expression of CSN8 increased significantly in colorectal cancerous tissues, which was correlated with lymph node metastasis and predicted poor patient survival. CSN8 overexpression induces the epithelial-mesenchymal transition (EMT) process in colorectal cancer cells, increasing migration and invasion. CSN8 overexpression arrested cell proliferation, upregulated key dormancy marker (NR2F1, DEC2, p27) and hypoxia response genes (HIF-1α, GLUT1), and dramatically enhanced survival under hypoxia, serum deprivation, or chemo-drug 5-fluorouracil treatment conditions. In particular, silenced CSN8 blocks the EMT and dormancy processes induced by the hypoxia of 1% O2 in vitro and undermines the adaptive capacity of colorectal cancer cells in vivo. The further study showed that CSN8 regulated EMT and dormancy partly by activating the HIF-1α signaling pathway, which increased HIF-1α mRNA expression by activating NF-κB and stabilized the HIF-1α protein via HIF-1α de-ubiquitination. Taken together, CSN8 endows primary colorectal cancer cells with highly aggressive/metastatic and adaptive capacities through regulating both EMT and dormancy induced by hypoxia. CSN8 could serve as a novel prognostic biomarker for colorectal cancer and would be an ideal target of disseminated dormant cell elimination and tumor metastasis, recurrence, and chemoresistance prevention.

scholarly journals Silencing of lncRNA MIR497HG via CRISPR/Cas13d Induces Bladder Cancer Progression Through Promoting the Crosstalk Between Hippo/Yap and TGF-β/Smad Signaling

2020 ◽  
Vol 7 ◽  
Author(s):  
Changshui Zhuang ◽  
Ying Liu ◽  
Shengqiang Fu ◽  
Chaobo Yuan ◽  
Jingwen Luo ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Line ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Pathological Process ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion

A subset of long non-coding RNAs (lncRNAs), categorized as miRNA-host gene lncRNAs (lnc-miRHGs), is processed to produce miRNAs and involved in cancer progression. This work aimed to investigate the influences and the molecular mechanisms of lnc-miRHGs MIR497HG in bladder cancer (BCa). The miR-497 and miR-195 were derived from MIR497HG. We identified that lnc-miRHG MIR497HG and two harbored miRNAs, miR-497 and miR-195, were downregulated in BCa by analyzing The Cancer Genome Atlas and our dataset. Silencing of MIR497HG by CRISPR/Cas13d in BCa cell line 5637 promoted cell growth, migration, and invasion in vitro. Conversely, overexpression of MIR497HG suppressed cell progression in BCa cell line T24. MiR-497/miR-195 mimics rescued significantly the oncogenic roles of knockdown of MIR497HG by CRISPR/Cas13d in BCa. Mechanistically, miR-497 and miR-195 co-ordinately suppressed multiple key components in Hippo/Yap and transforming growth factor β signaling and particularly attenuated the interaction between Yap and Smad3. In addition, E2F4 was proven to be critical for silencing MIR497HG transcription in BCa cells. In short, we propose for the first time to reveal the function and mechanisms of MIR497HG in BCa. Blocking the pathological process may be a potential strategy for the treatment of BCa.

scholarly journals Dihydropyrimidinase Like 2 Promotes Bladder Cancer Progression via Pyruvate Kinase M2-Induced Aerobic Glycolysis and Epithelial–Mesenchymal Transition

2021 ◽  
Vol 9 ◽  
Author(s):  
Jun Zou ◽  
Ruiyan Huang ◽  
Yanfei Chen ◽  
Xiaoping Huang ◽  
Huajun Li ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Pyruvate Kinase ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Aerobic Glycolysis ◽  
Mesenchymal Transition ◽  
Bladder Cancer Cells ◽  
Malignant Behavior

BackgroundAerobic glycolysis and epidermal–mesenchymal transition (EMT) play key roles in the development of bladder cancer. This study aimed to investigate the function and the underlying mechanism of dihydropyrimidinase like 2 (DPYSL2) in bladder cancer progression.MethodsThe expression pattern of DPYSL2 in bladder cancer and the correlation of DPYSL2 expression with clinicopathological characteristics of bladder cancer patients were analyzed using the data from different databases and tissue microarray. Gain- and loss-of-function assays were performed to explore the role of DPYSL2 in bladder cancer progression in vitro and in mice. Proteomic analysis was performed to identify the interacting partner of DPYSL2 in bladder cancer cells.FindingsThe results showed that DPYSL2 expression was upregulated in bladder cancer tissue compared with adjacent normal bladder tissue and in more aggressive cancer stages compared with lower stages. DPYSL2 promoted malignant behavior of bladder cancer cells in vitro, as well as tumor growth and distant metastasis in mice. Mechanistically, DPYSL2 interacted with pyruvate kinase M2 (PKM2) and promoted the conversion of PKM2 tetramers to PKM2 dimers. Knockdown of PKM2 completely blocked DPYSL2-induced enhancement of the malignant behavior, glucose uptake, lactic acid production, and epithelial–mesenchymal transition in bladder cancer cells.InterpretationIn conclusion, the results suggest that DPYSL2 promotes aerobic glycolysis and EMT in bladder cancer via PKM2, serving as a potential therapeutic target for bladder cancer treatment.

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