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

Huang, Zhengnan; Liu, Jiakuan; Yang, Jiale; Yan, Yi‐Lin; Yang, Chenkai; He, Xing; Huang, Ruimin; Tan, Mingyue; Wu, Denglong; Yan, Jun; Shen, Bing

doi:10.3389/fcell.2021.783050

Cited by 13 publications

(8 citation statements)

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“…It has been reported that PDE4B overexpression is associated with promoting the pathogenesis of hematologic malignancies and some solid tumors, such as colon cancer and bladder cancer [ 24 , 25 ]. However, few studies have explored the exact role of PDE4B in GC.…”

Section: Resultsmentioning

confidence: 99%

Loss of miR-26b-5p promotes gastric cancer progression via miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop

Xie

Jing

et al. 2023

J Transl Med

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Background Chronic inflammation is a well-known risk factor for the development of gastric cancer (GC). Nevertheless, the molecular mechanisms underlying inflammation-related GC progression are incompletely defined. Methods Bioinformatic analysis was performed based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and the expression of miR-26b-5p in GC cells and tissues was validated by quantitative real-time PCR (qRT-PCR). Cell proliferation was examined through Cell Counting Kit-8 (CCK8), 5-Ethynyl-2’-deoxyuridine (EdU), colony formation, flow cytometry, and tumor xenografts. Correlation between miR-26b-5p and Cyclin dependent kinase 8 (CDK8) or Phosphodiesterase 4B (PDE4B) was analyzed by dual-luciferase reporter assays, qRT-PCR, and Western blot. The effect of miR-26b-5p on the Signal transducer and activator of transcription 3 (STAT3) pathway was investigated using Western blot, immunofluorescence (IF), and immunohistochemistry (IHC). The impact of STAT3 on miR-26b-5p was determined by dual-luciferase reporter assays and qRT-PCR. Results The expression of miR-26b-5p was significantly downregulated in Helicobacter Pylori (H. pylori)-infected GC cells. The decreased expression of miR-26b-5p was also detected in GC cells and tissues compared to normal gastric epithelium cells (GES1) and normal adjacent gastric tissues. The low expression of miR-26b-5p promoted GC proliferation in vitro and in vivo and was related to the poor outcome of GC patients. In terms of mechanism, miR-26b-5p directly targeted PDE4B and CDK8, resulting in decreased phosphorylation and nuclear translocation of STAT3, which was associated with the regulation of GC proliferation by miR-26b-5p. Notably, miR-26b-5p was transcriptionally suppressed by STAT3, thus forming the miR-26b-5p-PDE4B/CDK8-STAT3 positive feedback loop. Conclusion The newly identified miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop plays an important role in inflammation-related GC progression and may serve as a promising therapeutic target for GC.

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Section: Resultsmentioning

confidence: 99%

Loss of miR-26b-5p promotes gastric cancer progression via miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop

Xie

Jing

et al. 2023

J Transl Med

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“…In addition, ORL1 also plays a role as a prognostic gene in the prognostic model of head and neck squamous cell carcinoma based on lipid metabolism-related genes ( Gao et al, 2021 ). It has been shown that PDE4B in our prognostic model gene induces epithelial-mesenchymal transition in bladder cancer cells and is transcriptionally repressed by CBX7 ( Huang et al, 2021 ). These results suggest that our prognostic genes play an important role in cancer, demonstrating that our model is of interest.The PCA and t-SNE plots showed that the model differentiated sufficiently between high- and low-risk groups.…”

Section: Discussionmentioning

confidence: 99%

Effects of immune inflammation in head and neck squamous cell carcinoma: Tumor microenvironment, drug resistance, and clinical outcomes

et al. 2022

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Background: Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor with a very high mortality rate, and a large number of studies have confirmed the correlation between inflammation and malignant tumors and the involvement of inflammation-related regulators in the progression of HNSCC. However, a prognostic model for HNSCC based on genes involved in inflammatory factors has not been established.Methods: First, we downloaded transcriptome data and clinical information from patients with head and neck squamous cell carcinoma from TCGA and GEO (GSE41613) for data analysis, model construction, and differential gene expression analysis, respectively. Genes associated with inflammatory factors were screened from published papers and intersected with differentially expressed genes to identify differentially expressed inflammatory factor-related genes. Subgroups were then typed according to differentially expressed inflammatory factor-related genes. Univariate, LASSO and multivariate Cox regression algorithms were subsequently applied to identify prognostic genes associated with inflammatory factors and to construct prognostic prediction models. The predictive performance of the model was evaluated by Kaplan-Meier survival analysis and receiver operating characteristic curve (ROC). Subsequently, we analyzed differences in immune composition between patients in the high and low risk groups by immune infiltration. The correlation between model genes and drug sensitivity (GSDC and CTRP) was also analyzed based on the GSCALite database. Finally, we examined the expression of prognostic genes in pathological tissues, verifying that these genes can be used to predict prognosis.Results: Using univariate, LASSO, and multivariate cox regression analyses, we developed a prognostic risk model for HNSCC based on 13 genes associated with inflammatory factors (ITGA5, OLR1, CCL5, CXCL8, IL1A, SLC7A2, SCN1B, RGS16, TNFRSF9, PDE4B, NPFFR2, OSM, ROS1). Overall survival (OS) of HNSCC patients in the low-risk group was significantly better than that in the high-risk group in both the training and validation sets. By clustering, we identified three molecular subtypes of HNSCC carcinoma (C1, C2, and C3), with C1 subtype having significantly better OS than C2 and C3 subtypes. ROC analysis suggests that our model has precise predictive power for patients with HNSCC. Enrichment analysis showed that the high-risk and low-risk groups showed strong immune function differences. CIBERSORT immune infiltration score showed that 25 related and differentially expressed inflammatory factor genes were all associated with immune function. As the risk score increases, specific immune function activation decreases in tumor tissue, which is associated with poor prognosis. We also screened for susceptibility between the high-risk and low-risk groups and showed that patients in the high-risk group were more sensitive to talazoparib-1259, camptothecin-1003, vincristine-1818, Azd5991-1720, Teniposide-1809, and Nutlin-3a (-) −1047.Finally, we examined the expression of OLR1, SCN1B, and PDE4B genes in HNSCC pathological tissues and validated that these genes could be used to predict the prognosis of HNSCC.Conclusion: In this experiment, we propose a prognostic model for HNSCC based on inflammation-related factors. It is a non-invasive genomic characterization prediction method that has shown satisfactory and effective performance in predicting patient survival outcomes and treatment response. More interdisciplinary areas combining medicine and electronics will be explored in the future.

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“…The present study found that embryonic development-related genes were prognostic risk factors for BLCA. Invasion and metastasis of BLCA are thought to be associated with EMT [30,31].Tumor cell stemness regulates tumor cell differentiation, proliferation, invasion and migration [4,[32][33][34].Numerous studies showed that cancer stem cells regulate EMT [35][36][37].Embryonic development is often closely related to stem cells and EMT [5,38,39]. Therefore, we established a micro-landscape of embryonic development-related genes for predicting prognostic risk in BLCA patients.…”

Section: Discussionmentioning

confidence: 99%

GATA2 as an outcome signature: promoting bladder cancer migration and inhibiting PD-L1 expression

Sun

2022

Preprint

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BackgroundEmbryonic development is regulated by stem cells, and epithelial-to-mesenchymal transition (EMT) is associated with cell stemness ; nevertheless, the EMT regulation by embryonic development-related genes has not been studied. Immune checkpoints exert an essential effect in tumor treatment ; however, their regulatory mechanisms have not been fully elucidated. MethodsWe obtained clinicopathological and transcriptome data from The Cancer Genome Atlas. Embryonic development- associated genes were obtained from The Human Gene Database. We identified genes using univariate Cox regression analysis and identified various subtypes using consensus clustering analysis. Immunoassays were performed using the CIBERSORT package and Estimation of Stromal and Immune cells in the Malignant Tumor tissues using an expression data algorithm. The least absolute shrinkage and selection operator algorithm and multivariate Cox regression analysis were adopted to generate the prognostic model. We used the OCLR and TIDE algorithms. We conducted functional experiments.ResultsTwenty-two embryonic development-associated genes were risk factors for bladder cancer, and their expression levels significantly correlated with the TNM stage. We assessed the extent of immune infiltration, regulation of immune checkpoints, and responses to immune checkpoint blockade based on these genes. These risk genes were associated with EMT and modulated immune checkpoints. Cellular experiments demonstrated that EVC2 and GATA2 drive BLCA invasion and migration. GATA2 regulated the PD-L1 expression.ConclusionWe identified three critical genes: RUNX2, GATA2 and EVC2. These three genes are related to EMT and immune cell infiltration and are independent prognostic elements for BLCA.

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

Cited by 13 publications

References 47 publications

Loss of miR-26b-5p promotes gastric cancer progression via miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop

Loss of miR-26b-5p promotes gastric cancer progression via miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop

Effects of immune inflammation in head and neck squamous cell carcinoma: Tumor microenvironment, drug resistance, and clinical outcomes

GATA2 as an outcome signature: promoting bladder cancer migration and inhibiting PD-L1 expression

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