Role of Periostin Expression in Canine Osteosarcoma Biology and Clinical Outcome

2021 ◽  
pp. 030098582199667
Author(s):  
Lauren N. Alfino ◽  
Kai C. Wilczewski-Shirai ◽  
Kathryn E. Cronise ◽  
Jonathan Coy ◽  
Kristina Glapa ◽  
...  
Keyword(s):  
Protein Expression ◽  
Epithelial Mesenchymal Transition ◽  
Inflammatory Diseases ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Matricellular Protein ◽  
Mesenchymal Transition ◽  
Canine Osteosarcoma ◽  
Normal Bone

Periostin is a matricellular protein important in regulating bone, tooth, and cardiac development. In pathologic conditions, periostin drives allergic and fibrotic inflammatory diseases and is also overexpressed in certain cancers. Periostin signaling in tumors has been shown to promote angiogenesis, metastasis, and cancer stem cell survival in rodent models, and its overexpression is associated with poor prognosis in human glioblastoma. However, the role of periostin in regulating tumorigenesis of canine cancers has not been evaluated. Given its role in bone development, we sought to evaluate mRNA and protein expression of periostin in canine osteosarcoma (OS) and assess its association with patient outcome. We validated an anti-human periostin antibody cross-reactive to canine periostin via western blot and immunohistochemistry and evaluated periostin expression in microarray data from 49 primary canine OS tumors and 8 normal bone samples. Periostin mRNA was upregulated greater than 40-fold in canine OS tumors compared to normal bone and was significantly correlated with periostin protein expression based on quantitative image analysis. However, neither periostin mRNA nor protein expression were associated with time to metastasis in this cohort. Gene Set Enrichment Analysis demonstrated significant enhancement of pro-tumorigenic pathways including canonical WNT signaling, epithelial-mesenchymal transition, and angiogenesis in periostin-high tumors, while periostin-low tumors demonstrated evidence of heightened antitumor immune responses. Overall, these data identify a novel antibody that can be used as a tool for evaluation of periostin expression in dogs and suggest that investigation of Wnt pathway-targeted drugs in periostin overexpressing canine OS may be a potential therapeutic target.

scholarly journals Identification of Epithelial–Mesenchymal Transition-Related Prognostic lncRNAs Biomarkers Associated With Melanoma Microenvironment

2021 ◽  
Vol 9 ◽  
Author(s):  
Bo Xiao ◽  
Liyan Liu ◽  
Zhuoyuan Chen ◽  
Aoyu Li ◽  
Pingxiao Wang ◽  
...  
Keyword(s):  
Cox Regression ◽  
Epithelial Mesenchymal Transition ◽  
Enrichment Analysis ◽  
Roc Curves ◽  
Risk Groups ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Mesenchymal Transition ◽  
Cox Regression Analysis ◽  
Kaplan Meier

Melanoma is the most common cancer of the skin, associated with a worse prognosis and distant metastasis. Epithelial–mesenchymal transition (EMT) is a reversible cellular biological process that plays significant roles in diverse tumor functions, and it is modulated by specific genes and transcription factors. The relevance of EMT-related lncRNAs in melanoma has not been determined. Therefore, RNA expression data and clinical features were collected from the TCGA database (N = 447). Melanoma samples were randomly assigned into the training (315) and testing sets (132). An EMT-related lncRNA signature was constructed via comprehensive analyses of lncRNA expression level and corresponding clinical data. The Kaplan-Meier analysis showed significant differences in overall survival in patients with melanoma in the low and high-risk groups in two sets. Receiver operating characteristic (ROC) curves were used to measure the performance of the model. Cox regression analysis indicated that the risk score was an independent prognostic factor in two sets. Besides, a nomogram was constructed based on the independent variables. Gene Set Enrichment Analysis (GSEA) was applied to evaluate the potential biological functions in the two risk groups. Furthermore, the melanoma microenvironment was evaluated using ESTIMATE and CIBERSORT algorithms in the risk groups. This study indicates that EMT-related lncRNAs can function as potential independent prognostic biomarkers for melanoma survival.

scholarly journals Identification of a Novel Epithelial-Mesenchymal Transition Gene Signature Regulated by KEAP1-NRF2 Pathway in Esophageal Carcinoma

2020 ◽  
Author(s):  
Mohamed Elshaer ◽  
Ahmed Hammad ◽  
Xiu Jun Wang ◽  
Xiuwen Tang
Keyword(s):  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Cell Line ◽  
Enrichment Analysis ◽  
Gene Signature ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Gene Set ◽  
Over Expression

Abstract BackgroundKEAP1-NRF2 pathway alterations were identified in many cancers including, esophageal cancer (ESCA). Identifying biomarkers that are associated with mutations in this pathway will aid in defining this cancer subset; and hence in supporting precision and personalized medicine. MethodsIn this study, 182 tumor samples from the Cancer Genome Atlas (TCGA)-ESCA RNA-Seq V2 level 3 data were segregated into two groups KEAP1-NRF2-mutated (22) and wild-type (160).The two groups were subjected to differential gene expression analysis, and we performed Gene Set Enrichment Analysis (GSEA) to determine all significantly affected biological pathways. Then, the enriched gene set was integrated with the differentially expressed genes (DEGs) to identify a gene signature regulated by the KEAP1-NRF2 pathway in ESCA. Furthermore, we validated the gene signature using mRNA expression data of ESCA cell lines provided by the Cancer Cell Line Encyclopedia (CCLE). The identified signature was tested in 3 independent ESCA datasets to assess its prognostic value.ResultsWe identified 11 epithelial-mesenchymal transition (EMT) genes regulated by the KEAP1-NRF2 pathway in ESCA patients. Five of the 11 genes showed significant over-expression in KEAP1-NRF2-mutated ESCA cell lines. In addition, the over-expression of these five genes was significantly associated with poor survival in 3 independent ESCA datasets, including the TCGA-ESCA dataset.ConclusionAltogether, we identified a novel EMT 5-gene signature regulated by the KEAP1-NRF2 axis and this signature is strongly associated with metastasis and drug resistance in ESCA. These 5-genes are potential biomarkers and therapeutic targets for ESCA patients in whom the KEAP1-NRF2 pathway is altered.

scholarly journals HCK promotes glioblastoma progression by TGFβ signaling

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Zhenlin Wang ◽  
Chenting Ying ◽  
Anke Zhang ◽  
Houshi Xu ◽  
Yang Jiang ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
B Lymphocyte ◽  
Epithelial Mesenchymal Transition ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Gene Set Enrichment Analysis ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition

Abstract The hematopoietic cell kinase (HCK), a member of the Src family protein-tyrosine kinases (SFKs), is primarily expressed in cells of the myeloid and B lymphocyte lineages. Nevertheless, the roles of HCK in glioblastoma (GBM) remain to be examined. Thus, we aimed to investigate the effects of HCK on GBM development both in vitro and in vivo, as well as the underlying mechanism. The present study found that HCK was highly expressed in both tumor tissues from patients with GBM and cancer cell lines. HCK enhanced cell viability, proliferation, and migration, and induced cell apoptosis in vitro. Tumor xenografts results also demonstrated that HCK knockdown significantly inhibited tumor growth. Interestingly, gene set enrichment analysis (GSEA) showed HCK was closed associated with epithelial mesenchymal transition (EMT) and TGFβ signaling in GBM. In addition, we also found that HCK accentuates TGFβ-induced EMT, suggesting silencing HCK inhibited EMT through the inactivation of Smad signaling pathway. In conclusion, our findings indicated that HCK is involved in GBM progression via mediating EMT process, and may be served as a promising therapeutic target for GBM.

Weighted correlation network analysis identifies FN1, COL1A1 and SERPINE1 associated with the progression and prognosis of gastric cancer

2021 ◽  
pp. 1-17
Author(s):  
Qiaoyun Zhao ◽  
Jun Xie ◽  
Jinliang Xie ◽  
Rulin Zhao ◽  
Conghua Song ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Correlation Network ◽  
Receptor Interaction ◽  
Hub Genes ◽  
Mesenchymal Transition ◽  
Weighted Correlation

BACKGROUND: Gastric cancer (GC) is one of the most deadliest tumours worldwide, and its prognosis remains poor. OBJECTIVE: This study aims to identify and validate hub genes associated with the progression and prognosis of GC by constructing a weighted correlation network. METHODS: The gene co-expression network was constructed by the WGCNA package based on GC samples and clinical data from the TCGA database. The module of interest that was highly related to clinical traits, including stage, grade and overall survival (OS), was identified. GO and KEGG pathway enrichment analyses were performed using the clusterprofiler package in R. Cytoscape software was used to identify the 10 hub genes. Differential expression and survival analyses were performed on GEPIA web resources and verified by four GEO datasets and our clinical gastric specimens. The receiver operating characteristic (ROC) curves of hub genes were plotted using the pROC package in R. The potential pathogenic mechanisms of hub genes were analysed using gene set enrichment analysis (GSEA) software. RESULTS: A total of ten modules were detected, and the magenta module was identified as highly related to OS, stage and grade. Enrichment analysis of magenta module indicated that ECM-receptor interaction, focal adhesion, PI3K-Akt pathway, proteoglycans in cancer were significantly enriched. The PPI network identified ten hub genes, namely COL1A1, COL1A2, FN1, POSTN, THBS2, COL11A1, SPP1, MMP13, COMP, and SERPINE1. Three hub genes (FN1, COL1A1 and SERPINE1) were finally identified to be associated with carcinogenicity and poor prognosis of GC, and all were independent risk factors for GC. The area under the curve (AUC) values of FN1, COL1A1 and SERPINE1 for the prediction of GC were 0.702, 0.917 and 0.812, respectively. GSEA showed that three hub genes share 15 common upregulated biological pathways, including hypoxia, epithelial mesenchymal transition, angiogenesis, and apoptosis. CONCLUSION: We identified FN1, COL1A1 and SERPINE1 as being associated with the progression and poor prognosis of GC.

scholarly journals Identification of an epithelial-mesenchymal transition-related lncRNA prognostic signature for patients with glioblastoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
XinJie Yang ◽  
Sha Niu ◽  
JiaQiang Liu ◽  
Jincheng Fang ◽  
ZeYu Wu ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cox Regression ◽  
Epithelial Mesenchymal Transition ◽  
Differential Expression Analysis ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Prognostic Signature ◽  
Mesenchymal Transition

AbstractGlioblastoma (GBM) is a strikingly heterogeneous and lethal brain tumor with very poor prognosis. LncRNAs play critical roles in the tumorigenesis of GBM through regulation of various cancer-related genes and signaling pathways. Here, we focused on the essential role of EMT and identified 78 upregulated EMT-related genes in GBM through differential expression analysis and Gene set enrichment analysis (GSEA). A total of 301 EMT-related lncRNAs were confirmed in GBM through Spearman correlation analysis and a prognostic signature consisting of seven EMT-related lncRNAs (AC012615.1, H19, LINC00609, LINC00634, POM121L9P, SNHG11, and USP32P3) was established by univariate and multivariate Cox regression analyses. Significantly, Kaplan–Meier analysis and receiver-operating-characteristic (ROC) curve validated the accuracy and efficiency of the signature to be satisfactory. Quantitative real-time (qRT)-PCR assay demonstrated the expression alterations of the seven lncRNAs between normal glial and glioma cell lines. Functional enrichment analysis revealed multiple EMT and metastasis-related pathways were associated with the EMT-related lncRNA prognostic signature. In addition, we observed the degree of immune cell infiltration and immune responses were significantly increased in high-risk subgroup compared with low-risk subgroup. In conclusion, we established an effective and robust EMT-related lncRNA signature which was expected to predict the prognosis and immunotherapy response for GBM patients.

scholarly journals Identification of a Novel Epithelial-mesenchymal Transition Gene Signature Regulated by KEAP1-NRF2 Pathway in Esophageal Carcinoma

2020 ◽  
Author(s):  
Mohamed Elshaer ◽  
Ahmed Hammad ◽  
Xiu Jun Wang ◽  
xiuwen Tang
Keyword(s):  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Cell Line ◽  
Enrichment Analysis ◽  
Gene Signature ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Gene Set ◽  
Over Expression

Abstract BackgroundKEAP1-NRF2 pathway alterations were identified in many cancers including, esophageal cancer (ESCA). Identifying biomarkers that are associated with mutations in this pathway will aid in defining this cancer subset; and hence in supporting precision and personalized medicine. MethodsIn this study, 182 tumor samples from the Cancer Genome Atlas (TCGA)-ESCA RNA-Seq V2 level 3 data were segregated into two groups KEAP1-NRF2-mutated (22) and wild-type (160).The two groups were subjected to differential gene expression analysis and we performed Gene Set Enrichment Analysis (GSEA). Then, the enriched gene set was integrated with the differentially expressed genes (DEGs) to identify a gene signature regulated by the KEAP1-NRF2 pathway in ESCA. Furthermore, we validated the gene signature using mRNA expression data of ESCA cell lines provided by the Cancer Cell Line Encyclopedia (CCLE). The identified signature was tested in 3 independent ESCA datasets to assess its prognostic value.ResultsWe identified 11 epithelial-mesenchymal transition (EMT) genes regulated by the KEAP1-NRF2 pathway in ESCA patients. Five of the 11 genes showed significant over-expression in KEAP1-NRF2-mutated ESCA cell lines. In addition, over-expression of these five genes was significantly associated with poor survival in 3 independent ESCA datasets, including the TCGA-ESCA dataset.ConclusionAltogether, we identified a novel EMT 5-gene signature regulated by the KEAP1-NRF2 axis and this signature is strongly associated with metastasis and drug resistance in ESCA. These 5-genes are potential biomarkers and therapeutic targets for ESCA patients in whom the KEAP1-NRF2 pathway is altered.

scholarly journals Six1 Promotes Epithelial-Mesenchymal Transition in Bronchial Epithelial Cells via the TGFβ1/Smad Signalling Pathway

2021 ◽  
pp. 1-10
Author(s):  
Wenxin Wang ◽  
Zhaochuan Yang ◽  
Meixiang Li ◽  
Zhenhong Wang ◽  
Yanchun Shan ◽  
...  
Keyword(s):  
Mouse Model ◽  
Protein Expression ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Signalling Pathway ◽  
Expression Vectors ◽  
Airway Remodelling ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition

Introduction: The homeodomain transcription factor sine oculis homeobox homolog 1 (Six1) plays a crucial role in embryogenesis and is not expressed in normal adult tissue but is expressed in many pathological processes, including airway remodelling in asthma. The current study aimed to reveal the effects of Six1 in regulating the airway remodelling and its possible mechanism. Methods: A mouse model of ovalbumin-induced asthma-associated airway wall remodelling and a bronchial epithelial cell (16HBE) model of transforming growth factor β1 (TGFβ1)-induced epithelial-mesenchymal transition (EMT) were used to investigate the role of Six1. Then, 16HBE cells were transformed with Six1 expression vectors and treated with a TGFβ1 pathway inhibitor to determine the role of Six1 in EMT. The effect of Six1 and its possible mechanism were assessed by immunohistochemistry, RT-PCR, and Western blot. Results: Six1 expression was elevated in the lungs in an OVA mouse model of allergic asthma and in 16HBE cells treated with TGFβ1. Six1 overexpression promoted an EMT-like phenotype with a decreased protein expression of E-cadherin and increased protein expression of α-smooth muscle actin (α-SMA) as well as fibronectin in 16HBE cells; these effects appeared to promote TGFβ1 and phospho-Smad2 (pSmad2) production, which are the main products of the TGFβ1/Smad signalling pathway, which could be reduced by a TGFβ1 inhibitor. Conclusion: These data reveal that Six1 and TGFβ1 are potentially a part of an autocrine feedback loop that induces EMT, and these factors can be reduced by blocking the TGFβ1/Smad signalling pathway. As such, these factors may represent a promising novel therapeutic target for airway remodelling in asthma.

scholarly journals Identification of An Epithelial-Mesenchymal Transition-Related lncRNA Prognostic Signature For Patients With Glioblastoma

2021 ◽  
Author(s):  
XinJie Yang ◽  
Sha Niu ◽  
JiaQiang Liu ◽  
ZeYu Wu ◽  
Shizhang Ling ◽  
...  
Keyword(s):  
High Risk ◽  
Signaling Pathways ◽  
Epithelial Mesenchymal Transition ◽  
Differential Expression Analysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Prognostic Signature ◽  
Mesenchymal Transition ◽  
Underlying Mechanisms

Abstract Purpose: Glioblastoma (GBM) is a class of strikingly heterogeneous and lethal brain tumor with very poor prognosis. LncRNAs play critical roles in the tumorigenesis and progression of GBM through regulation of various cancer-related genes and signaling pathways. Here, we aimed to establish an epithelial-mesenchymal transition (EMT)-related lncRNA signature for GBM and explore its underlying mechanisms. Methods: Differential expression analysis and Gene set enrichment analysis (GSEA) were performed to explore key genes and signaling pathways associated with GBM. Spearman correlation analysis, Univariate and multivariate Cox regression analyses were used to construct a lncRNA prognostic signature for GBM patients. Kaplan-Meier analysis and receiver-operating-characteristic (ROC) analysis were applied to assess the performance of the prognostic signature. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) enrichment analyses were performed to explore the underlying mechanisms of the signature. Single-sample GSEA (ssGSEA) was employed to explore the relationship of the signature and immune activities in GBM.Results: We focused on the essential role of EMT in GBM and identified 78 upregulated EMT-related genes in GBM. A total of 301 EMT-related lncRNAs were confirmed in GBM and a prognostic signature consisting of seven EMT-related lncRNAs (AC012615.1, H19, LINC00609, LINC00634, POM121L9P, SNHG11, and USP32P3) was established, which could divide GBM patients into low- and high-risk subgroups. The accuracy and efficiency of the signature were validated to be satisfactory. Functional enrichment analysis revealed multiple EMT and metastasis-related pathways were associated with the EMT-related lncRNA prognostic signature. In addition, we found the degree of immune cell infiltration and immune responses were significantly increased in high-risk subgroup compared with low-risk subgroup. Conclusion: we established an effective and robust EMT-related lncRNA signature which is expected to predict the prognosis and immunotherapy response for GBM patients.

scholarly journals Bioinformatics Analysis of Potential Biomarkers and Pathway Identification for Major Depressive Disorder

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Dong Qi ◽  
Kui Chen
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Hedgehog Signaling ◽  
Epithelial Mesenchymal Transition ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Gene Expression Omnibus ◽  
Gene Set Enrichment Analysis ◽  
Major Depressive ◽  
Mesenchymal Transition

Aiming at a more comprehensive understanding of the molecular biomarkers and potential mechanisms of major depressive disorder (MDD), from the Gene Expression Omnibus (GEO) database, we first obtained mRNA expression profiles and identified 585 differentially expressed genes (DEGs) through the R software, including 263 upregulated genes and 322 downregulated genes. Then, through the Kyoto Encyclopedia of Genome and Genome (KEGG) pathway and biological process (BP) analysis, we found that the upregulated and downregulated DEGs were abundant in different pathways, respectively. It was noteworthy that upregulated DEGs were the most significantly enriched in the mTOR signaling pathway. Subsequently, through the protein-protein interaction (PPI) network, we identified seven hub genes, namely, EXOSC2, CAMK2A, PRIM1, SMC4, TYMS, CDK6, and RPA2. Finally, through gene set enrichment analysis (GSEA), we obtained that hypoxia, epithelial-mesenchymal transition, hedgehog signaling, and reactive oxygen species pathway were the enriched pathways for MDD patients. The above data results would provide a new direction for the treatment of MDD patients.

scholarly journals Downregulation of RIPK4 Expression Inhibits Epithelial-Mesenchymal Transition in Ovarian Cancer through IL-6

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Huan Yi ◽  
Yan-zhao Su ◽  
Rong Lin ◽  
Xiang-qin Zheng ◽  
Diling Pan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Enrichment Analysis ◽  
Immunohistochemical Analysis ◽  
Suppressive Effect ◽  
Gene Set Enrichment Analysis ◽  
Multiple Cancer ◽  
Mesenchymal Transition ◽  
Interactive Analysis ◽  
Twist Expression

RIPK4 has been implicated in multiple cancer types, but its role in ovarian cancer (OC) has not been clearly elucidated. Our data from Gene Expression Profiling Interactive Analysis, RT-PCR, and immunohistochemical analysis showed that RIPK4 was expressed at higher levels in OC tissues and cells than in normal ovarian tissues and cells. Increased RIPK4 expression in OC markedly correlated with a worse overall survival than lower RIPK4 expression levels (hazard rate (HR) 1.5 (1.45–1.87); P = 0.001 ). In functional experiments, RIPK4 downregulation significantly inhibited metastatic behaviours in OC cells. Subsequently, based on data from 593 OC patients in the TCGA database, gene set enrichment analysis revealed that RIPK4 was involved in epithelial-mesenchymal transition (EMT) in OC. At the molecular level, silencing RIPK4 significantly downregulated vimentin, N-cadherin, and Twist expression but induced an increase in the protein level of E-cadherin and inhibited the IL-6 and STAT3 levels. Moreover, IL-6 levels were significantly decreased in RIPK4-silenced OC cells ( P < 0.05 ). The addition of IL-6 to OC cells rescued the suppressive effect of RIPK4 knockdown on EMT. Thus, our data illustrate that downregulation of RIPK4 expression can restrain EMT in OC by inhibiting IL-6. This finding may provide a novel diagnostic and therapeutic target for improving the poor prognoses of OC patients.

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