COPB2: A Novel Prognostic Biomarker That Affects Progression of HCC

Purpose. This study is aimed at investigating the expression, underlying biological function, and clinical significance of coatomer protein complex subunit beta 2 (COPB2) in hepatocellular carcinoma (HCC). Methods. HCC-related data were extracted from The Cancer Genome Atlas (TCGA) database, International Cancer Genome Consortium (ICGC) database, and Gene Expression Omnibus (GEO) database. A logistic regression module was applied to analyze the relationship between the expression of COPB2 and clinicopathologic characteristics. The Cox proportional hazard regression model and Kaplan–Meier method were used for survival analysis. Gene set enrichment analysis (GSEA) was used to annotate the underlying biological functions. Loss-of-function experiments were conducted to determine the underlying mechanisms. Results. COPB2 was overexpressed in HCC, and high expression of COPB2 was significantly correlated with higher alpha fetoprotein (AFP) (odds ratio OR = 1.616 , >20 vs. ≤20, p < 0.05 ), stage ( OR = 1.744 , III vs. I, p < 0.05 ), and grade ( OR = 1.746 , G4+G3 vs. G2+G1, p < 0.05 ). Kaplan–Meier survival analysis showed that HCC patients with high COPB2 expression had a worse prognosis than those with low COPB2 expression ( p < 0.0001 for TCGA cohort, p < 0.05 for ICGC cohort). The univariate Cox (hazard ratio HR = 1.068 , p < 0.0001 ) and multivariate Cox ( HR = 2.011 , p < 0.05 ) regression analyses suggested that COPB2 was an independent risk factor. GSEA showed that mTOR and other tumor-related signaling pathways were differentially enriched in the high COPB2 expression phenotype. Silencing of COPB2 inhibited the proliferation, migration, and invasion abilities by suppressing epithelial-mesenchymal transition and mTOR signaling. Conclusion. COPB2 is a novel prognostic biomarker and a promising therapeutic target for HCC.

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Co-Expression of Coxsackievirus/Adenovirus Receptors and Desmoglein 2 in Lung Adenocarcinoma: A Comprehensive Analysis of Bioinformatics and Tissue Microarrays

Journal of Clinical Medicine ◽

10.3390/jcm9113693 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3693

Author(s):

Ching-Fu Weng ◽

Chi-Jung Huang ◽

Mei-Hsuan Wu ◽

Henry Hsin-Chung Lee ◽

Thai-Yen Ling

Keyword(s):

Overall Survival ◽

Survival Analysis ◽

Lung Adenocarcinoma ◽

Cox Regression ◽

Epithelial Mesenchymal Transition ◽

Early Stage ◽

The Cancer Genome Atlas ◽

Cancer Tissue ◽

Mesenchymal Transition ◽

Kaplan Meier

Introduction: Coxsackievirus/adenovirus receptors (CARs) and desmoglein-2 (DSG2) are similar molecules to adenovirus-based vectors in the cell membrane. They have been found to be associated with lung epithelial cell tumorigenesis and can be useful markers in predicting survival outcome in lung adenocarcinoma (LUAD). Methods: A gene ontology enrichment analysis disclosed that DSG2 was highly correlated with CAR. Survival analysis was then performed on 262 samples from the Cancer Genome Atlas, forming “Stage 1A” or “Stage 1B”. We therefore analyzed a tissue microarray (TMA) comprised of 108 lung samples and an immunohistochemical assay. Computer counting software was used to calculate the H-score of the immune intensity. Cox regression and Kaplan–Meier analyses were used to determine the prognostic value. Results: CAR and DSG2 genes are highly co-expressed in early stage LUAD and associated with significantly poorer survival (p = 0.0046). TMA also showed that CAR/DSG2 expressions were altered in lung cancer tissue. CAR in the TMA was correlated with proliferation, apoptosis, and epithelial–mesenchymal transition (EMT), while DSG2 was associated with proliferation only. The Kaplan–Meier survival analysis revealed that CAR, DSG2, or a co-expression of CAR/DSG2 was associated with poorer overall survival. Conclusions: The co-expression of CAR/DSG2 predicted a worse overall survival in LUAD. CAR combined with DSG2 expression can predict prognosis.

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GPD1L Suppresses Colon Adenocarcinoma Via Repressing TGFβ1/EMT

10.21203/rs.3.rs-1120400/v1 ◽

2021 ◽

Author(s):

Yunqi Li ◽

Minghao Liu ◽

zhu xiang ◽

Xuhui Yang ◽

Hui Liu

Keyword(s):

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Colon Adenocarcinoma ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Human Beings ◽

Mesenchymal Transition ◽

Adenocarcinoma Cells ◽

Colon Adenocarcinoma Cells

Abstract Colon adenocarcinoma is one of the most prevalent malignant tumors in human beings. Hence, the identification of valuable biomarkers and therapeutic targets is vital for improved treatment and patient outcomes. The role of glycerol-3-phosphate dehydrogenase 1-like (GPD1L) in several tumors has been achieved in recent years. However, the underlying mechanisms of GPD1L in colon adenocarcinoma remain elusive. In this study, we identified that GPD1L was associated with better prognosis in colon adenocarcinoma patients using gene expression omnibus (GEO) and the cancer genome atlas (TCGA) database. In addition, knockdown of GPD1L promoted the proliferation, migration and invasion and reversed by re-expression GPD1L in colon adenocarcinoma cells in vitro. According to gene set enrichment analysis (GSEA), GPD1L is closely correlated with transforming growth factor-β (TGFβ) signaling pathway in colon adenocarcinoma. Moreover, GPD1L downregulates epithelial mesenchymal transition (EMT) marker proteins via TGFβ1 due to Western blot analysis. These findings demonstrate that GPD1L inhibits the growth of colon adenocarcinoma cells by inhibiting EMT induced by TGFβ1. GPD1L may be a promising molecular target for the treatment of colon adenocarcinoma patients.

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NKCC1 involvement in the epithelial-to-mesenchymal transition is a prognostic biomarker in gliomas

PeerJ ◽

10.7717/peerj.8787 ◽

2020 ◽

Vol 8 ◽

pp. e8787

Author(s):

Huaiyu Sun ◽

Shengrong Long ◽

Bingbing Wu ◽

Jia Liu ◽

Guangyu Li

Keyword(s):

Epithelial Mesenchymal Transition ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

High Expression ◽

Migration And Invasion ◽

Intracranial Tumors ◽

Transwell Assay ◽

Western Blots ◽

Mesenchymal Transition ◽

Expression Levels

Background Gliomas are the most prevalent type of intracranial tumors. NKCC1 is an important regulator in tumor cell volume. We noticed that abnormally high NKCC1 expression resulted in changes in the shape and adhesion of glioma cells. However, little is known about the role of NKCC1 in the epithelial-mesenchymal transition (EMT) of gliomas. This study aims to clarify the biological function of NKCC1 in glioblastoma multiforme (GBM) progression. Methods Using data from The Cancer Genome Atlas (TCGA), we performed a Kaplan–Meier analysis on NKCC1 expression levels to estimate the rate of survival of mesenchymal GBM patients. The correlation between NKCC1 and EMT-related proteins was analyzed from the Gene Expression Profiling Interactive Analysis (GEPIA) server. We conducted Gene Set Enrichment Analysis (GSEA) to verify molecular signatures and pathways. We then studied the expression of NKCC1 in grade I–IV glioma tissue samples collected from patients using immunohistochemistry (IHC). Finally, we evaluated the effects of NKCC1 migration and invasion on the cellular behaviors of U251 cells using the transwell assay and western blots. Results High NKCC1 expression was associated with poor prognoses in mesenchymal GBM. Our results suggest a correlation between NKCC1 and EMT-protein markers: CDH2 and VIM. GSEA showed that gliomas, TGF-beta signaling and EMT were enriched in the NKCC1 high expression phenotype. Higher expression levels of NKCC1 in gliomas correlate with higher glioma grades. Transwell assay and western blot results demonstrated that the knockdown of NKCC1 led to a reduction in migration and invasion, while also inhibiting MMP-2 and MMP-9 expression in U251. Conclusion These results suggest that high expression of NKCC1 regulates EMT in gliomas, providing a new therapeutic strategy for addressing the spread of gliomas by inhibiting the spread of intracranial tumors.

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Overexpressed P75CUX1 promotes EMT in glioma infiltration by activating β-catenin

Cell Death and Disease ◽

10.1038/s41419-021-03424-1 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Anqi Xu ◽

Xizhao Wang ◽

Jie Luo ◽

Mingfeng Zhou ◽

Renhui Yi ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Tumor Grade ◽

Prognostic Indicator ◽

Migration And Invasion ◽

Poor Overall Survival ◽

Mesenchymal Transition ◽

Kaplan Meier ◽

Homeobox Protein

AbstractThe homeobox protein cut-like 1 (CUX1) comprises three isoforms and has been shown to be involved in the development of various types of malignancies. However, the expression and role of the CUX1 isoforms in glioma remain unclear. Herein, we first identified that P75CUX1 isoform exhibited consistent expression among three isoforms in glioma with specifically designed antibodies to identify all CUX1 isoforms. Moreover, a significantly higher expression of P75CUX1 was found in glioma compared with non-tumor brain (NB) tissues, analyzed with western blot and immunohistochemistry, and the expression level of P75CUX1 was positively associated with tumor grade. In addition, Kaplan–Meier survival analysis indicated that P75CUX1 could serve as an independent prognostic indicator to identify glioma patients with poor overall survival. Furthermore, CUX1 knockdown suppressed migration and invasion of glioma cells both in vitro and in vivo. Mechanistically, this study found that P75CUX1 regulated epithelial–mesenchymal transition (EMT) process mediated via β-catenin, and CUX1/β-catenin/EMT is a novel signaling cascade mediating the infiltration of glioma. Besides, CUX1 was verified to promote the progression of glioma via multiple other signaling pathways, such as Hippo and PI3K/AKT. In conclusion, we suggested that P75CUX1 could serve as a potential prognostic indicator as well as a novel treatment target in malignant glioma.

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Phospholipase C Delta 3 inhibits apoptosis and promotes proliferation, migration, and invasion of thyroid cancer cells via Hippo pathway

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmab016 ◽

2021 ◽

Vol 53 (4) ◽

pp. 481-491

Author(s):

Lizhi Lin ◽

Jialiang Wen ◽

Bangyi Lin ◽

Hao Chen ◽

Adheesh Bhandari ◽

...

Keyword(s):

Thyroid Cancer ◽

Phospholipase C ◽

Cell Lines ◽

Epithelial Mesenchymal Transition ◽

Hippo Pathway ◽

Suppressive Effect ◽

The Cancer Genome Atlas ◽

Disease Stage ◽

Migration And Invasion ◽

Mesenchymal Transition

Abstract In recent decades, the incidence of thyroid cancer (TC) has rapidly increased, leading us to explore the complex underlying mechanisms. We identified the gene Phospholipase C Delta 3 (PLCD3) as a potential oncogene in TC by conducting the whole transcriptome sequencing. Our study is to understand the oncogenic role of PLCD3 in TC. We verified the overexpression of PLCD3 in TC from The Cancer Genome Atlas, Gene Expression Omnibus databases, and a locally validated cohort. Clinical correlation analysis showed that PLCD3 expression was related to histological type, T stage, lymph node metastasis (LNM), and disease stage. The high expression of PLCD3 could be a distinguishing factor for TC and its LNM. The biological function was examined using small interfering RNA-transfected TC cell lines. Silenced PLCD3 could inhibit colony formation, migration, and invasion ability and promote apoptosis of TC cell lines. PLCD3 silencing reversed the epithelial-mesenchymal transition but induced the apoptotic progress. Further exploration revealed that PLCD3 might be associated with critical genes of the Hippo pathway. The expressions of RHOA, YAP1/TAZ, and their downstream targets were decreased significantly when PLCD3 was down-regulated. YAP1 overexpression rescued the tumor-suppressive effect caused by PLCD3 silencing. This study demonstrates that PLCD3 is an oncogene that supports tumorigenesis and progression in TC, and PLCD3 may be a potential target gene for TC treatment.

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.679133 ◽

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.

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

10.21203/rs.3.rs-77379/v1 ◽

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.

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Hyperglycemia promotes Snail-induced epithelial–mesenchymal transition of gastric cancer via activating ENO1 expression

Cancer Cell International ◽

10.1186/s12935-019-1075-8 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 4

Author(s):

Xin Xu ◽

Bang Chen ◽

Shaopu Zhu ◽

Jiawei Zhang ◽

Xiaobo He ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Gastrointestinal Malignancies ◽

Mesenchymal Transition

Abstract Background Gastric cancer (GC) is one of the most common gastrointestinal malignancies worldwide. Emerging evidence indicates that hyperglycemia promotes tumor progression, especially the processes of migration, invasion and epithelial–mesenchymal transition (EMT). However, the underlying mechanisms of GC remain unclear. Method Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to detect the expression of glycolysis-related enzymes and EMT-related transcription factors. Small interfering RNA (siRNA) transfection was performed to decrease ENO1 expression. Immunohistochemistry (IHC), Western blot and qRT-PCR analyses were used to measure gene expression at the protein or mRNA level. CCK-8, wound-healing and Transwell assays were used to assess cell proliferation, migration and invasion. Results Among the glycolysis-related genes, ENO1 was the most significantly upregulated in GC, and its overexpression was correlated with poor prognosis. Hyperglycemia enhanced GC cell proliferation, migration and invasion. ENO1 expression was also upregulated with increasing glucose concentrations. Moreover, decreased ENO1 expression partially reversed the effect of high glucose on the GC malignant phenotype. Snail-induced EMT was promoted by hyperglycemia, and suppressed by ENO1 silencing. Moreover, ENO1 knockdown inhibited the activation of transforming growth factor β (TGF-β) signaling pathway in GC. Conclusions Our results indicated that hyperglycemia induced ENO1 expression to trigger Snail-induced EMT via the TGF-β/Smad signaling pathway in GC.

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Identification and Validation of the N6-Methyladenosine RNA Methylation Regulator YTHDF1 as a Novel Prognostic Marker and Potential Target for Hepatocellular Carcinoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.604766 ◽

2020 ◽

Vol 7 ◽

Author(s):

Saiyan Bian ◽

Wenkai Ni ◽

Mengqi Zhu ◽

Qianqian Song ◽

Jianping Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Biological Activities ◽

Enrichment Analysis ◽

Cancer Genome ◽

Gene Set Enrichment Analysis ◽

Cell Counting ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Rna Methylation ◽

Hcc Cells

Purpose: N6-methyladenosine (m6A) RNA methylation has been implicated in various malignancies. This study aimed to identify the m6A methylation regulator-based prognostic signature for hepatocellular carcinoma (HCC) as well as provide candidate targets for HCC treatment.Methods: The least absolute shrinkage and selection operator (LASSO) analyses were performed to identify a risk signature in The Cancer Genome Atlas (TCGA) datasets. The risk signature was further validated in International Cancer Genome Consortium (ICGC) and Pan-Cancer Analysis of Whole Genomes (PCAWG) datasets. Following transfection of short hairpin RNA (shRNA) targeting YTHDF1, the biological activities of HCC cells were evaluated by Cell Counting Kit-8 (CCK-8), wound-healing, Transwell, flow cytometry, and xenograft tumor assays, respectively. The potential mechanisms mediated by YTHDF1 were predicted by overrepresentation enrichment analysis (ORA)/gene set enrichment analysis (GSEA) and validated by Western blotting.Results: Overexpression of m6A RNA methylation regulators was correlated with malignant clinicopathological characteristics of HCC patients. The Cox regression and LASSO analyses identified a risk signature with five m6A methylation regulators (KIAA1429, ZC3H13, YTHDF1, YTHDF2, and METTL3). In accordance with HCC cases in TCGA, the prognostic value of risk signature was also determined in ICGC and PCAWG datasets. Following analyzing the expression and clinical implications in TCGA and Gene Expression Omnibus (GEO), YTHDF1 was chosen for further experimental validation. Knockdown of YTHDF1 significantly inhibited the proliferation, migration, and invasion of HCC cells, as well as enhanced the apoptosis in vitro. Moreover, silencing YTHDF1 repressed the growth of xenograft tumors in vivo. Mechanism investigation indicated that YTHDF1 might promote the aggressive phenotypes by facilitating epithelial–mesenchymal transition (EMT) and activating AKT/glycogen synthase kinase (GSK)-3β/β-catenin signaling.Conclusion: The current study identified a robust risk signature consisting of m6A RNA methylation regulators for HCC prognosis. In addition, YTHDF1 was a potential molecular target for HCC treatment.

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Abnormally expressed JunB transactivated by IL-6/STAT3 signaling promotes uveal melanoma aggressiveness via epithelial–mesenchymal transition

Bioscience Reports ◽

10.1042/bsr20180532 ◽

2018 ◽

Vol 38 (4) ◽

Cited By ~ 7

Author(s):

Chaoju Gong ◽

Jie Shen ◽

Zejun Fang ◽

Lei Qiao ◽

Ruifang Feng ◽

...

Keyword(s):

Uveal Melanoma ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Transcriptional Level ◽

Mesenchymal Transition ◽

Stat3 Signaling ◽

Epithelial Marker ◽

Cancer Genome Atlas

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and it carries a high risk of metastasis and mortality. Various proinflammatory cytokines have been found to be significantly increased in the aqueous humor or vitreous fluid of UM patients; however, the role of these cytokines in UM metastasis remains elusive. In the present study, we found that long-term interleukin (IL)-6 exposure promoted the migration and invasion of UM cells, diminished cell–cell adhesion, and enhanced focal adhesion. Moreover, IL-6 treatment decreased the membranous epithelial marker TJP1 and increased the cytoplasmic mesenchymal marker Vimentin. Further investigation demonstrated that JunB played a critical role in IL-6-induced UM epithelial–mesenchymal transition (EMT). In UM cells, the expression of JunB was significantly up-regulated during the IL-6-driven EMT process. Additionally, JunB induction occurred at the transcriptional level in a manner dependent on phosphorylated STAT3, during which activated STAT3 directly bound to the JunB promoter. Importantly, the knockdown of STAT3 prevented the IL-6-induced EMT phenotype as well as cell migration and invasion, whereas JunB overexpression recovered the attenuated aggressiveness of UM cells. Similarly, with IL-6 stimulation, the stable overexpression of JunB strengthened the migratory and invasive capabilities of UM cells and induced the EMT-promoting factors (Snail, Twist1, matrix metalloproteinase (MMP)-2, MMP-14, and MMP-19). Analysis of The Cancer Genome Atlas (TCGA) database indicated that JunB was positively correlated with IL-6 and STAT3 in UM tissues. The present study proposes an IL-6/STAT3/JunB axis leading to UM aggressiveness by EMT, which illustrates the negative side of inflammatory response in UM metastasis.

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