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

PeerJ ◽  
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.

scholarly journals GPD1L Suppresses Colon Adenocarcinoma Via Repressing TGFβ1/EMT

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.

scholarly journals COPB2: A Novel Prognostic Biomarker That Affects Progression of HCC

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Jiayao Zhang ◽  
Xiaoyu Wang ◽  
Guangbing Li ◽  
Jingyi He ◽  
Ziwen Lu ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Epithelial Mesenchymal Transition ◽  
Prognostic Biomarker ◽  
Cancer Genome ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Clinicopathologic Characteristics ◽  
Mesenchymal Transition ◽  
Kaplan Meier

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.

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

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.

scholarly journals High Expression of ANXA2 Pseudogene ANXA2P2 Promotes an Aggressive Phenotype in Hepatocellular Carcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Qiu-shuang Wang ◽  
Liang-Liang Shi ◽  
Fei Sun ◽  
Yi-fan Zhang ◽  
Ren-Wang Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Disease Free Survival ◽  
Annexin A2 ◽  
The Cancer Genome Atlas ◽  
High Expression ◽  
Migration And Invasion ◽  
Targeted Drugs ◽  
Noncancerous Tissue ◽  
Expression Levels ◽  
Hcc Cells

Objective. Accumulating evidence suggests that pseudogenes play potential roles in the regulation of their cognate wild-type genes, oncogenes, and tumor suppressor genes. ANXA2P2 (annexin A2 pseudogene 2) is one of three pseudogenes of annexin A2 that have recently been shown to be aberrantly transcribed in hepatocellular carcinoma (HCC) cells. However, its clinical meaning and biological function in HCC have remained unclear. Therefore, the present study was aimed at exploring the prognostic value of a high expression of ANXA2P2 in HCC tissue and at identifying whether it can affect the efficacy of targeted drugs (sorafenib, regorafenib, and lenvatinib). Methods. We obtained ANXA2P2 mRNA expression levels from The Cancer Genome Atlas (TCGA) RNA sequence database. The expression levels of ANXA2P2 in 49 pairs of intratumoral and peritumoral liver tissues were examined by RT-PCR. Wound healing and transwell assays were performed to confirm the tumor-promoting properties of ANXA2P2 in HCC cells. CCK8 assay was conducted to identify whether ANXA2P2 can affect the growth of HCC cells when administered with targeted drugs (sorafenib, regorafenib, and lenvatinib). Results. The expression of ANXA2P2 in HCC tissues was significantly higher than that in adjacent cancerous tissues from TCGA database and validation group. Additionally, patients with high ANXA2P2 expression in HCC tissue had a shorter overall survival, whereas no statistically significant correlation was found between ANXA2P2 expression and disease-free survival (p=0.08) as well as other clinical parameters, such as age, gender, histological grade, T classification, stage, albumin level, alpha-fetoprotein, and vascular invasion (p=0.7323, 0.8807, 0.5762, 0.8515, 0.7113, 0.242, 1.0000, and 0.7685, respectively). Furthermore, in vitro experiments showed that knockdown of ANXA2P2 inhibited migration and invasion of HCC cells but did not have an influence on the HCC cell proliferation when treated with targeted drugs (sorafenib, regorafenib, and lenvatinib). Conclusion. Our study confirmed elevated ANXA2P2 expression levels in HCC tissue compared with adjacent noncancerous tissue and a worse prognosis of patients with high ANXA2P2 levels in the HCC tissue. The newly found properties of promoting migration and invasion of ANXA2P2 in HCC help to explain this phenomenon. ANXA2P2 could be a novel and suitable predicative biomarker for the risk assessment of recurrence or metastasis of HCC patients but may not be effective to predict the efficacy of targeted drugs.

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

2019 ◽  
Vol 19 (1) ◽  
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.

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

2018 ◽  
Vol 38 (4) ◽  
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.

scholarly journals Silencing of the TROP2 gene suppresses proliferation and invasion of hepatocellular carcinoma HepG2 cells

2019 ◽  
Vol 47 (3) ◽  
pp. 1319-1329 ◽  
Author(s):  
Jian Zhang ◽  
Hai Ma ◽  
Liu Yang ◽  
Hongchun Yang ◽  
Zhenxing He
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Human Trophoblast ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Proliferation And Invasion

Objectives Overexpression of human trophoblast cell surface antigen 2 (Trop2) has been observed in many cancers; however, its roles in proliferation, apoptosis, migration, and invasion of hepatocellular carcinoma (HCC) remain unclear. Thus, this study aimed to characterize the function of Trop2 in HCC. Methods Trop2 protein expression was detected by immunohistochemistry in HCC tissues. Cell proliferation, apoptosis, and invasion were respectively measured by CCK-8, flow cytometry, Transwell, and wound healing assays. Expression levels of epithelial–mesenchymal transition-related proteins and Trop2 protein in HCC cell lines were detected by western blotting after silencing of the TROP2 gene. Results Trop2 protein was highly expressed in HCC tissues and HCC cell lines. Trop2 mRNA and protein expression levels decreased in HepG2 and HCCLM3 cells after transfection with Trop2 siRNA. Silencing of the TROP2 gene in HepG2 and HCCLM3 cells strongly inhibited cell proliferation and migration, while enhancing cell apoptosis. Investigation of the molecular mechanism revealed that silencing of the TROP2 gene suppressed epithelial–mesenchymal transition of HepG2 and HCCLM3 cells. Conclusions The results of the present study may improve understanding of the role of Trop2 in regulation of cell proliferation and invasion, and may aid in development of novel therapy for HCC.

scholarly journals MiR-1301-3p Inhibits Epithelial to Mesenchymal Transition via Targeting RhoA in Pancreatic Cancer

2020 ◽  
Author(s):  
Xinxue Zhang ◽  
Xin Zhao ◽  
Junming Xu ◽  
Jun Ma ◽  
Zhe Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
Pathological Differentiation

Abstract Background: Micro(mi)RNAs play an essential role in the epithelial-mesenchymal transition (EMT) process in human cancers. This study aimed to uncover the regulatory mechanism of miR-1301-3p on EMT in pancreatic cancer (PC).Methods: GEO database (GSE31568, GSE41372, and GSE32688) and the PC cohort of The Cancer Genome Atlas were applied to discover the expression and prognostic role of miR-1301-3p. In the validation cohort, qRT-PCR was performed in 72 paired PC tissue samples. CCK-8, wound healing, and transwell migration assays were used to detect miR-1301-3p function on PC cells. Luciferase reporter assays and western blotting were performed to discover the potential target of miR-1301-3p on EMT.Results: Our study revealed that miR-1301-3p was downregulated in PC tissues compared with normal samples. A low level of miR-1301-3p was associated with malignant pathological differentiation, lymphatic metastasis, tumor residual, and unsatisfactory overall survival. Gene Ontology analyses indicated that miR-1301-3p possibly regulated cell cycle and adheren junction. In vitro assays showed that miR-1301-3p suppressed proliferation, migration, and invasion ability of PC cells. Mechanically, miR-1301-3p inhibits RhoA expression, and knockdown of RhoA upregulated E-cadherin; however, downregulated N-cadherin and vimentin level.Conclusions: MiR-1301-3p acts as a prognostic biomarker for PC and inhibits PC progression by targeting RhoA induced EMT process.

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.

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