scholarly journals Amygdalin Attenuates Airway Epithelium Apoptosis, Inflammation, and Epithelial-Mesenchymal Transition through Restraining the TLR4/NF-κB Signaling Pathway on LPS-Treated BEAS-2B Bronchial Epithelial Cells

2021 ◽  
pp. 1-11 ◽  
Author(s):  
Zhenyang Si ◽  
Biao Zhang
Keyword(s):  
Signaling Pathway ◽  
Airway Epithelium ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Cell Counting ◽  
Mesenchymal Transition ◽  
Qrt Pcr ◽  
Tnf Α ◽  
E Cadherin

<b><i>Background:</i></b> Cough-variant asthma (CVA) is a special type of asthma, solely manifesting with coughing. Studies suggest that airway inflammation is associated with CVA pathogenesis. Amygdalin is found to have an anti-inflammatory potential, while how it affects CVA remains unexplored. <b><i>Methods:</i></b> Cytotoxicity delivered by various concentrations of LPS and amygdalin on BEAS-2B cells was determined by Cell Counting Kit-8 assay. CVA in vitro models were established via LPS exposure on BEAS-2B cells which underwent amygdalin pretreatment. Cell apoptosis was determined by flow cytometry. Production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and mucin 5AC (MUC5AC) in BEAS-2B cells was measured by ELISA and qRT-PCR. Expressions of TLR4, E-cadherin, N-cadherin, α-smooth muscle actin (SMA), vimentin, phosphorylated-p65 (p-p65), p65, phosphorylated-IκBα (p-IκBα), and IκBα in BEAS-2B cells were measured by qRT-PCR or Western blot. <b><i>Results:</i></b> LPS and high concentrations of amygdalin (over 600 μg/mL) decreased BEAS-2B cell toxicity. Exposure to LPS inhibited toxicity, enhanced apoptosis; and promoted production of TNF-α, IL-6, IL-8, and MUC5AC, increased the levels of N-Cadherin, α-SMA, vimentin, p-p65, and p-IκBα, and decreased the levels of E-cadherin and IκBα in BEAS-2B cells. Amygdalin pretreatment counteracted the effects of LPS on BEAS-2B cells. Overexpressing TLR4 reversed amygdalin-exerted effects in LPS-exposed BEAS-2B cells. <b><i>Conclusion:</i></b> Amygdalin attenuated airway epithelium apoptosis, inflammation and epithelial-mesenchymal transition through restraining the TLR4/NF-κB signaling pathway in CVA.

scholarly journals Intestinal dysbacteriosis activates tumor-associated macrophages to promote epithelial-mesenchymal transition of colorectal cancer

2018 ◽  
Vol 24 (8) ◽  
pp. 480-489 ◽  
Author(s):  
Guangsheng Wan ◽  
Manli Xie ◽  
Hongjie Yu ◽  
Hongyu Chen
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Cell Counting ◽  
Mice Model ◽  
Mesenchymal Transition ◽  
Tnf Α ◽  
Xenograft Mice Model ◽  
Intestinal Dysbacteriosis

In this study we investigated the association between intestinal dysbacteriosis with colorectal cancer progress and the underlying molecular mechanisms. Tumor progression was evaluated using xenograft mice model. The epithelial-mesenchymal transition (EMT) markers were quantified by both real-time PCR and immunoblotting. The serum content of IL-6 and TNF-α were measured with ELISA kits. Cell proliferation was determined by the Cell Counting Kit-8. Intestinal dysbacteriosis was successfully simulated by the administration of a large dose of antibiotics and was demonstrated to promote xenograft tumor growth and induce EMT. Accordingly, the serum concentrations of cytokines IL-6 and TNF-α were significantly increased. Furthermore, the production and secretion of IL-6 and TNF-α were remarkably elevated in macrophages isolated from intestinal dysbiotic mice in comparison with the normal counterparts, and conditioned medium from these was shown to significantly stimulate EMT process in HT29 cells in vitro. Macrophage depletion completely abrogated the pro-tumor effect of intestinal dysbacteriosis. Our results suggest that intestinal dysbacteriosis stimulates macrophage activation and subsequently induces EMT process via secreted pro-inflammatory cytokines IL-6 and TNF-α.

scholarly journals Inhibition of MIR4435-2HG on Invasion, Migration, and EMT of Gastric Carcinoma Cells by Mediating MiR-138-5p/Sox4 Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Li-Fei Gao ◽  
Wei Li ◽  
Ya-Gang Liu ◽  
Cui Zhang ◽  
Wei-Na Gao ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Tumor Growth ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cells ◽  
The Cancer Genome Atlas ◽  
Cell Counting ◽  
Pcr Analysis ◽  
Mesenchymal Transition ◽  
Qrt Pcr

BackgroundThe previous investigations have identified that long non-coding RNA (lncRNAs) act as crucial regulators in gastric carcinoma. However, the function of lncRNA MIR4435-2HG in the modulation of gastric carcinoma remains elusive. Here, we aimed to explore the role of MIR4435-2HG in gastric carcinoma.MethodThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were applied to select the differently expressed lncRNAs in gastric carcinoma. The qRT-PCR was applied to analyze MIR4435-2HG expression in carcinoma tissues and cell lines. The effect of MIR4435-2HG on proliferation, invasion, migration, and apoptosis of gastric carcinoma cells was detected by Cell Counting Kit-8 (CCK-8) assays, transwell assays, and flow cytometry in vitro. A subcutaneous tumor model was constructed to examine the tumor growth of gastric carcinoma cells after knocking out MIR4435-2HG. RNA immunoprecipitation and luciferase reporting assays were applied to evaluate the interaction of MIR4435-2HG, miR-138-5p, and Sox4.ResultsThe bioinformatics analysis based on TCGA and GEO databases indicated that MIR4435-2HG was obviously elevated in gastric carcinoma samples. The qRT-PCR analysis revealed that MIR4435-2HG was upregulated in clinical gastric carcinoma tissues and cells. The high expression of MIR4435-2HG is associated with the poor survival rate of patients. The knockout of MIR4435-2HG could repress the proliferation, invasion, migration, and epithelial–mesenchymal transition (EMT) and accelerate the apoptosis of gastric carcinoma cells. Moreover, the deletion of MIR4435-2HG was able to attenuate the tumor growth in vivo. Mechanically, we identified that MIR4435-2HG enhanced Sox4 expression by directly interacting with miR-138-5p as a competitive endogenous RNA (ceRNA) in gastric carcinoma cells, in which Sox4 was targeted by miR-138-5p.ConclusionMIR4435-2HG is elevated in gastric carcinoma cells and contributes to the growth, metastasis, and EMT of gastric carcinoma cells by targeting miR-138-5p/Sox4 axis. MIR4435-2HG may be applied as a potential therapeutic target in gastric carcinoma.

scholarly journals METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Ben Yue ◽  
Chenlong Song ◽  
Linxi Yang ◽  
Ran Cui ◽  
Xingwang Cheng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Qrt Pcr ◽  
Rna Immunoprecipitation ◽  
E Cadherin

Abstract Background As one of the most frequent chemical modifications in eukaryotic mRNAs, N6-methyladenosine (m6A) modification exerts important effects on mRNA stability, splicing, and translation. Recently, the regulatory role of m6A in tumorigenesis has been increasingly recognized. However, dysregulation of m6A and its functions in tumor epithelial-mesenchymal transition (EMT) and metastasis remain obscure. Methods qRT-PCR and immunohistochemistry were used to evaluate the expression of methyltransferase-like 3 (METTL3) in gastric cancer (GC). The effects of METTL3 on GC metastasis were investigated through in vitro and in vivo assays. The mechanism of METTL3 action was explored through transcriptome-sequencing, m6A-sequencing, m6A methylated RNA immunoprecipitation quantitative reverse transcription polymerase chain reaction (MeRIP qRT-PCR), confocal immunofluorescent assay, luciferase reporter assay, co-immunoprecipitation, RNA immunoprecipitation and chromatin immunoprecipitation assay. Results Here, we show that METTL3, a major RNA N6-adenosine methyltransferase, was upregulated in GC. Clinically, elevated METTL3 level was predictive of poor prognosis. Functionally, we found that METTL3 was required for the EMT process in vitro and for metastasis in vivo. Mechanistically, we unveiled the METTL3-mediated m6A modification profile in GC cells for the first time and identified zinc finger MYM-type containing 1 (ZMYM1) as a bona fide m6A target of METTL3. The m6A modification of ZMYM1 mRNA by METTL3 enhanced its stability relying on the “reader” protein HuR (also known as ELAVL1) dependent pathway. In addition, ZMYM1 bound to and mediated the repression of E-cadherin promoter by recruiting the CtBP/LSD1/CoREST complex, thus facilitating the EMT program and metastasis. Conclusions Collectively, our findings indicate the critical role of m6A modification in GC and uncover METTL3/ZMYM1/E-cadherin signaling as a potential therapeutic target in anti-metastatic strategy against GC.

Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin

2007 ◽  
Vol 293 (3) ◽  
pp. F723-F731 ◽  
Author(s):  
Aihua Zhang ◽  
Zhanjun Jia ◽  
Xiaohua Guo ◽  
Tianxin Yang
Keyword(s):  
Epithelial Cells ◽  
De Novo ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Oxidase Inhibitor ◽  
Mesenchymal Transition ◽  
Mitochondrial Respiratory Chain Complex ◽  
E Cadherin

It has been well appreciated that aldosterone (Aldo) plays a direct profibrotic role in the kidney but the underlying mechanism is unclear. We examined the role of Aldo in epithelial-mesenchymal transition (EMT) both in vitro and in vivo. Exposure of human renal proximal tubular cells to Aldo for 48 h dose dependently induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and de novo expression of α-smooth muscle actin (SMA); the effect was noticeable at 50 nM and maximal at 100 nM. The EMT was completely blocked by the selective mineralocorticoid receptor (MR) antagonist eplerenone. Aldo time dependently increased intracellular reactive oxygen species (ROS) production that was detectable at 15 min and peaked (2.3-fold) at 60 min, as assessed by 2′,7′-dichlorofluorescin diacetate fluorescence. Aldo-induced oxidative stress and EMT were both abolished by the mitochondrial respiratory chain complex I inhibitor rotenone, but not the NADPH oxidase inhibitor apocynin. Aldo induced phosphorylation of ERK1/2 that was completely blocked by rotenone. Male 129-C57/BL6 mice were treated with deoxycorticosterone acetate (DOCA) salt (subcutaneous implantation of 50 mg of DOCA pellet plus 1% NaCl as drinking fluid) for 3 wk and animals were treated with vehicle or rotenone (600 ppm in diet) for the last week. DOCA salt induced a 2.5-fold increase in α-SMA and a 30% reduction of E-cadherin, as assessed by real-time RT-PCR, that were both restricted to renal epithelial cells, as determined by immunohistochemistry. In contrast, DOCA salt-induced changes in α-SMA and E-cadherin were completely blocked by treatment with rotenone. These observations suggest that Aldo induces EMT via MR-mediated, mitochondrial-originated, ROS-dependent ERK1/2 activation in renal tubular epithelial cells.

scholarly journals Isoliquiritigenin Reverses Epithelial-Mesenchymal Transition Through Modulation of the TGF-β/Smad Signaling Pathway in Endometrial Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1236
Author(s):  
Hsin-Yuan Chen ◽  
Yi-Fen Chiang ◽  
Jia-Syuan Huang ◽  
Tsui-Chin Huang ◽  
Yin-Hwa Shih ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Signaling Pathway ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Smad Signaling Pathway ◽  
E Cadherin

Endometrial cancer is a common gynecological cancer with a poor prognosis, mostly attributed to tumor metastasis. Epithelial–mesenchymal transition (EMT) can be mediated via transforming growth factor beta (TGF-β) signaling pathway, facilitating the ability of cancer cell invasion and migration. Isoliquiritigenin (ISL) is a flavonoid derived from licorice with reported antineoplastic activities. This study aims to investigate the anti-metastatic potential of ISL on endometrial cancer both in vitro and in vivo. First, human endometrial cancer cell lines (HEC-1A, Ishikawa, and RL95-2) were treated with ISL and then subjected to functional assays such as migration assay as well as molecular analyses including immunoblotting, immunofluorescence and RT-qPCR. In addition, HEC-1A-LUC cells were implanted into female nude mice and treated with ISL by intraperitoneal injection for four weeks. Results showed that ISL inhibited cell migration and reversed the effect of TGF-β on the expression of E-cadherin, N-cadherin, vimentin, α-SMA, p-Smad3, and TWIST1/2 In vitro. Interestingly, In vivo study revealed that ISL reduced peritoneal dissemination and serum level of TGF-β1, as well as decreased the expression levels of N-cadherin, p-Smad2/3, TWIST1/2, while increased E-cadherin. Overall, ISL reverses the EMT through targeting the TGF-β/Smad signaling pathway and features a potential therapeutic treatment for metastatic endometrial cancer.

scholarly journals Snail Driving Alternative Splicing of CD44 by ESRP1 Enhances Invasion and Migration in Epithelial Ovarian Cancer

2017 ◽  
Vol 43 (6) ◽  
pp. 2489-2504 ◽  
Author(s):  
Le Chen ◽  
Ying Yao ◽  
Lijuan Sun ◽  
Jiajia Zhou ◽  
Minmin Miao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Alternative Splicing ◽  
Epithelial Ovarian Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Regulatory Protein ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Background/Aims: Our study aims to investigate the role, effect and mechanisms of ESRP1 (epithelial splicing regulatory protein 1) in epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer (EOC). Methods: Microarray and immunohistochemical analysis of ESRP1 expression were performed in EOC cases. The correlations between ESRP1 expression and clinical factors on EOC were assessed. Lentivirus-mediated RNA interference and EGFP vector which contains ESRP1 gene were used to down-regulate and up-regulate ESRP1 expression in human EOC cell lines. Roles of ESRP1 in cell growth, migration and invasion of EOC cells were also measured by Cell Counting Kit-8 and Transwell systems in vitro and by a nude mice intraperitoneal transplantation model in vivo. Results: By the analysis of Gene Expression Omnibus (GEO) (p<0.05) and our own microarray data (p<0.001), ESRP1 expression in EOC was significantly different from normal ovarian tissue. It was abundant in the nuclei of cancer cells and in malignant lesions. However, it was weakly expressed or negative in both normal and benign lesions. High ESRP1 expression in EOC was associated with poor clinical outcomes. Decreased ESRP1 expression significantly increased cell migration and invasion both in vivo and in vitro. Snail strongly repressed ESRP1 transcription through binding to the ESRP1 promoter in EOC cells. Furthermore, ESRP1 regulated the expression of CD44s. Down-regulated ESRP1 resulted in an isoform switching from CD44v to CD44s, which modulated epithelial-mesenchymal transition (EMT) program in EOC. Up-regulatin of ESRP1 was detected in mesenchymal to epithelial transition (MET) in vivo. Conclusions: ESRP1 regulates CD44 alternative splicing during the EMT process which plays an important role in EOC carcinogenesis. In addition, ESRP1 is associated with disease prognosis in EOC.

scholarly journals Value of Biomarkers in Liver Cancer EMT model under different interventions：A meta-analysis

2021 ◽  
Author(s):  
Jing Yan ◽  
Shuli Zou ◽  
Bei Xie ◽  
Ye Tian ◽  
Zhiheng Peng ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Gene Knockout ◽  
Meta Analysis ◽  
China National Knowledge Infrastructure ◽  
Mesenchymal Transition ◽  
Tumor Microenvironments ◽  
Genetic Intervention ◽  
E Cadherin

Abstract Background There are various interventions to establish the Liver cancer epithelial-mesenchymal transition (EMT) models. However, the ideal biomarkers for unique model are not well established. Further studies are necessary to evaluation of effective EMT biomarkers under different interventions in vitro studies. A meta-analysis was performed to evaluate the performance of different biomarkers in HepG2 cells during EMT under multiple interventions. Methods PubMed, Web of Science, Embase, the China National Knowledge Infrastructure (CNKI), the China Biology Medicine disc (CBM), Wan Fang Data, and VIP databases were systematically searched from inception to June 14, 2020 by two independent reviewers. Results A total of 58 studies were included in the meta-analysis. Our study showed that E-cadherin responds well to the intervention of medication, genetic intervention, gene knockout/knockdown, hypoxia, and other tumor microenvironments, as well as non-coding RNA (ncRNA) overexpression and silencing. N-cadherin can effectively evaluate the intervention effect of medication, genetic intervention, hypoxia and other tumor microenvironments, as well as ncRNA overexpression. Vimentin reflects the effects of medication, pro-EMT genetic intervention and gene knockout/knockdown, anti-EMT ncRNA overexpression and anti-EMT ncRNA silencing and hypoxia. Snail only responds to the intervention of anti-EMT genetic intervention and gene knockout/knockdown, tumor microenvironments other than hypoxia, anti-EMT ncRNA overexpression and ncRNA silencing. Conclusions Our results shows that some medicine, some gene, microenvironment and some ncRNA can effectively induce/inhibit EMT process. E-cadherin, N-cadherin, Vimentin and Snail are effective biomarkers during this process. They respond differently to different intervention. Therefore, different biomarkers should be chosen under different intervention based on their performance.

scholarly journals Inhibitor of DNA-Binding Protein 4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition in Lung Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2021 ◽  
Author(s):  
Chi-Chung Wang ◽  
Yuan-Ling Hsu ◽  
Chi-Jen Chang ◽  
Chia-Jen Wang ◽  
Tzu-Hung Hsiao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Binding ◽  
Lung Adenocarcinoma ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Inhibitor Of Dna Binding ◽  
E Cadherin

Metastasis is a predominant cause of cancer death and the major challenge in treating lung adenocarcinoma (LADC). Therefore, exploring new metastasis-related genes and their action mechanisms may provide new insights for developing a new combative approach to treat lung cancer. Previously, our research team discovered that the expression of the inhibitor of DNA binding 4 (Id4) was inversely related to cell invasiveness in LADC cells by cDNA microarray screening. However, the functional role of Id4 and its mechanism of action in lung cancer metastasis remain unclear. In this study, we report that the expression of Id4 could attenuate cell migration and invasion in vitro and cancer metastasis in vivo. Detailed analyses indicated that Id4 could promote E-cadherin expression through the binding of Slug, cause the occurrence of mesenchymal-epithelial transition (MET), and inhibit cancer metastasis. Moreover, the examination of the gene expression database (GSE31210) also revealed that high-level expression of Id4/E-cadherin and low-level expression of Slug were associated with a better clinical outcome in LADC patients. In summary, Id4 may act as a metastatic suppressor, which could not only be used as an independent predictor but also serve as a potential therapeutic for LADC treatment.

scholarly journals Characteristics of the Epithelial-Mesenchymal Transition in Primary and Paired Metastatic Canine Mammary Carcinomas

2018 ◽  
Vol 55 (5) ◽  
pp. 622-633 ◽  
Author(s):  
Talita M. M. Raposo-Ferreira ◽  
Becky K. Brisson ◽  
Amy C. Durham ◽  
Renee Laufer-Amorim ◽  
Veronica Kristiansen ◽  
...  
Keyword(s):  
Primary Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Cell Counting ◽  
Positive Staining ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Mammary Carcinomas ◽  
Slug Expression ◽  
E Cadherin

The epithelial-mesenchymal transition (EMT) is a dynamic process linked to metastasis in many tumor types, including mammary tumors. In this study, we evaluated E-cadherin and vimentin immunolocalization in primary canine mammary carcinomas (20 cases) and their respective metastases, as well as their relationship with the core regulators SNAIL/SLUG. To assess the number of cells undergoing the process of EMT, we quantitated double-positive (E-cadherin+/vimentin+) cells using immunofluorescence, via cell counting and image analysis. In addition, SNAIL/SLUG expression was evaluated by established immunohistochemical methods. Primary tumors had significantly more E-cadherin+/vimentin+ co-expression than their paired respective lymph node or distant metastasis, respectively. Furthermore, the percentage of E-cadherin+/vimentin+ cells in grade II and III carcinomas was significantly higher than in grade I tumors. Primary tumors had significantly higher SNAIL/SLUG expression when analyzed based on the percentage of positive cells compared with their respective distant metastases in pairwise comparisons. An inverse correlation was noted between SNAIL/SLUG immunoreactivity and percentage of E-cadherin+/vimentin+ immunopositive cells in primary tumor samples when SNAIL/SLUG immunoreactivity was grouped into 2 categories (high versus low) based on percentage-positive staining. These results show a positive correlation between E-cadherin+/vimentin+ cells and higher tumor grade, establish differences between primary tumor and their respective metastases, and provide further support that EMT plays a critical role in the metastasis of canine mammary carcinoma. Furthermore, these data suggest that modulation of this process could provide greater therapeutic control and provide support for further research to determine if E-cadherin+/vimentin+ co-immunoreactivity imparts predictive value in the clinical outcome of patients with canine mammary carcinomas.

scholarly journals NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype

2019 ◽  
Vol 11 (6) ◽  
pp. 251-263 ◽  
Author(s):  
Federico Bocci ◽  
Satyendra C Tripathi ◽  
Samuel A Vilchez Mercedes ◽  
Jason T George ◽  
Julian P Casabar ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Collective Cell Migration ◽  
Mesenchymal Transition ◽  
Regulatory Circuit ◽  
Clinical Records ◽  
E Cadherin

Abstract The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype – a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) – the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the ‘metastatic sweet spot’.

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