Nrf2 antioxidant pathway suppresses Numb-mediated epithelial–mesenchymal transition during pulmonary fibrosis

Zhang, Zhihui; Qu, Jiao; Cheng, Zheng; Zhang, Panpan; Zhou, Wencheng; Cui, Wenhui; Mo, Xiaoting; Li, Liucheng; Xu, Liang; Gao, Jian

doi:10.1038/s41419-017-0198-x

Cited by 92 publications

(60 citation statements)

References 30 publications

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“…Furthermore, NRF2 overexpression enhanced both epithelial and mesenchymal traits in RT4 bladder cancer cells that were already co-expressing E-cadherin and ZEB1. Previous experiments have shown the effect of NRF2 on TGF-β1-driven EMT in epithelial cells [13,16,47,48], and how initial levels of NRF2 can impact the response of cells to TGF-β1-driven EMT [49]. However, our study illustrates a different role for NRF2 in modulating EMT when NRF2 is pharmacologically overexpressed in hybrid E/M cells.…”

Section: Discussionmentioning

confidence: 52%

NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype

Bocci

Tripathi

Mercedes

et al. 2018

Preprint

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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. Here, 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 destabilised 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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Section: Discussionmentioning

confidence: 52%

NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype

Bocci

Tripathi

Mercedes

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…ROS disrupts Keap1–Nrf2 interactions and thus promotes Nrf2 activation. Nrf2 binds to antioxidant response element and induces the expression of numerous antioxidants, including heme oxygenase 1 (HO-1) and heat shock proteins [ 15 , 43 , 44 ]. In the present study, treatment with 3-NPA significantly increased the mRNA expression level of Ho-1 and Hspa2 .…”

Section: Discussionmentioning

confidence: 99%

Effect of 3-nitropropionic acid inducing oxidative stress and apoptosis of granulosa cells in geese

Kang

Wang

et al. 2018

Bioscience Reports

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The mechanism of action by which oxidative stress induces granulosa cell apoptosis, which plays a vital role in initiating follicular atresia, is not well understood. In the present study, the effect of 3-nitropropionic acid (3-NPA) on oxidative stress and apoptosis in granulosa cells in geese was investigated. Our results showed that treatment with 3-NPA at 5.0 mmol/l for 24 h increased intracellular reactive oxygen species (ROS) production by 25.4% and decreased granulosa cell viability by 45.5% (P<0.05). Catalase and glutathione peroxidase gene expression levels in granulosa cells treated with 3-NPA were 1.32- and 0.49-fold compared with those of the control cells, respectively (P <0.05). A significant decrease in the expression level of B-cell lymphoma 2 (Bcl-2) protein and remarkable increases in the levels of Bax, p53 and cleaved-Caspase 3 proteins and the ratio of Bax/Bcl-2 expression in granulosa cells treated with 3-NPA were observed (P<0.05). Furthermore, a 38.43% increase in the percentage of early apoptotic cells was also observed in granulosa cells treated with 3-NPA (P<0.05). Moreover, the expression levels of NF-κB, Nrf2, Fhc, Hspa2 and Ho-1 in granulosa cells treated with 3-NPA were elevated 4.36-, 1.63-, 3.62-, 27.54- and 10.48-fold compared with those of the control cells (P<0.05), respectively. In conclusion, the present study demonstrates that treatment with 3-NPA induces ROS production and apoptosis and inhibits the viability of granulosa cells in geese. Furthermore, 3-NPA triggers increases in the expression of cleaved-Caspase 3 protein and the ratio of Bax/Bcl-2 expression, and induces the early apoptosis of granulosa cells.

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“…MTA1 protein interacts with histone deacetylase to form a nucleosome remodelling histone deacetylase complex, which could regulate oncogenesis and angiogenesis in a variety of cancers . MTA1 promotes the progression of cancer by inducing EMT, which functions as a central mediating process that contributes to IPF . Up to now, however, the expression changes of MTA1 and its biological functions and mechanisms in the pathogenic process of IPF are unknown.…”

Section: Discussionmentioning

confidence: 99%

Metastasis‐associated protein 1 promotes epithelial‐mesenchymal transition in idiopathic pulmonary fibrosis by up‐regulating Snail expression

Qian

Cai

Qian

et al. 2020

J Cellular Molecular Medi

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Idiopathic pulmonary fibrosis (IPF) is a progressive and usually fatal lung disease that lacking effective interventions. It is well known that aberrant activation of transforming growth factor‐beta1 (TGF‐β1) frequently promotes epithelial‐mesenchymal transition (EMT) in IPF. Metastasis‐associated gene 1 (MTA1) has identified as an oncogene in several human tumours, and aberrant MTA1 expression has been related to the EMT regulation. However, its expression and function in IPF remain largely unexplored. Using a combination of in vitro and in vivo studies, we found that MTA1 was significantly up‐regulated in bleomycin‐induced fibrosis rats and TGF‐β1‐treated alveolar type Ⅱ epithelial (RLE‐6TN) cells. Overexpression of MTA1 induced EMT of RLE‐6TN cells, as well as facilitates cell proliferation and migration. In contrast, knockdown of MTA1 reversed TGF‐β1‐induced EMT of RLE‐6TN cells. The pro‐fibrotic action of MTA1 was mediated by increasing Snail expression through up‐regulating Snail promoter activity. Moreover, inhibition of MTA1 effectively attenuated bleomycin‐induced fibrosis in rats. Additionally, we preliminarily found astragaloside IV (ASV), which was previously validated having inhibitory effects on TGF‐β1‐induced EMT, could inhibit MTA1 expression in TGF‐β1‐treated RLE‐6TN cells. These findings highlight the role of MTA1 in TGF‐β1‐mediated EMT that offer novel strategies for the prevention and treatment of IPF.

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Nrf2 antioxidant pathway suppresses Numb-mediated epithelial–mesenchymal transition during pulmonary fibrosis

Cited by 92 publications

References 30 publications

NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype

NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype

Effect of 3-nitropropionic acid inducing oxidative stress and apoptosis of granulosa cells in geese

Metastasis‐associated protein 1 promotes epithelial‐mesenchymal transition in idiopathic pulmonary fibrosis by up‐regulating Snail expression

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