Reactive oxygen species stimulates epithelial mesenchymal transition in normal human epidermal keratinocytes via TGF-beta secretion

Fukawa, Teruhisa; Kajiya, Hiroshi; Ozeki, Satoru; Ikebe, Tetsuro; Okabe, Koji

doi:10.1016/j.yexcr.2012.05.023

Cited by 41 publications

(37 citation statements)

References 38 publications

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“…29,30 It has been reported that oxidative stress induces the EMT. Human epidermal keratinocytes exposed to H 2 O 2 showed protein expression that was consistent with the EMT, 31 and similar results were founded in renal tubular epithelial cells. 32 In the same way, chromium-induced EMT is dependent on intracellular ROS in lung epithelial cells.…”

supporting

confidence: 78%

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Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

123

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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supporting

confidence: 78%

“…31,32 In contrast, it was recently reported that ROS production inhibits the EMT in prostate cancer cells. 58 Because the EndMT is also observed in tumor cells, it would be interesting to explore whether oxidative stress inhibits the EndMT in cancer cells.…”

Section: Discussionmentioning

confidence: 97%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

123

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“…In this regard, it has been reported that human basaloid keratinocytes [57] and equine lamellar cells [58] were positive for vimentin. In addition, up-regulation of SMA has been reported in human epidermal keratinocytes under certain conditions (hydrogen peroxide treatment) as well [59]. In our hands, the intact skin samples that were used as positive controls also contained vimentin and SMA positive epidermal and follicular cells (data not shown).…”

Section: Discussionsupporting

confidence: 50%

Equine Epidermis: A Source of Epithelial-Like Stem/Progenitor Cells with In Vitro and In Vivo Regenerative Capacities

Broeckx¹,

Maes²,

Martinello

et al. 2014

Stem Cells and Development

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Besides the presence of somatic stem cells in hair follicles and dermis, the epidermis also contains a subpopulation of stem cells, reflecting its high regenerative capacity. However, only limited information concerning epidermis-derived epithelial-like stem/progenitor cells (EpSCs) is available to date. Nonetheless, this stem cell type could prove itself useful in skin reconstitution after injury. After harvesting from equine epidermis, the purified cells were characterized as EpSCs by means of positive expression for CD29, CD44, CD49f, CD90, Casein Kinase 2b, p63, and Ki67, low expression for cytokeratin (CK)14 and negative expression for CD105, CK18, Wide CK, and Pan CK. Furthermore, their self-renewal capacity was assessed in adhesion as well as in suspension. Moreover, the isolated cells were differentiated toward keratinocytes and adipocytes. To assess the regenerative capacities of EpSCs, six full-thickness skin wounds were made: three were treated with EpSCs and platelet-rich-plasma (EpSC/PRP-treated), while the remaining three were administered carrier fluid alone (PRP-treated). The dermis of EpSC/PRP-treated wounds was significantly thinner and exhibited more restricted granulation tissue than did the PRP-treated wounds. The EpSC/PRP-treated wounds also exhibited increases in EpSCs, vascularization, elastin content, and follicle-like structures. In addition, combining EpSCs with a PRP treatment enhanced tissue repair after clinical application.

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“…The most intriguing coupling between hypoxia, metabolism, and EMT is through reactive oxygen species (ROS), which not only mediates the mutual inhibition between HIF1 and HIF2 (87), but also activates both miR200 and ZEB (88,89). Because HIF1 and HIF2 are believed to govern the response to acute and chronic hypoxia, respectively (90,91), this coupling can unravel how epithelial-mesenchymal plasticity is linked to changes in tumor metabolism and tumor angiogenesis, as induced by hypoxia.…”

Section: Metabolismmentioning

confidence: 99%

Toward Decoding the Principles of Cancer Metastasis Circuits

Jolly

Onuchic

et al. 2014

Cancer Research

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Understanding epithelial-mesenchymal transitions (EMT) during cancer metastasis remains a major challenge in modern biology. Recent observations of cell behavior together with progress in mapping the underlying regulatory genetic networks led to new understandings of carcinoma metastasis. It is now established that the genetic network that regulates the EMT also enables an epithelial-mesenchymal hybrid phenotype. These hybrid cells possess mixed carcinoma epithelial and mesenchymal characteristics that enable specialized capabilities such as collective cell migration. On the gene network perspective, a fourcomponent decision unit composed of two highly interconnected chimeric modules-the miR34/SNAIL and the miR200/ZEB mutual-inhibition feedback circuits-regulates the coexistence of and transitions between the different phenotypes. Here, we present a new tractable theoretical framework to model and decode the underlying principles governing the operation of the regulatory unit. Our approach connects the knowledge about intracellular pathways with observations of cellular behavior and advances toward understanding the logic of cancer decision-making. We found that the miR34/SNAIL module acts as an integrator while the miR200/ZEB module acts as a three-way switch. Consequently, the combined unit can give rise to three phenotypes (stable states): (i) a high miR200 and low ZEB, or (1, 0) state; (ii) a low miR200 and high ZEB, or (0, 1) state; and (iii) a medium miR200 and medium ZEB, or ( 1 / 2 , 1 / 2 ) state. We associate these states with the epithelial, mesenchymal, and hybrid phenotypes, respectively. We reflect on the consistency between our theoretical predictions and recent observations in several types of carcinomas and suggest new testable predictions.

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Reactive oxygen species stimulates epithelial mesenchymal transition in normal human epidermal keratinocytes via TGF-beta secretion

Cited by 41 publications

References 38 publications

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Equine Epidermis: A Source of Epithelial-Like Stem/Progenitor Cells with In Vitro and In Vivo Regenerative Capacities

Toward Decoding the Principles of Cancer Metastasis Circuits

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