Caveolin‐1 deficiency induces a <scp>MEK</scp>‐<scp>ERK</scp>1/2‐Snail‐1‐dependent epithelial–mesenchymal transition and fibrosis during peritoneal dialysis

Strippoli, Raffaele; Loureiro, Jesús; Moreno, Vanessa; Benedicto, Ignacio; Lozano, María Luisa; Barreiro, Olga; Pellinen, Teijo; Minguet, Susana; Foronda, Miguel; Osteso, Maria Teresa; Vázquez, Jesús; Cabrera, Manuel López; Pozo, Miguel Á. del

doi:10.15252/emmm.201570010

Cited by 25 publications

(22 citation statements)

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“…Induction of EMT following reduction of Cav1 expression might likely be due to the release of the TGFβ and/or the ERK1/2 pathways which are major inducers of EMT. Both pathways were shown to be activated in glioblastoma [10] and in human peritoneal cells following Cav1 silencing [33].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, beside alterations of pathways involved in cell-cell adhesion, ECM, immune response and apoptosis, "R1" tumors are characterized by alterations of the EMT pathway [6]. Cav1 deficiency induces EMT during peritoneal dialysis [33] and in HNSCC [21] as well as EndoMT in pulmonary endothelial cells [34]. In accordance, reduced expression of Cav1 in our model is linked to a loss of the cobblestone epithelial morphology, a switch from epithelial (E-cadherin) to mesenchymal (vimentin) marker expression and the expression of various transcription factors such as Twist, Snail, Slug, ZEB1 and ZEB2 known to orchestrate EMT.…”

Section: Discussionmentioning

confidence: 99%

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Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties

Martin¹,

Jung²,

Ray³

et al. 2016

European Journal of Cancer

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties

Martin¹,

Jung²,

Ray³

et al. 2016

European Journal of Cancer

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“…An inverse relationship between caveolin-1 expression and Raf/MEK/Erk activity has also been reported. Overexpression of caveolin-1 was found to attenuate ERK activity, whereas downregulation of caveolin-1 leads to hyper phosphorylation of ERK1/2 [2].…”

mentioning

confidence: 91%

“…[1]. Besides of expressing mesenchymal markers (N-cadherin, vimentin, α-smooth muscle actin etc) they acquire the ability to produce extracellular matrix components, as well as metalloproteinases, inflammatorycytokines, fibrogenic and angiogenic factors [2]. Three types of EMTs have been distinguished so far: epithelial-mesenchymal transition during embryogenesis (type I), EMT associated with inflammation, wound healing, tissue regeneration and organ fibrosis (type II) and tumorigenesis (type III) [3].…”

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Caveolin-1/Caveolae are in Focus of Regulating EMT and MET

Kiss¹

2017

Histol Cytol Embryol

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During epithelial-mesenchymal transition (EMT) polarized epithelial cells undergo a complex proteomic remodelling, several biochemical and morphological changes converting them into mesenchymal-like cells. [1]. Besides of expressing mesenchymal markers (N-cadherin, vimentin, α-smooth muscle actin etc) they acquire the ability to produce extracellular matrix components, as well as metalloproteinases, inflammatorycytokines, fibrogenic and angiogenic factors [2]. Three types of EMTs have been distinguished so far: epithelial-mesenchymal transition during embryogenesis (type I), EMT associated with inflammation, wound healing, tissue regeneration and organ fibrosis (type II) and tumorigenesis (type III) [3]. EMT is triggered by extracellular signals including various cytokines, growth factors, extracellular matrix components. Transforming growth factorβ (TGFβ) family members are the most important regulators in this process. The TGFβ signalling pathways are generally divided into Smad-dependent and Smad-independent processes. When TGFβ binds to its primary serine/threonine kinase receptor (type II) it induces the formation of a heteroterameric receptor complex. Type II receptor thentrans phosphorylates (activates) the signalling receptor (type I) that can initiate Smad2/3 signalling pathway. The receptor internalization is required for the initiation of downstream signalling [4]. In addition to promoting the signalling process by transporting these molecules to the signalling organelles, the receptor-ligand internalization can control the number of receptors present on the cell surface. Thus, receptor internalization regulates the signalling, receptor turnover, the magnitude and duration of the events. In EMT clathrinmediated as well as caveolar endocytosis (internalization via caveolae) play an important role [5]. Caveolae are small omega-or flask-shaped plasma membrane invaginations, highly hydrophobic membrane domains (lipid rafts) containing a special protein, caveolin-1 [6,7]. It is generally accepted that endocytosis via caveolae directs the receptorligand complex to lysosomal and/or proteasomal degradation [8,9] which downregulates the receptors on the cell surface. Caveolin-1 downregulation together with caveolar internalization of TGFβ receptorsturns off the TGFβ signalling pathway,thereby blocking EMT.TGFβ can induce and/or promote EMT through a Smadindependent pathway as well. In response to TGFβ the type II TGFβ receptor can autophosphorylate tyrosine amino acids (Tyr259, 336 and 424) [10], and can undergo Src-mediated tyrosine phosphorylation as well [11,12]. Thetyrosine phosphorylated TGFβ receptor can activate MAP kinase (MEK) and ERK1/2. Members of the Ras/Raf/MEK/ ERK kinase cascades are present in caveolae and caveolin-1 promotes ERK activation. Kinase suppressor of Ras1 (KSR1) is a caveolin-1 interacting protein, and the KSR1-caveolin-1 interaction is required for the redistribution of MEK/ERK in caveolin-rich fractions, actually caveolin-1 facilitates the formation of KSR1/MEK/ERK complex.KSR1-...

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Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions

et al. 2016

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Peritoneal adhesions (PAs) are fibrotic bands formed between bowel loops, solid organs, and the parietal peritoneum, which may appear following surgery, infection or endometriosis. They represent an important health problem with no effective treatment. Mesothelial cells (MCs) line the peritoneal cavity and undergo a mesothelial-to-mesenchymal transition (MMT) under pathological conditions, transforming into myofibroblasts, which are abundant in peritoneal fibrotic tissue. The aim of this study was to investigate if peritoneal MCs undergo a MMT contributing to the formation of post-surgical adhesions. Biopsies from patients with PAs were analysed by immunohistochemistry, immunofluorescence, and quantitative RT-PCR. A mouse model of PAs based on ischaemic buttons was used to modulate MMT by blocking the transforming growth factor-beta (TGF-β) pathway. The severity of adhesions and MMT-related marker expression were studied. We observed myofibroblasts derived from the conversion of MCs in submesothelial areas of patients with PAs. In addition, MMT-related markers were dysregulated in adhesion zones when compared to distant normal peritoneal tissue of the same patient. In animal experiments, blockage of TGF-β resulted in molecular reprogramming of markers related to the mesenchymal conversion of MCs and in a significant decrease in the severity of the adhesions. These data indicate for the first time that MMT is involved in PA pathogenesis. This finding opens new therapeutic strategies to interfere with adhesion formation by modulating MMT with a wide range of pharmacological agents.

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Caveolin‐1 deficiency induces a MEK‐ERK1/2‐Snail‐1‐dependent epithelial–mesenchymal transition and fibrosis during peritoneal dialysis

Cited by 25 publications

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Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties

Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties

Caveolin-1/Caveolae are in Focus of Regulating EMT and MET

Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions

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