scholarly journals Phenotypic Plasticity of the Ovarian Surface Epithelium: TGF-β1 Induction of Epithelial to Mesenchymal Transition (EMT) in Vitro

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5497-5505 ◽  
Author(s):  
Yihong Zhu ◽  
Mikael Nilsson ◽  
Karin Sundfeldt
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
Mesenchymal Transition ◽  
Epithelial Markers ◽  
Ovarian Surface ◽  
Epithelial Junction ◽  
Tgf Β1 ◽  
E Cadherin

Ovarian surface epithelium (OSE) is the most conceivable cell origin of epithelial ovarian carcinomas. Unlike many other epithelial tumors, the precancerous lesion acquires expression of epithelial markers, e.g. E-cadherin and claudins, suggesting that OSE cells undergo mesenchymal to epithelial transition (MET) during transformation. Recent findings indicate that TGF-β1, a prototypic stimulus of epithelial to mesenchymal transition (EMT), i.e. reverse to MET, is produced at significant amounts in the intact ovary. In the present study, we therefore investigated whether TGF-β1 changes the OSE phenotype accordingly, focusing on epithelial junction proteins and transcriptional EMT regulators quantified by real-time RT-PCR and Western blotting in cultured normal human OSE. Early OSE passages were found to paradoxically express de novo E-cadherin and also establish tight junctions exhibiting claudin-1 (but not claudin-3 and -4) and occludin. Stimulation with TGF-β1 (100 ng/ml) for 3–5 d down-regulated all these epithelial markers including Crumbs3 and also prevented the formation of an epithelial barrier This was accompanied by sustained expression of Snail and N-cadherin and transient expression of Slug, whereas Zeb1 (zinc finger E-box binding homeobox 1) and Twist mRNA levels were not significantly changed. In conclusion, TGF-β1 enforces the mesenchymal phenotype of OSE cells in vitro by an EMT-like process, leading to an altered molecular composition of the epithelial junction complex that partly coincides with the expression pattern of the native OSE. This suggests a potential role of TGF-β1-induced EMT in OSE under physiological conditions and possibly also in epithelial ovarian tumorigenesis.

scholarly journals Non-canonical WNT5a regulates Epithelial-to-Mesenchymal Transition in the mouse ovarian surface epithelium

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Atefeh Abedini ◽  
Céline Sayed ◽  
Lauren E. Carter ◽  
Derek Boerboom ◽  
Barbara C. Vanderhyden
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
Mesenchymal Transition ◽  
Ovarian Surface

RETRACTED: TGF-β1 induces alveolar epithelial to mesenchymal transition in vitro

Life Sciences ◽  
2004 ◽  
Vol 76 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Hong-Wei Yao ◽  
Qiang-Min Xie ◽  
Ji-Qiang Chen ◽  
Yang-Mei Deng ◽  
Hui-Fang Tang
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Tgf Β1

scholarly journals A-Kinase Anchoring Proteins Diminish TGF-β1/Cigarette Smoke-Induced Epithelial-To-Mesenchymal Transition

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 356 ◽  
Author(s):  
Haoxiao Zuo ◽  
Marina Trombetta-Lima ◽  
Irene H. Heijink ◽  
Christina H. T. J. van der Veen ◽  
Laura Hesse ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cigarette Smoke ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Epithelial Cell Line ◽  
Intracellular Camp ◽  
Mesenchymal Transition ◽  
Anchoring Proteins ◽  
Tgf Β1 ◽  
E Cadherin

Epithelial-to-mesenchymal transition (EMT) plays a role in chronic obstructive pulmonary diseases (COPD). Cyclic adenosine monophosphate (cAMP) can inhibit transforming growth factor-β1 (TGF-β1) mediated EMT. Although compartmentalization via A-kinase anchoring proteins (AKAPs) is central to cAMP signaling, functional studies regarding their therapeutic value in the lung EMT process are lacking. The human bronchial epithelial cell line (BEAS-2B) and primary human airway epithelial (pHAE) cells were exposed to TGF-β1. Epithelial (E-cadherin, ZO-1) and mesenchymal markers (collagen Ӏ, α-SMA, fibronectin) were analyzed (mRNA, protein). ELISA measured TGF-β1 release. TGF-β1-sensitive AKAPs Ezrin, AKAP95 and Yotiao were silenced while using siRNA. Cell migration was analyzed by wound healing assay, xCELLigence, Incucyte. Prior to TGF-β1, dibutyryl-cAMP (dbcAMP), fenoterol, rolipram, cilostamide, and forskolin were used to elevate intracellular cAMP. TGF-β1 induced morphological changes, decreased E-cadherin, but increased collagen Ӏ and cell migration, a process that was reversed by the inhibitor of δ/epsilon casein kinase I, PF-670462. TGF-β1 altered (mRNA, protein) expression of Ezrin, AKAP95, and Yotiao. St-Ht31, the AKAP antagonist, decreased E-cadherin (mRNA, protein), but counteracted TGF-β1-induced collagen Ӏ upregulation. Cigarette smoke (CS) increased TGF-β1 release, activated TGF signaling, augmented cell migration, and reduced E-cadherin expression, a process that was blocked by TGF-β1 neutralizing antibody. The silencing of Ezrin, AKAP95, and Yotiao diminished TGF-β1-induced collagen Ӏ expression, as well as TGF-β1-induced cell migration. Fenoterol, rolipram, and cilostamide, in AKAP silenced cells, pointed to distinct cAMP compartments. We conclude that Ezrin, AKAP95, and Yotiao promote TGF-β1-mediated EMT, linked to a TGF-β1 release by CS. AKAP members might define the ability of fenoterol, rolipram, and cilostamide to modulate the EMT process, and they might represent potential relevant targets in the treatment of COPD.

scholarly journals Microparticles derived from human erythropoietin mRNA-transfected mesenchymal stem cells inhibit epithelial-to-mesenchymal transition and ameliorate renal interstitial fibrosis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mirae Lee ◽  
Seok-hyung Kim ◽  
Jong Hyun Jhee ◽  
Tae Yeon Kim ◽  
Hoon Young Choi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mdck Cells ◽  
Mesenchymal Transition ◽  
Human Erythropoietin ◽  
Renal Tubulointerstitial Fibrosis ◽  
Tgf Β1 ◽  
E Cadherin

Abstract Background Renal tubulointerstitial fibrosis (TIF) plays an important role in the progression of chronic kidney disease (CKD) and its pathogenesis involves epithelial-to-mesenchymal transition (EMT) upon renal injury. Recombinant human erythropoietin (rhEPO) has been shown to display novel cytoprotective effects, in part by inhibiting transforming growth factor (TGF)-β1-induced EMT. Here, we evaluated the inhibitory effects of microparticles (MPs) derived from human EPO gene-transfected kidney mesenchymal stem cells (hEPO-KMSCs) against TGF-β1-induced EMT in Madin-Darby canine kidney (MDCK) cells and against TIF in mouse kidneys with unilateral ureteral obstruction (UUO). Methods EMT was induced in MDCK cells by treatment with TGF-β1 (5 ng/mL) for 48 h and then inhibited by co-treatment with rhEPO (100 IU/mL), mock gene-transfected KMSC-derived MPs (MOCK-MPs), or hEPO-KMSC-derived MPs (hEPO-MPs) for a further 48 h. UUO was induced in FVB/N mice, which were then treated with rhEPO (1000 IU/kg, intraperitoneally, every other day for 1 week), MOCK-MPs, or hEPO-MPs (80 μg, intravenously). Alpha-smooth muscle actin (α-SMA), fibronectin, and E-cadherin expression were evaluated in MDCK cells and kidney tissues, and the extent of TIF in UUO kidneys was assessed by immunohistochemical staining. Results TGF-β1 treatment significantly increased α-SMA and fibronectin expression in MDCK cells and decreased that of E-cadherin, while co-treatment with rhEPO, MOCK-MPs, or hEPO-MPs markedly attenuated these changes. In addition, rhEPO and hEPO-MP treatment effectively decreased phosphorylated Smad2 and Smad3, as well as phosphorylated p38 mitogen-activated protein kinase (MAPK) expression, suggesting that rhEPO and rhEPO-MPs can inhibit TGF-β1-induced EMT via both Smad and non-Smad pathways. rhEPO and hEPO-MP treatment also significantly attenuated the extent of renal TIF after 1 week of UUO compared to MOCK-MPs, with hEPO-MPs significantly reducing myofibroblast and F4/80+ macrophage infiltration as well as EMT marker expression in UUO renal tissues in a similar manner to rhEPO. Conclusions Our results demonstrate that hEPO-MPs modulate TGF-β1-induced EMT in MDCK cells via the Smad2, Smad3, and p38 MAPK pathways and significantly attenuated renal TIF in UUO kidneys.

scholarly journals Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1340 ◽  
Author(s):  
Olaia Martinez-Iglesias ◽  
Alba Casas-Pais ◽  
Raquel Castosa ◽  
Andrea Díaz-Díaz ◽  
Daniel Roca-Lema ◽  
...  
Keyword(s):  
Small Molecule ◽  
Ubiquitin Ligase ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
E3 Ubiquitin Ligase ◽  
Therapeutic Drug ◽  
Mesenchymal Transition ◽  
E Cadherin

The requirement of the E3 ubiquitin-ligase Hakai for the ubiquitination and subsequent degradation of E-cadherin has been associated with enhanced epithelial-to-mesenchymal transition (EMT), tumour progression and carcinoma metastasis. To date, most of the reported EMT-related inhibitors were not developed for anti-EMT purposes, but indirectly affect EMT. On the other hand, E3 ubiquitin-ligase enzymes have recently emerged as promising therapeutic targets, as their specific inhibition would prevent wider side effects. Given this background, a virtual screening was performed to identify novel specific inhibitors of Hakai, targeted against its phosphotyrosine-binding pocket, where phosphorylated-E-cadherin specifically binds. We selected a candidate inhibitor, Hakin-1, which showed an important effect on Hakai-induced ubiquitination. Hakin-1 also inhibited carcinoma growth and tumour progression both in vitro, in colorectal cancer cell lines, and in vivo, in a tumour xenograft mouse model, without apparent systemic toxicity in mice. Our results show for the first time that a small molecule putatively targeting the E3 ubiquitin-ligase Hakai inhibits Hakai-dependent ubiquitination of E-cadherin, having an impact on the EMT process. This represents an important step forward in a future development of an effective therapeutic drug to prevent or inhibit carcinoma tumour progression.

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