scholarly journals β-Catenin/Smad3 Interaction Regulates Transforming Growth Factor-β-Induced Epithelial to Mesenchymal Transition in the Lens

2019 ◽  
Vol 20 (9) ◽  
pp. 2078 ◽  
Author(s):  
Aftab Taiyab ◽  
Julie Holms ◽  
Judith A. West-Mays
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Vision Loss ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Ex Vivo ◽  
Smooth Muscle Actin ◽  
Posterior Capsular Opacification ◽  
Mesenchymal Transition

Cataracts are the leading cause of blindness worldwide. Although surgery is a successful method to restore vision loss due to cataracts, post-surgical complications can occur, such as secondary cataracts, also known as posterior capsular opacification (PCO). PCO arises when lens epithelial cells (LEC) are left behind in the capsular bag following surgery and are induced to undergo epithelial to mesenchymal transition (EMT). Following EMT, LEC morphology and phenotype are altered leading to a loss of transparency and vision. Transforming growth factor (TGF)-β-induced signaling through both canonical, TGF-β/Smad, and non-canonical, β-catenin/Wnt and Rho/ROCK/MRTF-A, pathways have been shown to be involved in lens EMT, and thus PCO. However, the interactions between these signaling pathways in the lens have not been thoroughly explored. In the current study we use rat LEC explants as an ex vivo model, to examine the interplay between three TGF-β-mediated pathways using α-smooth muscle actin (α-SMA) as a molecular marker for EMT. We show that Smad3 inhibition via SIS3 prevents nuclear translocation of β-catenin and MRTF-A, and α-SMA expression, suggesting a key role of Smad3 in regulation of MRTF-A and β-catenin nuclear transport in LECs. Further, we demonstrate that inhibition of β-catenin/CBP interaction by ICG-001 decreased the amount of phosphorylated Smad3 upon TGF-β stimulation in addition to significantly decreasing the expression levels of TGF-β receptors, TBRII and TBRI. Overall, our findings demonstrate interdependence between the canonical and non-canonical TGF-β-mediated signaling pathways controlling EMT in the lens.

scholarly journals Microparticles as Potential Mediators of High Glucose-Induced Renal Cell Injury

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 348 ◽  
Author(s):  
Ravindran ◽  
Pasha ◽  
Agouni ◽  
Munusamy
Keyword(s):  
Er Stress ◽  
Signaling Pathways ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Cell Injury ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Mesenchymal Transition

Diabetic nephropathy (DN) is the most common cause of chronic kidney disease worldwide. Activation of signaling pathways such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), endoplasmic reticulum (ER) stress, transforming growth factor-beta (TGF-β), and epithelial-mesenchymal transition (EMT), are thought to play a significant role in the etiology of DN. Microparticles (MPs), the small membrane vesicles containing bioactive signals shed by cells upon activation or during apoptosis, are elevated in diabetes and were identified as biomarkers in DN. However, their exact role in the pathophysiology of DN remains unclear. Here, we examined the effect of MPs shed from renal proximal tubular cells (RPTCs) exposed to high glucose conditions on naïve RPTCs in vitro. Our results showed significant increases in the levels of phosphorylated forms of 4E-binding protein 1 and ERK1/2 (the downstream targets of mTOR and ERK pathways), phosphorylated-eIF2α (an ER stress marker), alpha smooth muscle actin (an EMT marker), and phosphorylated-SMAD2 and nuclear translocation of SMAD4 (markers of TGF-β signaling). Together, our findings indicate that MPs activate key signaling pathways in RPTCs under high glucose conditions. Pharmacological interventions to inhibit shedding of MPs from RPTCs might serve as an effective strategy to prevent the progression of DN.

scholarly journals Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-β1

2017 ◽  
Vol 313 (4) ◽  
pp. F961-F972 ◽  
Author(s):  
Junpeng Wang ◽  
Yang Chen ◽  
Di Gu ◽  
Guihao Zhang ◽  
Jiawei Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Bladder Wall ◽  
Transforming Growth Factor Β1 ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Tgf Β1

Bladder wall fibrosis is a major complication of ketamine-induced cystitis (KC), but the underlying pathogenesis is poorly understood. The aim of the present study was to elucidate the mechanism of ketamine-induced fibrosis in association with epithelial-to-mesenchymal transition (EMT) mediated by transforming growth factor-β1 (TGF-β1). Sprague-Dawley rats were randomly distributed into four groups, which received saline, ketamine, ketamine combined with a TGF-β receptor inhibitor (SB-505124) for 16 wk, or 12 wk of ketamine and 4 wk of abstinence. In addition, the profibrotic effect of ketamine was confirmed in SV-40 immortalized human uroepithelial (SV-HUC-1) cells. The ketamine-treated rats displayed voiding dysfunction and decreased bladder compliance. Bladder fibrosis was accompanied by the appearance of a certain number of cells expressing both epithelial and mesenchymal markers, indicating that epithelial cells might undergo EMT upon ketamine administration. Meanwhile, the expression level of TGF-β1 was significantly upregulated in the urothelium of bladders in ketamine-treated rats. Treatment of SV-HUC-1 cells with ketamine increased the expression of TGF-β1 and EMT-inducing transcription factors, resulting in the downregulation of E-cadherin and upregulation of fibronectin and α-smooth muscle actin. Administration of SB-505124 inhibited EMT and fibrosis both in vitro and vivo. In addition, withdrawal from ketamine did not lead to recovery of bladder urinary function or decreased fibrosis. Taken together, our study shows for the first time that EMT might contribute to bladder fibrosis in KC. TGF-β1 may have an important role in bladder fibrogenesis via an EMT mechanism.

scholarly journals Roles of microRNAs in Regulating Cancer Stemness in Head and Neck Cancers

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1742
Author(s):  
Melysa Fitriana ◽  
Wei-Lun Hwang ◽  
Pak-Yue Chan ◽  
Tai-Yuan Hsueh ◽  
Tsai-Tsen Liao
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Cancer Stemness ◽  
Mesenchymal Transition

Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40–50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor initiation, progression, metastasis, immune evasion, chemo-/radioresistance, and recurrence. The acquisition of stem-like properties of cancer cells further provides cellular plasticity for stress adaptation and contributes to therapeutic resistance, resulting in a worse clinical outcome. Thus, targeting cancer stemness is fundamental for cancer treatment. MicroRNAs (miRNAs) are known to regulate stem cell features in the development and tissue regeneration through a miRNA–target interactive network. In HNSCCs, miRNAs act as tumor suppressors and/or oncogenes to modulate cancer stemness and therapeutic efficacy by regulating the CSC-specific tumor microenvironment (TME) and signaling pathways, such as epithelial-to-mesenchymal transition (EMT), Wnt/β-catenin signaling, and epidermal growth factor receptor (EGFR) or insulin-like growth factor 1 receptor (IGF1R) signaling pathways. Owing to a deeper understanding of disease-relevant miRNAs and advances in in vivo delivery systems, the administration of miRNA-based therapeutics is feasible and safe in humans, with encouraging efficacy results in early-phase clinical trials. In this review, we summarize the present findings to better understand the mechanical actions of miRNAs in maintaining CSCs and acquiring the stem-like features of cancer cells during HNSCC pathogenesis.

Transforming growth factor-β2-mediated mesenchymal transition in lens epithelial cells is repressed in the absence of RAGE

2021 ◽  
Vol 478 (12) ◽  
pp. 2285-2296
Author(s):  
Mi-Hyun Nam ◽  
Mina B. Pantcheva ◽  
Johanna Rankenberg ◽  
Ram H. Nagaraj
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Knockout Mice ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Lens Epithelial Cells ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Transforming Growth Factor Β2

Transforming growth factor-β2 (TGFβ2)-mediated epithelial to mesenchymal transition (EMT) in lens epithelial cells (LECs) has been implicated in fibrosis associated with secondary cataracts. In this study, we investigated whether the receptor for advanced glycation end products (RAGE) plays a role in TGFβ2-mediated EMT in LECs. Unlike in the LECs from wild-type mice, TGFβ2 failed to elicit an EMT response in LECs from RAGE knockout mice. The lack of RAGE also diminished TGFβ2-mediated Smad signaling. In addition, treatment with TGFβ2 increased IL-6 levels in LECs from wild-type mice but not in those from RAGE knockout mice. Treatment of human LECs with the RAGE inhibitor FPS-ZM1 reduced TGFβ2-mediated Smad signaling and the EMT response. Unlike that in wild-type lenses, the removal of fiber cell tissue in RAGE knockout lenses did not result in elevated levels of α-smooth muscle actin (α-SMA), fibronectin (FN), and integrin β1 in capsule-adherent LECs. Taken together, these results suggest that TGFβ2 signaling is intricately linked to RAGE. Targeting RAGE could be explored as a therapeutic strategy against secondary cataracts.

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

2018 ◽  
Vol 39 (01) ◽  
pp. 053-069 ◽  
Author(s):  
Serena Mancarella ◽  
Antonio Cigliano ◽  
Annarita Chieti ◽  
Gianluigi Giannelli ◽  
Francesco Dituri
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Large Fraction ◽  
Poor Response ◽  
Tumor Promoter ◽  
Molecular Heterogeneity ◽  
Metastatic Progression ◽  
Functional Link ◽  
Mesenchymal Transition

AbstractTherapeutic attempts to treat hepatocellular carcinoma (HCC) frequently result in a poor response or treatment failure. The efficacy of approved drugs and survival expectancies is affected by an ample degree of variability that can be explained at least in part by the enormous between-patient cellular and molecular heterogeneity of this neoplasm. Transforming growth factor-β (TGF-β) is hyperactivated in a large fraction of HCCs, where it influences complex interactive networks covering multiple cell types and a plethora of other local soluble ligands, ultimately establishing several malignancy traits. This cytokine boosts the invasiveness of cancerous epithelial cells through promoting the epithelial-to-mesenchymal transition program, but also skews the phenotype of immune cells toward a tumor-supporting status. Here, we discuss recent strategies pursued to offset TGF-β-dependent processes that promote metastatic progression and immune surveillance escape in solid cancers, including HCC. Moreover, we report findings indicating that TGF-β reduces the expression of the proinflammatory factors CCL4 and interleukin-1β (IL-1β in human ex vivo treated HCC tissues. While this is consistent with the anti-inflammatory properties of TGF-β, whether it is an outright tumor promoter or suppressor is still a matter of some debate. Indeed, IL-1β has also been shown to support angiogenesis and cell invasiveness in some cancers. In addition, we describe an inhibitory effect of TGF-β on the secretion of CCL2 and CXCL1 by HCC-derived fibroblasts, which suggests the existence of an indirect stroma-mediated functional link between TGF-β and downstream immunity.

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