scholarly journals Ursolic Acid Attenuates TGF-β1-Induced Epithelial‐Mesenchymal Transition in NSCLC by Targeting Integrin αVβ5/MMPs Signaling

2019 ◽  
Vol 27 (5) ◽  
pp. 593-600 ◽  
Author(s):  
Jun Shan Ruan ◽  
Huan Zhou ◽  
Lin Yang ◽  
Ling Wang ◽  
Zong Sheng Jiang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ursolic Acid ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β1 ◽  
Nsclc Cell Line ◽  
Mesenchymal Transition ◽  
New Findings ◽  
Underlying Mechanisms ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced epithelial‐mesenchymal transition (EMT) of non-small cell lung cancer (NSCLC) may contribute to tumor metastasis. TGF-β1-induced EMT in H1975 cells (a human NSCLC cell line) resulted in the adoption of mesenchymal responses that were predominantly mediated via the TGF-β1‐integrin signaling pathway. Ursolic acid has been previously reported to inhibit tumor growth and metastasis in several cancers. However, whether ursolic acid can attenuate TGF-β1-induced EMT in H1975 cells and its underlying mechanisms remain unknown. In this study, ursolic acid significantly attenuated the TGF-β1-induced decrease in E-cadherin level and elevated the level of N-cadherin. Furthermore, ursolic acid inhibited the mesenchymal-like responses in H1975 cells, including cell migration, invasion, and activity of matrix metallopeptidase (MMP)-2 and -9. Finally, our new findings provided evidence that ursolic acid could inhibit EMT in NSCLC through TGF-β1 signaling pathway-mediated integrin αVβ5 expression, and this might be the potential mechanism of resveratrol on the inhibition of invasion and metastases in NSCLC. We conclude that ursolic acid attenuated TGF-β1-induced EMT in H1975 cells and thus might be a promising therapeutic agent for treating NSCLC.

Rho kinase mediates transforming growth factor-β1-induced vasculogenic mimicry formation: involvement of the epithelial–mesenchymal transition and cancer stemness activity

2020 ◽  
Vol 52 (4) ◽  
pp. 411-420 ◽  
Author(s):  
Xue Zhang ◽  
Jigang Zhang ◽  
Heming Zhou ◽  
Gaolin Liu ◽  
Qin Li
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Vasculogenic Mimicry ◽  
Rho Kinase ◽  
Transforming Growth Factor Β1 ◽  
Cell Phenotype ◽  
Mesenchymal Transition ◽  
Tgf Β1

Abstract Vasculogenic mimicry (VM), a newly defined pattern of tumor blood supply, has been identified in several malignant tumors, including hepatocellular carcinoma (HCC). Rho kinase (ROCK) plays an important role in various types of cancers. However, whether ROCK participates in transforming growth factor-β1 (TGF-β1)-induced VM formation is unclear. Here, we evaluated the role of ROCK in TGF-β1-induced VM formation in HCC. Our findings showed that the TGF-β1/ROCK signaling pathway is involved in VM formation by inducing the epithelial–mesenchymal transition. Furthermore, TGF-β1 and ROCK were found to play distinct roles in the cancer stem cell phenotype during VM formation. These results provide insights into potential antitumor therapies for inhibiting VM by targeting the TGF-β1/ROCK signaling pathway in HCC.

scholarly journals Melatonin Inhibits Transforming Growth Factor-β1-Induced Epithelial–Mesenchymal Transition in AML12 Hepatocytes

Biology ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 84 ◽  
Author(s):  
Kim ◽  
Park ◽  
Kim ◽  
Leem ◽  
Park
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Protective Action ◽  
Transforming Growth Factor Β1 ◽  
Membrane Receptors ◽  
Mitogen Activated Protein Kinase ◽  
Independent Manner ◽  
Mesenchymal Transition ◽  
Tgf Β1

Recent studies showed that melatonin, a well-known pineal hormone that modulates the circadian rhythm, exerts beneficial effects against liver fibrosis. However, mechanisms for its protective action against the fibrotic processes remain incompletely understood. Here, we aimed to explore the effects of the hormone on transforming growth factor-β1 (TGF-β1)-stimulated epithelial–mesenchymal transition (EMT) in AML12 hepatocytes. Pretreatment with melatonin dose-dependently reversed downregulation of an epithelial marker and upregulation of mesenchymal markers after TGF-β1 stimulation. Additionally, melatonin dose-dependently suppressed an increased phosphorylation of Smad2/3 after TGF-β1 treatment. Besides the canonical Smad signaling pathway, an increase in phosphorylation of extracellular signal-regulated kinase 1/2 and p38 was also dose-dependently attenuated by melatonin. The suppressive effect of the hormone on EMT stimulated by TGF-β1 was not affected by luzindole, an antagonist of melatonin membrane receptors, suggesting that its membrane receptors are not required for the inhibitory action of melatonin. Moreover, melatonin suppressed elevation of intracellular reactive oxygen species (ROS) levels in TGF-β1-treated cells. Finally, TGF-β1-stimulated EMT was also inhibited by the antioxidant N-acetylcysteine. Collectively, these results suggest that melatonin prevents TGF-β1-stimulated EMT through suppression of Smad and mitogen-activated protein kinase signaling cascades by deactivating ROS-dependent mechanisms in a membrane receptor-independent manner.

miR-30d Blocked Transforming Growth Factor β1–Induced Epithelial-Mesenchymal Transition by Targeting Snail in Ovarian Cancer Cells

2015 ◽  
Vol 25 (9) ◽  
pp. 1574-1581 ◽  
Author(s):  
Zhongxue Ye ◽  
Le Zhao ◽  
Jie Li ◽  
Wei Chen ◽  
Xu Li
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β1 ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Transition ◽  
Polymerase Chain ◽  
Tgf Β1

ObjectiveMicroRNAs (miRs) are essential regulators of gene expression by suppressing translation or causing degradation of target mRNA. Growing evidence sheds light on the crucial roles of miR dysregulation in cancer development and progression. In this study, we focused on the role of miR-30d in transforming growth factor β1 (TGF-β1)–initiated epithelial-mesenchymal transition (EMT) in ovarian cancer cells.MethodsTransforming growth factor β1 (10 ng/mL) was used to initiate EMT in SKOV3 and 3AO cells. The expression of miR-30 family members was determined by quantitative real-time polymerase chain reaction. Messenger RNA and protein levels of E-cadherin, N-cadherin, vimentin, and Snail were detected by quantitative real-time polymerase chain reaction and Western blot, respectively. Cell migration and invasion capacities were evaluated by Transwell chamber assay. Luciferase activity assay was performed to verify the direct inhibition of Snail by miR-30d.ResultsMiR-30b, MiR-30c, and MiR-30d were down-regulated during TGF-β1–induced EMT in SKOV3 and 3AO ovarian cancer cells. Restoration of miR-30d by miR-30d mimic reversed TGF-β1–induced EMT phenotypes including the morphological changes, expression pattern of molecular markers (E-cadherin, N-cadherin), and migratory and invasive capabilities in ovarian cancer cells. Furthermore, Snail was identified as the direct target of miR-30d.ConclusionsOur results revealed that miR-30d functioned as a suppressor of ovarian cancer progression by decreasing Snail expression and thus blocking TGF-β1–induced EMT process, suggesting the potentiality of miR-30d analogs to be used as therapeutics for ovarian cancer.

scholarly journals Klotho prevents epithelial–mesenchymal transition through Egr-1 downregulation in diabetic kidney disease

2021 ◽  
Vol 9 (1) ◽  
pp. e002038
Author(s):  
Yang Li ◽  
Meng Xue ◽  
Fang Hu ◽  
Yijie Jia ◽  
Zongji Zheng ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Signaling Pathway ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Diabetic Kidney ◽  
Mesenchymal Transition ◽  
Hk2 Cells ◽  
Tgf Β1

IntroductionAs a key event leading to tubulointerstitial fibrosis in diabetic kidney disease (DKD), epithelial–mesenchymal transition (EMT) has drawn increasing attention from researchers. The antiaging protein Klotho attenuates renal fibrosis in part by inhibiting ERK1/2 signaling in DKD. Early growth response factor 1 (Egr-1), which is activated mainly by ERK1/2, has been shown to play an important role in EMT. However, whether Klotho prevents EMT by inhibiting ERK1/2-dependent Egr-1 expression in DKD is unclear.The aim of this study was to investigate whether Klotho prevents EMT through Egr-1 downregulation by inhibiting the ERK1/2 signaling pathway in DKD.Research design and methodsMale C57BL/6J mice fed an high-fat diet for 4 weeks received 120 mg/kg streptozotocin (STZ), which was injected intraperitoneally. Klotho and Egr-1 expression was detected in the renal cortices of these mice on their sacrifice at 6 and 12 weeks after STZ treatment. In In vitro studies, we incubated HK2 cells under high-glucose (HG) or transforming growth factor-β1 (TGF-β1) conditions to mimic DKD. We then transfected the cells with an Klotho-containing plasmid, Klotho small interfering RNA.ResultsKlotho expression was significantly decreased in the renal cortices of mice with diabetes mellitus (DM) compared with the renal cortices of control mice at 6 weeks after treatment and even more significantly decreased at 12 weeks. In contrast, Egr-1 expression was significantly increased in mice with DM compared with control mice only at 12 weeks. We also found that Klotho overexpression downregulated Egr-1 expression and the (p-ERK1/2):(ERK1/2) ratio in HG-treated or TGF-β1-treated HK2 cells. Conversely, Klotho silencing upregulated Egr-1 expression and the (p-ERK1/2):(ERK1/2) ratio in HG-treated or TGF-β1-treated HK2 cells. Moreover, the effects of si-Klotho were abolished by the ERK1/2 inhibitor PD98059.ConclusionsKlotho prevents EMT during DKD progression, an effect that has been partially attributed to Egr-1 downregulation mediated by ERK1/2 signaling pathway inhibition.

scholarly journals A New TGF-β1 Inhibitor, CTI-82, Antagonizes Epithelial–Mesenchymal Transition through Inhibition of Phospho-SMAD2/3 and Phospho-ERK

Biology ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 143
Author(s):  
Ji-Hoon Jeong ◽  
Hyunhee Kim ◽  
Seung-Ho Park ◽  
Hayeon Park ◽  
Minseok Jeong ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β1 ◽  
Inhibitory Effects ◽  
Mesenchymal Transition ◽  
Tgf Β1 ◽  
A549 Lung

Transforming growth factor-β1 (TGF-β1) is highly expressed in the tumor microenvironment and known to play a multifunctional role in cancer progression. In addition, TGF-β1 promotes metastasis by inducing epithelial–mesenchymal transition (EMT) in a variety of tumors. Thus, inhibition of TGF-β1 is considered an important strategy in the treatment of cancer. In most tumors, TGF-β1 signal transduction exhibits modified or non-functional characteristics, and TGF-β1 inhibitors have various inhibitory effects on cancer cells. Currently, many studies are being conducted to develop TGF-β1 inhibitors from non-toxic natural compounds. We aimed to develop a new TGF-β1 inhibitor to suppress EMT in cancer cells. As a result, improved chalcone-like chain CTI-82 was identified, and its effect was confirmed in vitro. We showed that CTI-82 blocked TGF-β1-induced EMT by inhibiting the cell migration and metastasis of A549 lung cancer cells. In addition, CTI-82 reduced the TGF-β1-induced phosphorylation of SMAD2/3 and inhibited the expression of various EMT markers. Our results suggest that CTI-82 inhibits tumor growth, migration, and metastasis.

scholarly journals MiR-203a-3p regulates TGF-β1-induced epithelial–mesenchymal transition (EMT) in asthma by regulating Smad3 pathway through SIX1

2020 ◽  
Vol 40 (2) ◽  
Author(s):  
Qi Fan ◽  
Yu Jian
Keyword(s):  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Airway Disease ◽  
Transforming Growth Factor Β1 ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Sine Oculis ◽  
Protein Levels ◽  
Tgf Β1

Abstract Asthma is a common chronic airway disease with increasing prevalence. MicroRNAs act as vital regulators in cell progressions and have been identified to play crucial roles in asthma. The objective of the present study is to clarify the molecular mechanism of miR-203a-3p in the development of asthma. The expression of miR-203a-3p and Sine oculis homeobox homolog 1 (SIX1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of SIX1, fibronectin, E-cadherin, vimentin, phosphorylated-drosophila mothers against decapentaplegic 3 (p-Smad3) and Smad3 were measured by Western blot. The interaction between miR-203a-3p and SIX1 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. MiR-203a-3p was down-regulated and SIX1 was up-regulated in asthma serums, respectively. Transforming growth factor-β1 (TGF-β1) treatment induced the reduction of miR-203a-3p and the enhancement of SIX1 in BEAS-2B and 16HBE cells in a time-dependent manner. Subsequently, functional experiments showed the promotion of epithelial–mesenchymal transition (EMT) induced by TGF-β1 treatment could be reversed by miR-203a-3p re-expression or SIX1 deletion in BEAS-2B and 16HBE cells. SIX1 was identified as a target of miR-203a-3p and negatively regulated by miR-203a-3p. Then rescue assay indicated that overexpressed miR-203a-3p ameliorated TGF-β1 induced EMT by regulating SIX1 in BEAS-2B and 16HBE cells. Moreover, miR-203a-3p/SIX1 axis regulated TGF-β1 mediated EMT process in bronchial epithelial cells through phosphorylating Smad3. These results demonstrated that MiR-203a-3p modulated TGF-β1-induced EMT in asthma by regulating Smad3 pathway through targeting SIX1.

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