scholarly journals Integrative analysis of the canonical TGF?-Smad signaling pathway in breast cancer (Preprint)

2017 ◽  
Author(s):  
Dan Zhou ◽  
Weiwei Tang ◽  
Yun Zhang ◽  
Hanxiang An
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Luminal A ◽  
Independent Manner ◽  
Free Survival ◽  
Smad Pathway ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Cancer Pathogenesis ◽  
Smad Signaling Pathway

BACKGROUND Breast cancer deaths are mainly attributed to metastasis, while epithelial to mesenchymal transition (EMT) plays a pivotal role in promoting cancer cell metastasis. EMT is activated by various stimuli, resulting in different therapeutic responses. The TGFβ signaling pathway is a canonical driver of EMT, and many molecular drugs are developed to target this pathway. However, the alternations of this pathway in BC remain elusive. OBJECTIVE The aim of this study was to investigate the relationship between the canonical TGFβ-Smad signaling pathway and breast cancer pathogenesis. METHODS Herein, we investigated the mutational, transcriptional, epigenetic and post-transcriptional alternations of 14 core members in this pathway through bioinformatics approach by analyses of 56,496 BC patients from various public databases, including COSMIC, Oncomine, DiseaseMeth and Starbase. A protein-protein interaction network was derived from Cytoscape software. Associations of these selected members with relapse free survival (RFS), overall survival (OS), distant metastases free survival (DMFS) and post progression survival (PPS) were performed using the Kaplan-Meier plotter online tool. RESULTS Our integrated analyses revealed that Smad4 was the most frequently mutated member of the TGFβ-Smad pathway in BC with a mutation frequency of 0.85% (30/3537). The expression levels of TGFβ1, TGFβ3, Smad1, Smad2 and Smad7 were significantly higher, whereas TGFβ2, ALK1, ALK2, ALK5, TGFβR2, Smad3, Smad4, Smad5 and Smad6 were downregulated in BC compared with normal subjects (P<0.001). Evaluation of epigenetic alteration identified that the promoters of ALK1 (P=0.000e+00), ALK2 (P=2.22e-16) and ALK5 (P=1.625e-12) were hypermethylated in 1,274 BC samples. In contrast, Smad2 (P=6.56e-04) was significantly hypomethylated in BC. Although all 14 members had potential diagnostic significances with different prediction power (AUC ranging from 0.788 to 1.00) in various subtypes of BC, only TGFβ3 could predict RFS (HR=0.69, 95% CI [0.62-0.77]), OS (HR=0.69, 95% CI [0.56-0.86]), DMFS (HR=0.8, 95% CI [0.66-0.97]) and PPS (HR=0.76, 95% CI [0.6-0.97]) for patients with BC in an independent manner. Additionally, 11 out of 14 members were associated with RFS in luminal A BC. CONCLUSIONS Our results indicated that TGFβ-Smad pathway core members could serve as novel diagnostic and prognostic biomarkers in BC.

scholarly journals LncRNA NEAT1 promotes proliferation, migration, invasion and epithelial-mesenchymal transition process in TGF-β2-stimulated lens epithelial cells through regulating the miR-486-5p/SMAD4 axis

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Huajun Wang ◽  
Guangying Zheng
Keyword(s):  
Epithelial Cells ◽  
Signaling Pathway ◽  
Luciferase Reporter ◽  
Posterior Capsular Opacification ◽  
Lens Epithelial Cells ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Smad Signaling Pathway ◽  
Mesenchymal Transformation

Abstract Background Abnormal proliferation, metastasis and epithelial-mesenchymal transformation (EMT) of lens epithelial cells (LECs) are direct factors of posterior capsular opacification (PCO). Nuclear enriched abundant transcript 1 (NEAT1) has been shown to promote cell proliferation, metastasis and EMT, but whether it affects the progression of PCO is unclear. Methods The expression of NEAT1, microRNA-486-5p (miR-486-5p) and Drosophila mothers against decapentaplegic 4 (SMAD4) was determined using quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation of cells was measured via 3-(4, 5-dimethyl-2 thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Transwell assay was employed to detect the migration and invasion of cells. The levels of EMT marker proteins, SMAD4 protein and transforming growth factor-β (TGF-β)/SMAD signaling pathway-related proteins were assessed by western blot (WB) analysis. Further, the relationship between miR-486-5p and NEAT1 or SMAD4 was confirmed by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and biotin-labeled RNA pull-down assay. Results NEAT1 is upregulated and miR-486-5p is downregulated in the posterior capsular tissues of PCO patients and TGF-β2-induced LECs. Interference of NEAT1 reverses the promoting effect of TGF-β2 on the proliferation, migration, invasion and EMT of LECs. MiR-486-5p can be sponged by NEAT1, and its inhibitor reverses the suppression effect of NEAT1 silencing on the progression of TGF-β2-induced LECs. SMAD4 functions as a target of miR-486-5p, and its overexpression recovers the inhibition effect of miR-486-5p overexpression on the progression of TGF-β2-induced LECs. The activity of the TGF-β/SMAD signaling pathway is regulated by the NEAT1/miR-486-5p/SMAD4 axis. Conclusion Our study shows that NEAT1 has a positive effect on the progression of PCO and is expected to become a new target for PCO treatment.

Calycosin Inhibits Intestinal Fibrosis on CCD-18Co Cells via Modulating Transforming Growth Factor-β/Smad Signaling Pathway

Pharmacology ◽  
2019 ◽  
Vol 104 (1-2) ◽  
pp. 81-89 ◽  
Author(s):  
Jing Liu ◽  
Tan Deng ◽  
Yaxin Wang ◽  
Mengmeng Zhang ◽  
Guannan Zhu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Collagen I ◽  
Smad Pathway ◽  
Smad Signaling ◽  
Intestinal Fibrosis ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Background: Intestinal fibrosis is the major complication of Crohn’s disease (CD). There are no other good treatments for CD except surgery and remains a refractory disease. Calycosin (CA), the active component of astragalus membranaceus, has been reported the potential effect on lung fibrosis and renal fibrosis. In this study, we aim to explore the effect of CA on intestinal fibrosis in vitro and the possible signal pathway. Methods: The antifibrotic effect of CA is investigated in human intestinal fibroblasts (CCD-18Co) cells induced by transforming growth factor-β1 (TGF-β1). MTT method was used to screen the concentration of CA. Real-time polymerase chain reaction and western blot analysis were used to evaluate the expression of α-smooth muscle actin (α-SMA), collagen I, and TGF-β/Smad pathway. Results: The results showed that the concentration of CA was 12.5, 25, 50 μmol/L. CA could inhibit the expression of α-SMA and collagen I. In addition, CA regulated the expression of TGF-β/Smad signaling pathway. Conclusion: This study demonstrated that CA could inhibit the activation of CCD-18Co cells and reduce the expression of extracellular matrix. Our study highlighted that CA-inhibited TGF-β/Smad pathway through inhibiting the expression of p-Smad2, p-Smad3, Smad4, and TGF-β1 and raised the Smad7 expression. Therefore, CA might inhibit intestinal fibrosis by inhibiting the TGF-β/Smad pathway.

scholarly journals Tangzhiqing Granules Alleviate Podocyte Epithelial-Mesenchymal Transition in Kidney of Diabetic Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Haiyan Xu ◽  
Xu Wang ◽  
Mingming Liu ◽  
Xueyuan He
Keyword(s):  
Molecular Markers ◽  
Treatment Group ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Diabetic Rats ◽  
High Dose ◽  
Mesenchymal Transition ◽  
Dose Treatment ◽  
Smad Signaling ◽  
Smad Signaling Pathway

This study discussed the effect of Tangzhiqing granules on podocyte epithelial-mesenchymal transition in kidney of diabetic rats. The diabetic rats were divided randomly into five groups: DM group treated with vehicle, Tangzhiqing granules low-dose treatment group, Tangzhiqing granules middle-dose treatment group, and Tangzhiqing granules high-dose treatment group. Eight Wistar rats used as control group were given saline solution. The intervention was all intragastric administration for 8 weeks. At the end of the 8 weeks, biochemical parameters and kidney weight/body weight ratio were measured. The kidney tissues were observed under light microscope and transmission electron microscopy. To search for the underlying mechanism, we examined the epithelial-to-mesenchymal transition (EMT) related molecular markers and TGF-β/smad signaling pathway key proteins expression. The results showed that Tangzhiqing granules relieved the structural damage and functional changes of diabetic kidneys. Kidney podocyte EMT related molecular markers nephrin and CD2AP expression were increased, when desmin and α-SMA levels were decreased by Tangzhiqing granules in diabetic rats. Further TGF-β/smad signaling pathway key proteins TGF-β1 and p-smad2/3 levels were decreased in diabetic rats after treatment with Tangzhiqing granules. These findings suggest that Tangzhiqing granules may protect the podocytes of diabetic nephropathy rats via alleviating podocyte EMT and likely activating TGFβ/smad signaling pathway.

scholarly journals DcR3 induces epithelial-mesenchymal transition through activation of the TGF-β3/SMAD signaling pathway in CRC

Oncotarget ◽  
2016 ◽  
Vol 7 (47) ◽  
pp. 77306-77318 ◽  
Author(s):  
Yan-Ping Liu ◽  
Hui-Fang Zhu ◽  
Ding-li Liu ◽  
Zhi-Yan Hu ◽  
Sheng-Nan Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Smad Signaling Pathway

Abstract 187: Epigenetic memory during breast cancer progression is sustained by Smad signaling pathway

2010 ◽  
Author(s):  
Sam Thiagalingam ◽  
Arthur W. Lambert ◽  
Sait Ozturk ◽  
Hamid M. Abdolmaleky ◽  
Panagiotis Papageorgis
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Breast Cancer Progression ◽  
Epigenetic Memory ◽  
Smad Signaling ◽  
Smad Signaling Pathway

scholarly journals Effects of Astragaloside IV Against the TGF-β1-Induced Epithelial-to-Mesenchymal Transition in Peritoneal Mesothelial Cells by Promoting Smad 7 Expression

2015 ◽  
Vol 37 (1) ◽  
pp. 43-54 ◽  
Author(s):  
Lu Zhang ◽  
Zhenghong Li ◽  
Weiming He ◽  
Lingdong Xu ◽  
Jing Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Treated Group ◽  
Mesothelial Cells ◽  
Vehicle Group ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Peritoneal Mesothelial Cells ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Background/Aims: To investigate the effect of Astragaloside IV (AS-IV) on the regulation of the TGF-β1/Smad signaling pathway in peritoneal mesothelial cells with an epithelial-to-mesenchymal transition (EMT). Methods: EMT of human peritoneal mesothelial cells (HMrSV5) was induced using 2 ng/ml TGF-β1. Cells were randomly divided into a vehicle group, a vehicle group with AS-IV, a TGF-β1 treated group, and a TGF-β1 treated group receiving varied doses of AS-IV or NAC. Real-time quantitative PCR and western blot were used to detect the expression of genes and proteins associated with the TGF-β1/Smad signaling pathway and EMT. DCFH-DA was used to detect the generation of ROS in HMrSV5 cells, and a transwell migration assay was used to verify the capacity of AS-IV to inhibit EMT in HMrSV5 cells. Lentiviruses were used as carriers for the overexpression or knockdown of the Smad7 gene. Results: Expression levels of E-cadherin (epithelial marker) was decreased and vimentin, α-SMA (EMT markers) and collagen I (extracellular matrix protein) phospho-Smad2/3, Snail1 and Snail2 was increased significantly in the TGF-β1-treated HMrSV5 cells. AS-IV was associated with downregulated expression of vimentin and phospho-Smad2/3 in a dose-dependent manner, while the expression of Smad7 increased. Silenced or forced expression of Smad7 verified its role in the inhibitory effect of AS-IV on TGF-β1-induced EMT in HMrSV5 cells. Conclusion: AS-IV effectively promotes the upregulation of Smad7 in the TGF-β1/Smad signaling pathway during the EMT of HMrSV5 cells, indicating its potential therapeutic effect for the control of PF.

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