Transforming growth factor-β stimulates human ovarian cancer cell migration by up-regulating connexin43 expression via Smad2/3 signaling

Qiu, Xiu; Cheng, Jung‐Chien; Zhao, Jingjie; Chang, Hsun‐Ming

doi:10.1016/j.cellsig.2015.07.010

Cited by 25 publications

(18 citation statements)

References 46 publications

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“…BioMed Research International signaling pathway may be involved in the neuroprotective effects of ISPOC and play a potential role in the mediation of p-Cx43 during ISPOC. Studies have shown that the activation of Smad2 and Smad3 is involved in the Cx43 expression induced by TGF-β1 [36]. In this study, we indeed found enhanced expression of TGF-β1 and p-Smad2/3 in ISPOC against cerebral I/R injury.…”

supporting

confidence: 76%

Isoflurane Postconditioning Upregulates Phosphorylated Connexin 43 in the Middle Cerebral Artery Occlusion Model and Is Probably Associated with the TGF-β1/Smad2/3 Signaling Pathway

Yin

Liu

et al. 2020

BioMed Research International

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Aim. Connexin 43 (Cx43) has been identified to be important for cerebral ischemia/reperfusion (I/R) injury as well as protection from it. This study was aimed at investigating the relationship between phosphorylated Cx43 (p-Cx43), transforming growth factor-β1 (TGF-β1)/Smad2/3 signaling pathway, and isoflurane postconditioning (ISPOC), which has effects on brain injury in rats with cerebral ischemia/reperfusion (I/R) injury. Methods. The middle cerebral artery occlusion (MCAO) model was induced in 96 male Sprague-Dawley rats, weighing 250-300 g. The rats were randomized into 12 groups, namely, sham, middle cerebral artery occlusion (MCAO)/I/R, I/R+1.5% ISPOC, I/R+LY2157299 (blocker of TGF-β1), I/R+LY2157299+1.5% ISPOC, I/R+Ro318220 (inhibitor of p-Cx43), I/R+Ro318220+1.5% ISPOC, I/R+18β-GA (activator of p-Cx43), I/R+18β-GA+1.5% ISPOC, I/R+1.5%ISPOC+LY2157299+Ro318220, dimethyl sulfoxide (DMSO), and 1.5% ISPOC+DMSO. The protective effect of 1.5% ISPOC was tested by neurological deficit scoring and 2,3,5-triphenyl tetrazolium chloride staining (TTC staining). The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method and hematoxylin-eosin (HE) staining were used to observe apoptosis of CA1 cells in the hippocampus. The function of protein synthesis in neurons was tested by Nissl staining. Expression levels of TGF-β1, Smad2/3, phosphorylated Smad2/3 (p-Smad2/3), Cx43, and phosphorylated Cx43 (p-Cx43) were measured by Western blot, immunofluorescence (IF), and quantitative real-time polymerase chain reaction (qRT-PCR). Results. Neurological deficit scores, brain infarct volume, and damaged neurons in the I/R group significantly increased compared to those in the sham group (P<0.05). However, in the ISPOC group, damage of the brain was significantly ameliorated (P<0.05). qRT-PCR showed more p-Cx43 mRNA expression in the hippocampal tissue of the ISPOC group than of the I/R group (P<0.05). Western blot and immunofluorescence results showed similar changes in p-Cx43 protein levels of both groups. The expression levels of related proteins (TGF-β1 and p-Smad2/3) both increased in the ISPOC group (P<0.05), whereas total Smad2/3 and total Cx43 expression did not change in all groups. However, when a TGF-β1 inhibitor (LY2157299) was applied, expression levels of p-Cx43 significantly decreased as well as neuronal density (P<0.05). By contrast, expression levels of TGF-β1 did not change significantly after the application of a p-Cx43 inhibitor (Ro318220) or the p-Cx43 activator 18β-GA (P>0.05). Conclusion. Isoflurane postconditioning (ISPOC) may alleviate cerebral I/R injury through upregulating the expression of p-Cx43, and the TGF-β1/Smad2/3 signaling pathway may be involved in the process.

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confidence: 76%

Isoflurane Postconditioning Upregulates Phosphorylated Connexin 43 in the Middle Cerebral Artery Occlusion Model and Is Probably Associated with the TGF-β1/Smad2/3 Signaling Pathway

Yin

Liu

et al. 2020

BioMed Research International

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“…We selected human SKOV3 and mouse ID8 cell lines for testing, as these widely used EOC models are responsive to TGF-β treatment. [19][20][21] Indeed, pretreatment of SKOV3 and ID8 cells with increasing doses of F5775 (0.5-4 μM) led to dose-dependent suppression of TGF-β1-induced SMAD2/3 phosphorylation in both cell models (Figure 2(a)). The higher doses required for F5775 to suppress pSMAD in ID8 cells expressing mouse TGFBR2, is consistent with F5775 being cross-reactive with mouse TGFBR2, but with lower affinity than the human ortholog.…”

Section: Fab 5775 Suppresses Tgf-β Signaling and Cell Invasion In Moumentioning

confidence: 96%

Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models

et al. 2018

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Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models, OncoImmunology, 8:2, e1539613, ABSTRACT Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. EOC is often diagnosed at late stages, with peritoneal metastases and ascites production. Current surgery and platinum-based chemotherapy regimes fail to prevent recurrence in most patients. High levels of Transforming growth factor-β (TGF-β) within ascites has been linked to poor prognosis. TGF-β signaling promotes epithelial-mesenchymal transition (EMT) in EOC tumor cells, and immune suppression within the tumor microenvironment, with both contributing to chemotherapy resistance and metastasis. The goal of this study was to develop specific synthetic inhibitory antibodies to the Type II TGF-β receptor (TGFBR2), and test these antibodies in EOC cell and tumor models. Following screening of a phage-displayed synthetic antigen-binding fragment (Fab) library with the extracellular domain of TGFBR2, we identified a lead inhibitory Fab that suppressed TGF-β signaling in mouse and human EOC cell lines. Affinity maturation of the lead inhibitory Fab resulted in several derivative Fabs with increased affinity for TGFBR2 and efficacy as suppressors of TGF-β signaling, EMT and EOC cell invasion. In EOC xenograft and syngeneic tumor models, blockade of TGFBR2 with our lead antibodies led to improved chemotherapy response. This correlated with reversal of EMT and immune exclusion in these tumor models with TGFBR2 blockade. Together, these results describe new inhibitors of the TGF-β pathway that improve antitumor immunity, and response to chemotherapy in preclinical EOC models. ARTICLE HISTORY

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“…Treatment of OC cell lines with TGF-β and EGF upregulates the gap junction protein Connexin43 (Cx43) by activating SMAD2/3, ERK1/2, and Akt signaling pathways. This upregulation in Cx43 then promotes cancer cell migration and proliferation (204, 205). Epigenetic mechanisms have also been shown to underline TGF-β-induced EMT as alterations in the expression of genes associated with EMT induced by global and gene-specific DNA-metylation (200, 206).…”

Section: Microenvironmental Regulation Of Emt In Cancers Of the Femalmentioning

confidence: 99%

Epithelial-to-Mesenchymal Transition in the Female Reproductive Tract: From Normal Functioning to Disease Pathology

et al. 2017

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Epithelial-to-mesenchymal transition (EMT) is a physiological process that is vital throughout the human lifespan. In addition to contributing to the development of various tissues within the growing embryo, EMT is also responsible for wound healing and tissue regeneration later in adulthood. In this review, we highlight the importance of EMT in the development and normal functioning of the female reproductive organs (the ovaries and the uterus) and describe how dysregulation of EMT can lead to pathological conditions, such as endometriosis, adenomyosis, and carcinogenesis. We also summarize the current literature relating to EMT in the context of ovarian and endometrial carcinomas, with a particular focus on how molecular mechanisms and the tumor microenvironment can govern cancer cell plasticity, therapy resistance, and metastasis.

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Transforming growth factor-β stimulates human ovarian cancer cell migration by up-regulating connexin43 expression via Smad2/3 signaling

Cited by 25 publications

References 46 publications

Isoflurane Postconditioning Upregulates Phosphorylated Connexin 43 in the Middle Cerebral Artery Occlusion Model and Is Probably Associated with the TGF-β1/Smad2/3 Signaling Pathway

Isoflurane Postconditioning Upregulates Phosphorylated Connexin 43 in the Middle Cerebral Artery Occlusion Model and Is Probably Associated with the TGF-β1/Smad2/3 Signaling Pathway

Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models

Epithelial-to-Mesenchymal Transition in the Female Reproductive Tract: From Normal Functioning to Disease Pathology

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