Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant

Bordignon, Pino; Bottoni, Giulia; Xu, Xiaoying; Popescu, Alma S.; Truan, Zinnia; Guenova, Emmanuella; Kofler, Lukas; Jafari, Paris; Ostano, Paola; Röcken, Martin; Neel, Victor A.; Dotto, G. Paolo

doi:10.1016/j.celrep.2019.07.092

Cited by 77 publications

(75 citation statements)

References 56 publications

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“…Such models will allow to find common mechanisms underlying tissue-protective functions of astrocytes and assess their translatability in a defined setting. Furthermore, it will become essential to investigate the combinatorial effects of astrocyte-derived factors as multiple studies have demonstrated synergistic effects and cross-regulatory mechanisms between several of the discussed mediators (308)(309)(310)(311)(312)(313)(314)(315). Lastly, we are just beginning to grasp the versatile roles glial cells play in the diseased CNS and the extensive characterization of astrocytic subsets beyond a dualistic concept will be inevitable to understand their roles in the context of CNS inflammation.…”

Section: Therapeutic Outlook and Discussionmentioning

confidence: 99%

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

2020

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Astrocytes play important roles in numerous central nervous system disorders including autoimmune inflammatory, hypoxic, and degenerative diseases such as Multiple Sclerosis, ischemic stroke, and Alzheimer's disease. Depending on the spatial and temporal context, activated astrocytes may contribute to the pathogenesis, progression, and recovery of disease. Recent progress in the dissection of transcriptional responses to varying forms of central nervous system insult has shed light on the mechanisms that govern the complexity of reactive astrocyte functions. While a large body of research focuses on the pathogenic effects of reactive astrocytes, little is known about how they limit inflammation and contribute to tissue regeneration. However, these protective astrocyte pathways might be of relevance for the understanding of the underlying pathology in disease and may lead to novel targeted approaches to treat autoimmune inflammatory and degenerative disorders of the central nervous system. In this review article, we have revisited the emerging concept of protective astrocyte functions and discuss their role in the recovery from inflammatory and ischemic disease as well as their role in degenerative disorders. Focusing on soluble astrocyte derived mediators, we aggregate the existing knowledge on astrocyte functions in the maintenance of homeostasis as well as their reparative and tissue-protective function after acute lesions and in neurodegenerative disorders. Finally, we give an outlook of how these mediators may guide future therapeutic strategies to tackle yet untreatable disorders of the central nervous system.

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Section: Therapeutic Outlook and Discussionmentioning

confidence: 99%

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

2020

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“…TGFβ may induce EMT through multiple distinct signalling mechanisms, including regulation of tight junction formation by certain cytoplasmic proteins and phosphorylation by ligand-activated receptors of SMAD transcription factors. TGFβRII can directly phosphorylate both SMAD2 and SMAD3 proteins [27][28][29]. Our studies indicate a direct connection between TGFβ1 and EMT in choriocarcinoma.…”

Section: Discussionmentioning

confidence: 64%

miR-373-3p inhibits EMT via regulation of TGFβR2 in choriocarcinoma

Zuo

et al. 2020

Preprint

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Background: Previous studies have indicated that early metastasis is a major cause of mortality in patients with choriocarcinoma. However, what determines whether early metastasis of choriocarcinoma has occurred is unknown. The emerging role of miRNA in regulating cancer development and progression has been recognized. MiR-373 has been shown to play pivotal roles in tumorigenesis and metastasis. However, whether miR-373 functions to promote choriocarcinoma metastasis is not clear. The purpose of this study is to determine the function of miR-373-3p in the progression of this cancer. Methods: In this study, we first compared epithelial-to-mesenchymal transition (EMT)-related markers, which were inversely correlated with miR-373-3p expression, in trophoblast and choriocarcinoma cell lines. Using PCR and Western blot, upregulation of miR-373-3p was observed to inhibit EMT progression. Similarly, gain- and loss-of-function studies revealed that ectopic miR-373-3p overexpression inhibited the metastasis of choriocarcinoma cells. Results: Our results revealed that miR-373-3p acted as an EMT inhibitor in JEG-3 and JAR cells; this was due to its mediation of the TGF-β signalling pathway, which was responsible for EMT. Bioinformatic analysis demonstrated that miR-373-3p interacted with the 3' untranslated region of TGFβR2 mRNA, and then Western blot and dualluciferase reporter gene assays verified this interaction. Conclusions: Our findings suggest that miR-373-3p upregulation partly accounts for TGFβR2 downregulation and leads to a restraint of EMT and metastasis. MiR-373-3p may therefore serve as a valuable potential target in the treatment of choriocarcinoma.

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“…These results suggested that DEQA restores type I procollagen expression by stimulating TGF-β via the effects on UVA-irradiated HDFs (i.e., Smad 2/3 phosphorylation, Smad 4 activation and Smad 7 inhibition). The TGF-β pathway was shown to be involved in the cancer-associated fibroblast (CAF) activation [ 35 ], using HDFs, and high collagen I expression was linked with normal fibroblast reprogramming in CAFs [ 36 ]. Considering the effects of DEQA on TGF- β signaling and collagen production in HDFs, further studies might promote translational applications of DEQA or its derivatives with detailed analyses of action mechanism, structure–activity relationship and effective doses.…”

Section: Discussionmentioning

confidence: 99%

Antiphotoaging Effect of 3,5-Dicaffeoyl-epi-quinic Acid against UVA-Induced Skin Damage by Protecting Human Dermal Fibroblasts In Vitro

Karadeniz

Kong

et al. 2020

IJMS

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Cutaneous aging is divided into intrinsic and exogenous aging correspondingly contributing to the complex biological phenomenon in skin. Intrinsic aging is also termed chronological aging, which is the accumulation of inevitable changes over time and is largely genetically determined. Superimposed on this intrinsic process, exogenous aging is associated with environmental exposure, mainly to ultraviolet (UV) radiation and more commonly termed as photoaging. UV-induced skin aging induces increased expression of matrix metalloproteinases (MMPs) which in turn causes the collagen degradation. Therefore, MMP inhibitors of natural origin are regarded as a primary approach to prevent or treat photoaging. This study investigated the effects of 3,5-dicaffeoyl-epi-quinic acid (DEQA) on photoaging and elucidated its molecular mechanisms in UVA-irradiated human dermal fibroblasts (HDFs). The results show that treatment with DEQA decreases MMP-1 production and increases type I collagen production in UVA-damaged HDFs. In addition, treatment of UVA-irradiated HDFs with DEQA downregulates MMP-1, MMP-3 and MMP-9 expression via blocking MAPK-cascade-regulated AP-1 transcriptional activity in UVA-irradiated HDFs. Furthermore, DEQA relieves the UVA-mediated suppression of type I procollagen and collagen expression through stimulating TGF-β/Smad signaling, leading to activation of the Smad 2/3 and Smad 4 nuclear translocation. These results suggest that DEQA could be a potential cosmetic agent for prevention and treatment of skin photoaging.

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Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant

Cited by 77 publications

References 56 publications

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

miR-373-3p inhibits EMT via regulation of TGFβR2 in choriocarcinoma

Antiphotoaging Effect of 3,5-Dicaffeoyl-epi-quinic Acid against UVA-Induced Skin Damage by Protecting Human Dermal Fibroblasts In Vitro

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