Lysyl oxidase enzymes mediate TGF-β1-induced fibrotic phenotypes in human skin-like tissues

Huang, Meng; Liu, Zhiyi; Baugh, Lauren; DeFuria, Jason; Maione, Anna G.; Smith, Avi; Kashpur, Olga; Black, Lauren D.; Georgakoudi, Irene; Whitfield, Michael L.; Garlick, Jonathan A.

doi:10.1038/s41374-018-0159-8

Cited by 28 publications

(45 citation statements)

References 53 publications

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“…For example, TGFβ-1 treatment of hepatocellular carcinoma cells and osteoarthritic fibroblasts leads to increased expression of specific cross-linking enzymes from the LOXL and LH families [32,33], while similar treatment of dermal fibroblasts increased the expression and activity of TG2 [29]. In addition, increased LOXL and LH enzyme activity in response to TGFβ-1 has been shown in an in vitro model of skin [31]. However, as these previous studies assayed total cell extracts, changes in the ECM levels and activities of cross-linking enzymes were not understood.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, ECM-localised changes in crosslinking enzyme levels are unclear in studies on LOX and LOXL enzymes. For example, upregulated LOX and LOXL-4 mRNA levels were found in an in vitro model of skin tissue as a result of TGFβ-1 treatment together with an enrichment of the corresponding pyridinoline cross-linked products [31]. Moreover, TGFβ treatment also increases the expression of lysyl oxidase like 2 (LOXL2) in hepatocellular carcinoma cell cultures [32], and lysyl hydroxylase 2b (LH2b) in human synovial osteoarthritic fibroblast cultures [33].…”

Section: Introductionmentioning

confidence: 99%

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TGFβ-1 Induced Cross-Linking of the Extracellular Matrix of Primary Human Dermal Fibroblasts

Semkova

Hsuan

2021

IJMS

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Excessive cross-linking is a major factor in the resistance to the remodelling of the extracellular matrix (ECM) during fibrotic progression. The role of TGFβ signalling in impairing ECM remodelling has been demonstrated in various fibrotic models. We hypothesised that increased ECM cross-linking by TGFβ contributes to skin fibrosis in Systemic Sclerosis (SSc). Proteomics was used to identify cross-linking enzymes in the ECM of primary human dermal fibroblasts, and to compare their levels following treatment with TGFβ-1. A significant upregulation and enrichment of lysyl-oxidase-like 1, 2 and 4 and transglutaminase 2 were found. Western blotting confirmed the upregulation of lysyl hydroxylase 2 in the ECM. Increased transglutaminase activity in TGFβ-1 treated ECM was revealed from a cell-based assay. We employed a mass spectrometry-based method to identify alterations in the ECM cross-linking pattern caused by TGFβ-1. Cross-linking sites were identified in collagens I and V, fibrinogen and fibronectin. One cross-linking site in fibrinogen alpha was found only in TGFβ-treated samples. In conclusion, we have mapped novel cross-links between ECM proteins and demonstrated that activation of TGFβ signalling in cultured dermal fibroblasts upregulates multiple cross-linking enzymes in the ECM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TGFβ-1 Induced Cross-Linking of the Extracellular Matrix of Primary Human Dermal Fibroblasts

Semkova

Hsuan

2021

IJMS

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“…Supplementation of TGF‐β1, a cytokine that is overexpressed in hepatic fibrogenesis, induced LOXL4 expression in fibroblast through activation of mothers against decapentaplegic homolog and activator protein 1 transcription factors, ( 44 ) and LOXL4 expression was responsible for TGF‐β1–induced fibrogenesis. ( 45 ) The inflammatory factor IL‐1β was able to induce LOXL4 expression in vitro . ( 46 ) Different profibrogenic factors as well as their interaction during fibrogenesis may jointly contribute to the increased LOXL4 expression in cirrhotic liver of patients with HCC.…”

Section: Discussionmentioning

confidence: 99%

Lysyl Oxidase‐Like 4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis

et al. 2021

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Background and Aims Lysyl oxidase‐like 4 (LOXL4) is an amine oxidase that is primarily involved in extracellular matrix remodeling and is highly expressed in HCC tissues, but its functional role in mediating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of LOXL4 in hepatocarcinogenesis. Approach and Results Here, we demonstrate that hepatic LOXL4 expression was increased during the liver carcinogenesis in mice concomitantly fed a choline‐deficient, l‐amino acid–defined diet. LOXL4 was secreted by the neoplastic cells and primarily localized within hepatic macrophages through exosome internalization. Supplementation of LOXL4 had minimal effect on neoplastic cells. In vitro exposure of macrophages to LOXL4 invoked an immunosuppressive phenotype and activated programmed death ligand 1 (PD‐L1) expression, which further suppressed the function of CD8+ T cells. Injection of LOXL4 promoted macrophages infiltration into the liver and accelerated tumor growth, which was further abolished by adoptive T‐cell transfer or PD‐L1 neutralization. Label‐free proteomics analysis revealed that the immunosuppressive function of LOXL4 on macrophages primarily relied on interferon (IFN)‐mediated signal transducer and activator of transcription–dependent PD‐L1 activation. Hydrogen peroxide scavenger or copper chelation on macrophages abolished the IFN‐mediated PD‐L1 presentation by LOXL4. In human HCC tissue, expression of LOXL4 in CD68+ cells was positively correlated with PD‐L1 level. High expression of LOXL4 in CD68+ cells and low expression of CD8A in tumor tissue cooperatively predict poor survival of patients with HCC. Conclusions LOXL4 facilitates immune evasion by tumor cells and leads to hepatocarcinogenesis. Our study unveils the role of LOXL4 in fostering an immunosuppressive microenvironment during hepatocarcinogenesis.

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“…of IκB. 37 Moreover, some new strategies could suppress IκB activity via increasing IκB protein degradation. 38,39 Similarly, our results revealed that IκB was suppressed from transferring into the nucleus under the effect of nobiletin on BC cells.…”

Section: Discussionmentioning

confidence: 99%

Nobiletin promotes the pyroptosis of breast cancer via regulation of miR‐200b/JAZF1 axis

Wang¹,

Jian

Li³

et al. 2021

The Kaohsiung J of Med Scie

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Nobiletin is a polymethoxylated flavone present in citrus fruits, which has been reported to have inhibitory effects on tumorigenesis of cancers. However, the biological function of nobiletin in breast cancer (BC) is largely unknown. To investigate the effect of nobiletin on growth of BC cells, the cell viability of BC was measured by MTT assay. In addition, gene and protein expressions were detected by qRT-PCR and western blot, respectively. The apoptosis and pyroptosis of BC cells were tested by flow cytometry. Finally, the correlation between miR-200b and JAZF1 was detected by dual luciferase report. The data indicated that nobiletin inhibited the proliferation of BC cells in a dose-dependent manner. Moreover, miR-200b mimics-induced pyroptosis of BC cells was further increased by nobiletin. Meanwhile, JAZF1 was found to be the target of miR-200b. Moreover, nobiletin induced apoptosis and pyroptosis of BC cells via miR-200b/JAZF1/NF-κB axis. In conclusion, nobiletin inhibited the tumorigenesis of BC via regulation of miR-200b/JAZF1 axis. Thus, nobiletin might serve as a new agent for the treatment of BC.

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Lysyl oxidase enzymes mediate TGF-β1-induced fibrotic phenotypes in human skin-like tissues

Cited by 28 publications

References 53 publications

TGFβ-1 Induced Cross-Linking of the Extracellular Matrix of Primary Human Dermal Fibroblasts

TGFβ-1 Induced Cross-Linking of the Extracellular Matrix of Primary Human Dermal Fibroblasts

Lysyl Oxidase‐Like 4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis

Nobiletin promotes the pyroptosis of breast cancer via regulation of miR‐200b/JAZF1 axis

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