Hypoxia induces pulmonary fibroblast proliferation through NFAT signaling

Senavirathna, Lakmini; Huang, Chaoqun; Yang, Xiaoyun; Munteanu, Maria Cristina; Sathiaseelan, Roshini; Xu, Dao; Henke, Craig A.; Liu, Lin

doi:10.1038/s41598-018-21073-x

Cited by 68 publications

(66 citation statements)

References 62 publications

(85 reference statements)

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“…4). This is consistent with previous studies which have reported hypoxia results in dependence on glycolysis for cell proliferation 54 . A recent glycoproteomic analysis performed on the isogenic human OS cell lines, HOS and 143B, also indicated upregulation of glycolysis/PPP proteins in the highly metastatic 143B cell line 55 .…”

Section: Discussionsupporting

confidence: 94%

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Song

Pearce

Jiang

et al. 2020

Sci Rep

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osteosarcoma (oS) is the most common bone cancer in children and young adults. Solid tumors are characterized by intratumoral hypoxia, and hypoxic cells are associated with the transformation to aggressive phenotype and metastasis. the proteome needed to support an aggressive osteosarcoma cell phenotype remains largely undefined. To link metastatic propensity to a hypoxia-induced proteotype, we compared the protein profiles of two isogenic canine OS cell lines, POS (low metastatic) and HMpoS (highly metastatic), under normoxia and hypoxia. Label-free shotgun proteomics was applied to comprehensively characterize the hypoxia-responsive proteome profiles in the OS cell phenotypes. Hypothesis-driven parallel reaction monitoring was used to validate the differential proteins observed in the shotgun data and to monitor proteins of which we expected to exhibit hypoxia responsiveness, but which were absent in the label-free shotgun data. We established a "distance" score (|z HMPOS − z POS |), and "sensitivity" score (|z Hypoxia − z Normoxia ) to quantitatively evaluate the proteome shifts exhibited by oS cells in response to hypoxia. evaluation of the sensitivity scores for the proteome shifts observed and principal component analysis of the hypoxia-responsive proteins indicated that both cell types acquire a proteome that supports a Warburg phenotype with enhanced cell migration and proliferation characteristics. Cell migration and glucose uptake assays combined with protein function inhibitor studies provided further support that hypoxia-driven adaption of pathways associated with glycolytic metabolism, collagen biosynthesis and remodeling, redox regulation and immunomodulatory proteins typify a proteotype associated with an aggressive cancer cell phenotype. Our findings further suggest that proteins involved in collagen remodeling and immune editing may warrant further evaluation as potential targets for anti-metastatic treatment strategies in osteosarcoma.

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Section: Discussionsupporting

confidence: 94%

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Song

Pearce

Jiang

et al. 2020

Sci Rep

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“…Proliferation of myofibroblasts is a key feature of wound healing and adverse fibrosis 6,31 . In the present study, we observed upregulated levels of proliferation marker MKI67 32,33 under hypoxic conditions, consistent with other reports, showing increased hypoxia-mediated proliferation of cardiac 20 and pulmonary fibroblasts 34 . The strongly reduced expression of MKI67 ascribed Rhein a novel anti-proliferative property in regard to cardiac fibrosis.…”

Section: Discussionsupporting

confidence: 93%

Rhein, a novel Histone Deacetylase (HDAC) inhibitor with antifibrotic potency in human myocardial fibrosis

Barbosa

Fahlbusch

Wiza

et al. 2020

Sci Rep

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Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. The anthraquinone Rhein was examined for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration during hypoxia, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein acts inhibitory on HDAC classes I/II as enzymatic inhibitor. Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent protein stabilization of p53 under normoxic but not hypoxic conditions. Functionally, Rhein inhibited collagen contraction, indicating anti-fibrotic property in cardiac remodeling. This was accompanied by increased abundance of SMAD7, but not SMAD2/3, and consistently SMAD-specific E3 ubiquitin ligase SMURF2. In conclusion, this study identifies Rhein as a novel potent direct HDAC inhibitor that may contribute to the treatment of cardiac fibrosis as antifibrotic agent. As readily available drug with approved safety, Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.

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“…Hypoxia is another feature in IPF (Kawakami, Mimura, Shoji, Tanaka, & Nangaku, ; Tzouvelekis et al, ). We and others have shown that hypoxia stimulates lung fibroblast proliferation (Bodempudi et al, ; Mizuno et al, ; Senavirathna et al, ). There is evidence that hypoxia and TGFβ signaling cross‐talk to promote fibrosis (Abdul‐Hafez, Shu, & Uhal, ; Qian et al, ; Ueno et al, ).…”

Section: Introductionmentioning

confidence: 81%

Hypoxia and transforming growth factor β1 regulation of long non‐coding RNA transcriptomes in human pulmonary fibroblasts

et al. 2020

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One of the key characteristics of idiopathic pulmonary fibrosis (IPF) is accumulation of excess fibrous tissue in the lung, which leads to hypoxic conditions. Transforming growth factor (TGF) β is a major mediator that promotes the differentiation of fibroblasts to myofibroblasts. However, how hypoxia and TGFβ together contribute the pathogenesis of IPF is poorly understood. Long non‐coding RNAs (lncRNAs) have regulatory effects on certain genes and are involved in many diseases. In this study, we determined the effects of hypoxia and/or TGFβ on mRNA and lncRNA transcriptomes in pulmonary fibroblasts. Hypoxia and TGFβ1 synergistically increased myofibroblast marker expression. RNA sequencing revealed that hypoxia and TGFβ1 treatment resulted in significant changes in 669 lncRNAs and 2,676 mRNAs compared to 150 lncRNAs and 858 mRNAs in TGFβ1 alone group and 222 lncRNAs and 785 mRNAs in hypoxia alone group. TGFβ1 induced the protein expression of HIF‐1α, but not HIF‐2α. On the other hand, hypoxia enhanced the TGFβ1‐induced phosphorylation of Smad3, suggesting a cross‐talk between these two signaling pathways. In all, 10 selected lncRNAs (five‐up and five‐down) in RNA sequencing data were validated using real‐time PCR. Two lncRNAs were primarily located in cytoplasm, three in nuclei and five in both nuclei and cytoplasm. The silencing of HIF‐1α and Smad3, but not Smad2 and HIF‐2α rescued the downregulation of FENDRR by hypoxia and TGFβ1. In conclusion, hypoxia and TGFβ1 synergistically regulate mRNAs and lncRNAs involved in several cellular processes, which may contribute to the pathogenesis of IPF.

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Hypoxia induces pulmonary fibroblast proliferation through NFAT signaling

Cited by 68 publications

References 62 publications

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Rhein, a novel Histone Deacetylase (HDAC) inhibitor with antifibrotic potency in human myocardial fibrosis

Hypoxia and transforming growth factor β1 regulation of long non‐coding RNA transcriptomes in human pulmonary fibroblasts

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