Publications by authors named "Jong-Wan Park"

179 Publications

Metastasis-on-a-chip reveals adipocyte-derived lipids trigger cancer cell migration via HIF-1α activation in cancer cells.

Biomaterials 2021 Feb 21;269:120622. Epub 2020 Dec 21.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea; Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea. Electronic address:

Although obesity is a newly considered risk factor for cancer, the mechanisms by which adipocyte-derived metabolites accelerate cancer malignancy have yet to be elucidated. To identify the connection among heterogeneous cell types, conventional methods including Transwell assays or conditioned media (CM) have been used; however, these methods do not fully reflect niche effects in the tumor microenvironment (TME). Here, we established an oxygen permeable polydimethylsiloxane (PDMS)-based three-dimensional (3D) culture system to allow direct attachment between human adipocyte derived stem cells (ADSCs) and cancer cells. By doing so, a physiologically bioactive TME was created, which could be used to reveal further the relationships between different cell types. We found that co-culture of cancer cells with ADSCs resulted in a dispersion phenomenon, and the dispersed spheroid was well matched with the enhanced metastatic potential of cancer cells. Lipid profiling and in vitro migration assays suggested that lipids are the driving force for cancer cell migration via HIF-1α upregulation. In addition, the lipid/HIF-1α axis promoted tumor metastasis in a xenograft mouse model. This study presents an in vitro model of a biomimetic TME and provides new mechanistic insights into the effects of ADSC-released fatty acids on cancer cells as oncometabolites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2020.120622DOI Listing
February 2021

Fatty-acid-induced FABP5/HIF-1 reprograms lipid metabolism and enhances the proliferation of liver cancer cells.

Commun Biol 2020 Oct 30;3(1):638. Epub 2020 Oct 30.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.

Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor essential for cancer cell survival. The reprogramming of lipid metabolism has emerged as a hallmark of cancer, yet the relevance of HIF-1α to this process remains elusive. In this study, we profile HIF-1α-interacting proteins using proteomics analysis and identify fatty acid-binding protein 5 (FABP5) as a critical HIF-1α-binding partner. In hepatocellular carcinoma (HCC) tissues, both FABP5 and HIF-1α are upregulated, and their expression levels are associated with poor prognosis. FABP5 enhances HIF-1α activity by promoting HIF-1α synthesis while disrupting FIH/HIF-1α interaction at the same time. Oleic-acid treatment activates the FABP5/HIF-1α axis, thereby promoting lipid accumulation and cell proliferation in HCC cells. Our results indicate that fatty-acid-induced FABP5 upregulation drives HCC progression through HIF-1-driven lipid metabolism reprogramming.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-020-01367-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599230PMC
October 2020

Ketohexokinase-A acts as a nuclear protein kinase that mediates fructose-induced metastasis in breast cancer.

Nat Commun 2020 10 28;11(1):5436. Epub 2020 Oct 28.

Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.

Harmful effects of high fructose intake on health have been widely reported. Although fructose is known to promote cancer, little is known about the underlying mechanisms. Here, we found that fructose triggers breast cancer metastasis through the ketohexokinase-A signaling pathway. Molecular experiments showed that ketohexokinase-A, rather than ketohexokinase-C, is necessary and sufficient for fructose-induced cell invasion. Ketohexokinase-A-overexpressing breast cancer was found to be highly metastatic in fructose-fed mice. Mechanistically, cytoplasmic ketohexokinase-A enters into the nucleus during fructose stimulation, which is mediated by LRRC59 and KPNB1. In the nucleus, ketohexokinase-A phosphorylates YWHAH at Ser25 and the YWHAH recruits SLUG to the CDH1 promoter, which triggers cell migration. This study provides the effect of nutrition on breast cancer metastasis. High intake of fructose should be restricted in cancer patients to reduce the risk of metastasis. From a therapeutic perspective, the ketohexokinase-A signaling pathway could be a potential target to prevent cancer metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19263-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595112PMC
October 2020

Neddylation blockade induces HIF-1α driven cancer cell migration via upregulation of ZEB1.

Sci Rep 2020 10 23;10(1):18210. Epub 2020 Oct 23.

Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Korea.

Neddylation is a process by which NEDD8 is covalently conjugated to target proteins by sequential enzymatic reaction. Its role in cancer cell migration has only been recently acknowledged. Previously in cancer cell migration, the epithelial to mesenchymal transition (EMT) process has been well-known to play an important role in both invasion and metastasis by promoting mesenchymal phenotype in epithelial cells. However, the role of neddylation in the EMT process and its mechanistic details are yet to be elucidated. We recently reported that neddylation plays a crucial role in cancer cell migration through the PI3K-Akt pathway. Here, we report that inhibiting neddylation activates the hypoxia-inducible factor 1α (HIF-1α) through the PI3K-Akt pathway, which eventually regulates the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) in various cancer cell lines. As induction of HIF-1α is known to deteriorate the state of cancer and EMT process is one of the hallmarks of metastasis in cancer, our findings uncover the role of neddylation between HIF-1α and ZEB1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-75286-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585416PMC
October 2020

Loss of EGR3 is an independent risk factor for metastatic progression in prostate cancer.

Oncogene 2020 09 14;39(36):5839-5854. Epub 2020 Aug 14.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.

Identification of pro-metastatic genomic alterations is urgently needed to help understand and prevent the fatal course of prostate cancer. Here, we found that the transcription factor EGR3, located at chromosome 8p21.3, is a critical metastasis suppressor. Aberrant deletion of EGR3 was found in up to 59.76% (deep deletions, 16.87%; shallow deletions, 42.89%) of prostate cancer patients. In informatics analysis, EGR3 loss was associated with prostate cancer progression and low survival rates. EGR3 expression inversely correlated with the expressions of epithelial-to-mesenchymal transition (EMT) and metastasis-related gene sets in prostate cancer tissues. In prostate cancer cells, EGR3 blocked the EMT process and suppressed cell migration and invasion. In a mouse model for cancer metastasis, EGR3 overexpression significantly suppressed bone metastases of PC3 and 22Rv1 prostate cancer cells. Mechanistically, EGR3 transcriptionally activated ZFP36, GADD45B, and SOCS3 genes by directly binding to their promoter regions. The EMT-inhibitory and tumor-suppressive roles of the EGR3 downstream genes were identified through in vitro and in silico analyses. Together, our results showed that EGR3 may be a biomarker to predict clinical outcomes and that it plays an important role in the metastatic progression of prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-020-01418-5DOI Listing
September 2020

Hypoxia-driven epigenetic regulation in cancer progression: A focus on histone methylation and its modifying enzymes.

Cancer Lett 2020 10 6;489:41-49. Epub 2020 Jun 6.

Department of Pharmacology, Cancer Research Institute, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

The mechanism underlying hypoxia-driven chromatin remodeling is a long-lasting question. For the last two decades, this question has been resolved in part. It is now widely agreed that hypoxia dynamically changes the methylation status of histones to control gene expression. Hypoxia-inducible factor (HIF) plays a central role in cellular responses to hypoxia through transcriptional activation of numerous genes. At least in part, the hypoxic regulation of histone methylation is attributed to the HIF-mediated expression of histone modifying enzymes. Protein hydroxylation and histone demethylation have emerged as the oxygen sensing processes because they are catalyzed by a family of 2-oxoglutarate (2OG)-dependent dioxygenases whose activities depend upon the ambient oxygen level. Recently, it has been extensively investigated that the 2OG dioxygenases oxygen-dependently regulate histone methylation. Nowadays, the hypoxic change in the histone methylation status is regarded as an important event to drive malignant behaviors of cancer cells. In this review, we introduced and summarized the cellular processes that govern hypoxia-driven regulation of histone methylation in the context of cancer biology. We also discussed the emerging roles of histone methyltransferases and demethylases in epigenetic response to hypoxia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2020.05.025DOI Listing
October 2020

Validation of CDr15 as a new dye for detecting neutrophil extracellular trap.

Biochem Biophys Res Commun 2020 06 15;527(3):646-653. Epub 2020 May 15.

Department of Tumor Biology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Ischemic/Hypoxic Disease Institute, and Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul National University Hospital Biomedical Research Institute, Seoul, Republic of Korea. Electronic address:

Neutrophil extracellular trap (NET) is one of the first-line defenses against microbes. Under certain circumstances, however, it also plays an aggravating factor in diverse inflammation-related diseases including cancers and vascular diseases. Our aim is to develop a new method to detect NET in cells and tissues using a DNA-specific fluorescence probe CDr15. CDr15 was characterized to be impermeable to the cell membranes and to emit a strong fluorescence in association with extracellular DNAs in NET. Due to these properties, CDr15 was successfully shown to quantify NETs in vitro and to be applicable for real-time monitoring NET formation in PMA-stimulated neutrophils. Even in formaldehyde-fixed tumor specimens, CDr15 could detect NETs spreading around cancer cells. Compared with DAPI and SYTOX DNA dyes, CDr15 showed a lower level of background fluorescence and a higher specificity in NET detection. Based on these results, we propose CDr15 as a novel marker of NET to be applicable in experimental and clinical studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.04.153DOI Listing
June 2020

Erratum: In-Depth, Proteomic Analysis of Nasal Secretions from Patients With Chronic Rhinosinusitis and Nasal Polyps.

Allergy Asthma Immunol Res 2020 07;12(4):744

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

This corrects the article on p. 691 in vol. 11, PMID: 31332980.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4168/aair.2020.12.4.744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224994PMC
July 2020

Neddylation of sterol regulatory element-binding protein 1c is a potential therapeutic target for nonalcoholic fatty liver treatment.

Cell Death Dis 2020 04 24;11(4):283. Epub 2020 Apr 24.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for progression of steatohepatitis, liver cirrhosis, and liver cancer. Although pathological condition of NAFLD, which arises from an excessive accumulation of triglyceride in the liver, is accompanied by elevated sterol regulatory element-binding protein 1c (SREBP1c) level, it is largely unknown which factors are involved in the modification of SREBP1c. In this study, we discovered that neddylation of SREBP1c competes with its ubiquitination and stabilizes SREBP1c protein level, and eventually promotes hepatic steatosis. We also demonstrated that human homolog of mouse double minute 2 (HDM2) acts as an E3 neddylation ligase of SREBP1c. Further, treatment with the neddylation inhibitor, MLN4924, attenuates high-fat diet-induced hepatic steatosis by reducing the levels of SREBP1c protein and hepatic triglyceride. Our results indicate that the blockade of SREBP1c neddylation could be a novel approach in the defense against NAFLD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-020-2472-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181738PMC
April 2020

Extracellular Acidosis Promotes Metastatic Potency via Decrease of the Circadian Clock Gene in Breast Cancer.

Cells 2020 04 16;9(4). Epub 2020 Apr 16.

Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.

Circadian oscillation is an essential process that influences many physiological and biological mechanisms and a decrease of circadian genes is associated with many diseases such as cancer. Despite many efforts to identify the detailed mechanism for decreasing circadian genes and recovering reduced circadian genes in cancer, it is still largely unknown. We found that BMAL1 was reduced in tumor hypoxia-induced acidosis, and recovered by selectively targeting acidic pH in breast cancer cell lines. Surprisingly, BMAL1 was reduced by decrease of protein stability as well as inhibition of transcription under acidosis. In addition, melatonin significantly prevented acidosis-mediated decrease of BMAL1 by inhibiting lactate dehydrogenase-A during hypoxia. Remarkably, acidosis-mediated metastasis was significantly alleviated by BMAL1 overexpression in breast cancer cells. We therefore suggest that tumor hypoxia-induced acidosis promotes metastatic potency by decreasing BMAL1, and that tumor acidosis could be a target for preventing breast cancer metastasis by sustaining BMAL1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9040989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226966PMC
April 2020

Evaluation of Neo-Osteogenesis in Eosinophilic Chronic Rhinosinusitis Using a Nasal Polyp Murine Model.

Allergy Asthma Immunol Res 2020 03;12(2):306-321

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Osteitis refers to the development of new bone formation and remodeling of bone in chronic rhinosinusitis (CRS) patients; it is typically associated with eosinophilia, nasal polyps (NPs), and recalcitrant CRS. However, the roles of ossification in CRS with or without NPs remain unclear due to the lack of appropriate animal models. Thus, it is necessary to have a suitable animal model for greater advances in the understanding of CRS pathogenesis.

Methods: BALB/c mice were administered ovalbumin (OVA) and staphylococcal enterotoxin B (SEB). The numbers of osteoclasts and osteoblasts and bony changes were assessed. Micro computed tomography (micro-CT) scans were conducted to measure bone thickness. Immunofluorescence, immunohistochemistry, and quantitative polymerase chain reaction were performed to evaluate runt-related transcription factor 2 (RUNX2), osteonectin, interleukin (IL)-13, and RUNX2 downstream gene expression. Gene set enrichment analysis was performed in mucosal tissues from control and CRS patients. The effect of resveratrol was evaluated in terms of osteogenesis in a murine eosinophilic CRS NP model.

Results: The histopathologic changes showed markedly thickened bones with significant increase in osteoblast numbers in OVA/SEB-treated mice compared to the phosphate-buffered saline-treated mice. The structural changes in bone on micro-CT were consistent with the histopathological features. The expression of RUNX2 and IL-13 was increased by the administration of OVA/SEB and showed a positive correlation. RUNX2 expression mainly co-localized with osteoblasts. Bioinformatic analysis using human CRS transcriptome revealed that IL-13-induced bony changes via RUNX2. Treatment with resveratrol, a candidate drug against osteitis, diminished the expression of IL-13 and RUNX2, and the number of osteoblasts in OVA/SEB-treated mice.

Conclusions: In the present study, we found the histopathological and radiographic evidence of osteogenesis using a previously established murine eosinophilic CRS NP model. This animal model could provide new insights into the pathophysiology of neo-osteogenesis and provide a basis for developing new therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4168/aair.2020.12.2.306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997277PMC
March 2020

Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages.

J Mol Cell Biol 2020 07;12(7):543-555

Macrophage Lab, Department of Microbiology and Immunology and Institute of Endemic Disease, Seoul National University College of Medicine, Chongno-gu, Seoul 03080, Republic of Korea.

Interleukin-10 (IL-10) is the most potent anti-inflammatory cytokine in the body and plays an essential role in determining outcomes of many inflammatory diseases. Cellular metabolism is a critical determinant of immune cell function; however, it is currently unclear whether metabolic processes are specifically involved in IL-10 production. In this study, we aimed to find the central metabolic molecule regulating IL-10 production of macrophages, which are the main producers of IL-10. Transcriptomic analysis identified that metabolic changes were predominantly enriched in Kupffer cells at the early inflammatory phase of a mouse endotoxemia model. Among them, pyruvate dehydrogenase kinase (PDK)-dependent acute glycolysis was negatively involved in IL-10 production. Inhibition or knockdown of PDK selectively increased macrophage IL-10 expression. Mechanistically, PDK inhibition increased IL-10 production via profound phosphorylation of adenosine monophosphate (AMP)-activated protein kinase alpha 1 (AMPKα1) by restricting glucose uptake in lipopolysaccharide-stimulated macrophages. AMPKα1 consequently activated p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and cyclic AMP-responsive element-binding protein to regulate IL-10 production. Our study uncovers a previously unknown regulatory mechanism of IL-10 in activated macrophages involving an immunometabolic function of PDK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jmcb/mjz113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493030PMC
July 2020

α-Helical cell-penetrating peptide-mediated nasal delivery of resveratrol for inhibition of epithelial-to-mesenchymal transition.

J Control Release 2020 01 27;317:181-194. Epub 2019 Nov 27.

Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:

In the present study, we examined the potential of cell-penetrating peptide (CPP)-based intranasal drug delivery for the treatment of localized nasal diseases. Many charged or non-hydrophobic drugs have difficulty penetrating into the nasal epithelium due to intrinsic membrane impermeability and rapid mucociliary clearance in the nasal cavity. To treat chronic rhinosinusitis with nasal polyps (CRSwNP), one of the most common localized nasal diseases, we conjugated resveratrol (RSV) to an amphiphilic α-helical leucine (L)- and lysine (K)-rich CPP (LK) and intranasally delivered it to the interior of nasal epithelial cells for inhibiting epithelial-to-mesenchymal transition (EMT) caused by hypoxia-inducible factor 1α. The RSV-LK conjugate could penetrate into the nasal epithelium and efficiently inhibit EMT, nasal polyp formation, epithelial disruption, and related inflammation in an eosinophilic CRSwNP mouse model, at 10-fold lower doses and with 3-fold less frequent administration than free RSV. Due to the rapid penetration into the nasal epithelium and the therapeutic effect of the RSV-LK conjugate at much lower doses than free RSV, this CPP-based delivery system, with the ability to overcome the tight nasal epithelial barrier, may provide a new strategy for the treatment of localized nasal diseases without the systemic side effects of cargo drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2019.11.034DOI Listing
January 2020

Histone demethylase PHF2 activates CREB and promotes memory consolidation.

EMBO Rep 2019 09 30;20(9):e45907. Epub 2019 Jul 30.

Department of Physiology and Biomedical Science, Seoul National University College of Medicine, Seoul, Korea.

Long-term memory formation is attributed to experience-dependent gene expression. Dynamic changes in histone methylation are essential for the epigenetic regulation of memory consolidation-related genes. Here, we demonstrate that the plant homeodomain finger protein 2 (PHF2) histone demethylase is upregulated in the mouse hippocampus during the experience phase and plays an essential role in memory formation. PHF2 promotes the expression of memory-related genes by epigenetically reinforcing the TrkB-CREB signaling pathway. In behavioral tests, memory formation is enhanced by transgenic overexpression of PHF2 in mice, but is impaired by silencing PHF2 in the hippocampus. Electrophysiological studies reveal that PHF2 elevates field excitatory postsynaptic potential (fEPSP) and NMDA receptor-mediated evoked excitatory postsynaptic current (EPSC) in CA1 pyramidal neurons, suggesting that PHF2 promotes long-term potentiation. This study provides insight into the epigenetic regulation of learning and memory formation, which advances our knowledge to improve memory in patients with degenerative brain diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embr.201845907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726911PMC
September 2019

In-Depth, Proteomic Analysis of Nasal Secretions from Patients With Chronic Rhinosinusitis and Nasal Polyps.

Allergy Asthma Immunol Res 2019 Sep;11(5):691-708

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Chronic rhinosinusitis (CRS) is a complex immunological condition, and novel experimental modalities are required to explore various clinical and pathophysiological endotypes; mere evaluation of nasal polyp (NP) status is inadequate. Therefore, we collected patient nasal secretions on filter paper and characterized the proteomes.

Methods: We performed liquid chromatography-mass spectrometry (MS)/MS in the data-dependent acquisition (DDA) and data-independent acquisition (DIA) modes. Nasal secretions were collected from 10 controls, 10 CRS without NPs (CRSsNP) and 10 CRS with NPs (CRSwNP). We performed Orbitrap MS-based proteomic analysis in the DDA (5 controls, 5 CRSsNP and 5 CRSwNP) and the DIA (5 controls, 5 CRSsNP and 5 CRSwNP) modes, followed by a statistical analysis and a hierarchical clustering to identify differentially expressed proteins in the 3 groups.

Results: We identified 2,020 proteins in nasal secretions. Canonical pathway analysis and gene ontology (GO) evaluation revealed that interleukin (IL)-7, IL-9, IL-17A and IL-22 signaling and neutrophil-mediated immune responses like neutrophil degranulation and activation were significantly increased in CRSwNP compared to control. The GO terms related to the iron ion metabolism that may be associated with CRS and NP development.

Conclusions: Collection of nasal secretions on the filter paper is a practical and non-invasive method for in-depth study of nasal proteomics. Our proteomic signatures also support that Asian NPs could be characterized as non-eosinophilic inflammation features. Therefore, the proteomic profiling of nasal secretions from CRS patients may enhance our understanding of CRS endotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4168/aair.2019.11.5.691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658407PMC
September 2019

PIN1 transcript variant 2 acts as a long non-coding RNA that controls the HIF-1-driven hypoxic response.

Sci Rep 2019 07 22;9(1):10599. Epub 2019 Jul 22.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.

The transcription factor HIF-1 induces the expression of genes that are essential for cell survival and oxygen homeostasis in hypoxic conditions. The prolyl isomerase Pin1 plays a role in the regulation of HIF-1α. However, the mechanism by which Pin1 controls HIF-1α remains controversial. Surprisingly, we here show that a PIN1 transcript downregulates HIF-1α as a long non-coding RNA. Pin1-silencing siRNAs augmented the hypoxia-induced expression of HIF-1α, thereby upregulating the expression of HIF-1 target genes. However, the overexpression of Pin1 protein did not inhibit the hypoxic expression of HIF-1α. Pin1 restoration in Pin1-depleted cells also failed to reverse the induction of HIF-1α by Pin1 knockdown. Unexpectedly, HIF-1α was found to be induced by both siRNAs for PIN1 transcript variants 1/2 and that for PIN1 transcript variants 2/3, indicating that the PIN1 transcript variant 2 (PIN1-v2) is responsible for HIF-1α induction. Mechanistically, PIN1-v2, which is classified as a long non-coding RNA due to early termination of translation, was evaluated to inhibit the transcription of HIF1A gene. In conclusion, PIN1-v2 may function in balancing the HIF-1-driven gene expression under hypoxia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-47071-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646326PMC
July 2019

Interleukin (IL)-13 and IL-17A contribute to neo-osteogenesis in chronic rhinosinusitis by inducing RUNX2.

EBioMedicine 2019 Aug 19;46:330-341. Epub 2019 Jul 19.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Ischemic/hypoxic disease institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: There is increasing evidence supporting the impact of neoosteogenesis in the pathophysiology of chronic rhinosinusitis (CRS), especially in the recalcitrant group of patients. Runt-related transcription factor 2 (RUNX2), a member of the RUNX family, controls osteoblast differentiation and bone formation. However, the role and regulation of RUNX2 in CRS patients with neoosteogenesis remain unclear. The aim of the study is to determine the role of RUNX2 in neoosteogenesis of CRS patients.

Methods: Sinonasal bone and overlying mucosa samples were obtained from CRS patients with or without neoosteogenesis (n = 67) and healthy controls (n = 11). Double immunofluorescence, immunohistochemistry, and immunoblotting were used to evaluate RUNX2 expression in CRS patients with and without neoosteogenesis. In addition, the osteogenic activity of pro-inflammatory cytokines was examined by measuring alkaline phosphatase (ALP) activity and bone mineralisation in vitro.

Findings: RUNX2 was highly expressed in osteoblasts of CRS patients with neoosteogenesis compared with tissues from control subjects and those with CRS without neoosteogenesis. Mucosal extracts from CRS patients with neoosteogenesis showed increased RUNX2 expression and ALP activity in C2C12 cells, whereas those from patients without neoosteogenesis did not. Expression of interleukin (IL)-13 and IL-17A was upregulated in CRS patients with neoosteogenesis. ALP activity and Alizarin Red staining showed IL-13 and IL-17A dose-dependent osteoblast differentiation and mineralisation in vitro.

Interpretation: These findings suggested that IL-13- or IL-17A-induced RUNX2 contributed to new bone formation in CRS patients through its effect on the activity of osteoblasts. RUNX2 may be a novel target for preventing neoosteogenesis in CRS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2019.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710985PMC
August 2019

Nuclear FGFR2 negatively regulates hypoxia-induced cell invasion in prostate cancer by interacting with HIF-1 and HIF-2.

Sci Rep 2019 03 5;9(1):3480. Epub 2019 Mar 5.

Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea.

The fibroblast growth factor receptor 2 (FGFR2) is a membrane receptor that promotes cell proliferation and differentiation. FGFR2 is also present in the nucleus, which raises a question on a new role of FGFR2 in regulating gene expression. Hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2) are nuclear proteins that transactivate many genes essential for cancer survival and metastasis under hypoxic conditions. Here, we investigated if nuclear FGFR2 modulates the HIF-driven hypoxic response. Using the TCGA database, we found that FGFR2 downregulation is associated with poor prognosis in prostate cancer. A gene-set enrichment analysis showed that metastasis- and hypoxia-related genes are associated with a low expression of FGFR2 in prostate cancer. Thus, we tested the possibility that FGFR2 negatively regulates the hypoxia-triggered metastasis of prostate cancer. FGFR2 controls migration and invasion of prostate cancer cells under hypoxia by inhibiting the HIF-driven gene expression. FGFR2 and HIF proteins co-localize and associate in the nucleus under hypoxia. FGFR2 interacts with the transactivation domain of HIF-1α and blocks the recruitment of coactivator p300, resulting in repression of HIF target genes. Based on these results, we propose a novel function of FGFR2 as a metastasis suppressor by controlling HIF-mediated hypoxic responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-39843-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401139PMC
March 2019

The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition.

Mucosal Immunol 2019 05 25;12(3):601-611. Epub 2019 Feb 25.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammatory disease characterized by involvement of diverse types of inflammatory cells. Asian CRS patients frequently show infiltration of neutrophils and an elevated level of interferon (IFN)-γ; by contrast, western patients exhibit eosinophil infiltration and enhanced levels of Th2-related cytokines. Neutrophilia in tissues decreases sensitivity to corticosteroids, but the mechanisms underlying the progression of neutrophilic CRS are unclear. In this study, we investigated the role of IFN-γ in CRS patients with marked neutrophil infiltration. We report that the IFN-γ level is upregulated in the tissues of these patients, particularly those with non-eosinophilic nasal polyps. The level of IFN-γ was significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT). We further demonstrated that IFN-γ induced the EMT via the p38 and extracellular signal-regulated kinase (ERK) pathways in a manner distinct from the hypoxia-inducible factor (HIF)-1α, SMAD, and NF-κB signaling pathways. In a murine nasal polyp (NP) model, blocking the p38 and ERK signaling pathways prevented NP formation and chemotactic cytokine secretion by neutrophils but not eosinophils. Taken together, our results suggest that IFN-γ can induce the EMT in nasal epithelial cells, and thus blocking the p38 and ERK pathways could be an effective therapeutic strategy against neutrophil-dominant CRS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41385-019-0149-1DOI Listing
May 2019

Oxygen sensor FIH inhibits HACE1-dependent ubiquitination of Rac1 to enhance metastatic potential in breast cancer cells.

Oncogene 2019 05 18;38(19):3651-3666. Epub 2019 Jan 18.

Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Republic of Korea.

Oxygen is an indispensable element for cell survival and maintenance. Eukaryotic cells are equipped with a series of signaling pathways that cope with hypoxia. The dioxygenase factor inhibiting HIF (FIH) is an oxygen sensor that regulates the transcriptional activity of hypoxia-inducible factor (HIF) through asparaginyl hydroxylation. Given that HACE1 was detected as an FIH-interacting protein in a previous proteomics study, we tested whether the E3 ubiquitin ligase HACE1 is a substrate for FIH. FIH interacted with HACE1, in cells and in vitro, and was determined to hydroxylate HACE1 at the N191 residue within the ankyrin repeat domain. Hydroxylation disrupted the physical association between HACE1 and its representative target, Rac1. Under hypoxic conditions, HACE1 is less hydroxylated due to the inactivation of FIH, and subsequently functions to ubiquitinate the active form of Rac1, leading to the proteasomal degradation of Rac1. Since Rac1 stimulates cell movement, HACE1 inhibits cell migration and invasion in breast cancer by removing active Rac1. Such an effect of HACE1 is reinforced under hypoxia because HACE1 escapes from FIH-mediated hydroxylation. In clinical datasets, HACE1 downregulation is associated with poor outcomes in patients with breast cancer. Taken together, FIH is likely to act as an oxygen sensor that determines oxygen-dependent cancer progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-019-0676-yDOI Listing
May 2019

Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis.

Cancer Res 2019 02 4;79(4):795-806. Epub 2019 Jan 4.

Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea.

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy. SIGNIFICANCE: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-2545DOI Listing
February 2019

Intermittent hypoxia promotes carcinogenesis in azoxymethane and dextran sodium sulfate-induced colon cancer model.

Mol Carcinog 2019 05 20;58(5):654-665. Epub 2019 Jan 20.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Intermittent hypoxia (IH), a characteristic of obstructive sleep apnea, is known to promote cancer progression and aggressiveness in mouse models. However, little is known regarding the effect of IH on cancer initiation. Here, the effect of IH on carcinogenesis was explored in azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced colon cancer models with three different protocols. In the first protocol, two other application time points (early or late initiation of IH) were applied. In the second protocol, mice were divided into only two groups, and then exposed to either N or IH conditions for 14 days. In the third protocol, a pharmacological inhibition study for anti-inflammation (5-aminosalicylate) or anti-oxidative stress (N-acetylcysteine [NAC]) was performed. The number of tumors was significantly higher in the IH-1 than in the N or IH-2 groups. 8-oxo-2'-deoxyguanosine (8-OHdG) levels were higher in tumors of the IH-1 group than in that of the N and IH-2 groups. Gene expression related to reactive oxygen species production was higher in the IH-1 group than in the N and IH-2 groups, and it showed a positive correlation with 8-OHdG levels. Prior to cancer development 8-OHdG levels were already elevated in colonic epithelial regions in the IH group, possibly due to an imbalance between oxidative stress and antioxidant systems. NAC treatment resulted in a significant reduction in the number of tumors in mice exposed to IH. In conclusion, IH promotes carcinogenesis in a chemically-induced colon cancer model where elevated 8-OHdG may contribute to the increased tumor induction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mc.22957DOI Listing
May 2019

Aberrant expression of CITED2 promotes prostate cancer metastasis by activating the nucleolin-AKT pathway.

Nat Commun 2018 10 5;9(1):4113. Epub 2018 Oct 5.

Department of Biomedical Science, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, Korea.

Despite many efforts to develop hormone therapy and chemotherapy, no effective strategy to suppress prostate cancer metastasis has been established because the metastasis is not well understood. We here investigate a role of CBP/p300-interacting transactivator with E/D-rich carboxy-terminal domain-2 (CITED2) in prostate cancer metastasis. CITED2 is highly expressed in metastatic prostate cancer, and its expression is correlated with poor survival. The CITED2 gene is highly activated by ETS-related gene that is overexpressed due to chromosomal translocation. CITED2 acts as a molecular chaperone to guide PRMT5 and p300 to nucleolin, thereby activating nucleolin. Informatics and experimental data suggest that the CITED2-nucleolin axis is involved in prostate cancer metastasis. This axis stimulates cell migration through the epithelial-mesenchymal transition and promotes cancer metastasis in a xenograft mouse model. Our results suggest that CITED2 plays a metastasis-promoting role in prostate cancer and thus could be a target for preventing prostate cancer metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-06606-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173745PMC
October 2018

FIH permits NAA10 to catalyze the oxygen-dependent lysyl-acetylation of HIF-1α.

Redox Biol 2018 10 7;19:364-374. Epub 2018 Sep 7.

Department of Biomedical Science, BK21-plus education program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea. Electronic address:

The N-terminal acetyltransferase A (NatA) complex, which is composed of NAA10 and NAA15, catalyzes N-terminal acetylation of many proteins in a co-translational manner. Structurally, the catalytic subunit NAA10 was believed to have no activity toward an internal lysine residue because the gate of its catalytic pocket is too narrow. However, several studies have demonstrated that the monomeric NAA10 can acetylate the internal lysine residues of several substrates including hypoxia-inducible factor 1α (HIF-1α). How NAA10 acetylates lysine residues has been an unsolved question. We here found that human FIH (factor inhibiting HIF) hydroxylates human NAA10 at W38 oxygen-dependently and this permits NAA10 to express the lysyl-acetyltransferase activity. The hydroxylated W38 forms a new hydrogen-bond with A67 and widens the gate at the catalytic pocket, which allows the entrance of a lysine residue to the site. Since the FIH-dependent hydroxylation of NAA10 occurs oxygen-dependently, NAA10 acetylates HIF-1α under normoxia but does not under hypoxia. Consequently, the acetylation promotes the pVHL binding to HIF-1α, and in turn HIF-1α is destructed via the ubiquitin-proteasome system. This study provides a novel oxygen-sensing process that determines the substrate specificity of NAA10 depending on an ambient oxygen tension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2018.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142190PMC
October 2018

The E3 ligase C-CBL inhibits cancer cell migration by neddylating the proto-oncogene c-Src.

Oncogene 2018 10 13;37(41):5552-5568. Epub 2018 Jun 13.

Department of Biomedical Science, Seoul, 110-799, Korea.

Neddylation is a cellular process that covalently conjugates substrate proteins with the small ubiquitin-like molecule NEDD8. As neddylation is required for fast turnover of proteins in proliferating cancer cells, the neddylation process is currently regarded as a potential target for cancer therapy. However, little is known about the role of neddylation in cancer invasion and metastasis. Unexpectedly, we here found that the neddylation blockade stimulates migration of lung cancer and glioblastoma cells. Mechanistically, C-CBL acts as the E3 ligase for neddylation of the proto-oncogene c-Src. After neddylation, c-Src is poly-ubiquitinated and degraded through the proteasome, which inhibits the PI3K-AKT pathway responsible for cell migration. In human lung cancer tissues, the downregulation of C-CBL was associated with c-Src/AKT, cancer metastasis, and poor survival in patients. Therefore, C-CBL is likely to play a tumor suppressive role by antagonizing a robust oncogenic signaling driven by c-Src. This study provides new insight about the role of neddylation in cancer metastasis. It also implies that the metastasis risk should be carefully evaluated before the clinical application of neddylation inhibitors as anticancer regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-018-0354-5DOI Listing
October 2018

Cervical cancer is addicted to SIRT1 disarming the AIM2 antiviral defense.

Oncogene 2018 09 29;37(38):5191-5204. Epub 2018 May 29.

Department of Biomedical Science, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.

Mammalian cells are equipped with antiviral innate immunity. To survive and grow, human papilloma virus (HPV)-infected cervical cancer cells must overcome this host defense system. However, the precise mechanism whereby cervical cancer cells evade the immunity is not fully understood. We noted that Sirtuin 1 (SIRT1) is overexpressed in HPV-infected cervical cancer cells and hypothesized that SIRT1 counteracts antiviral immunity. Here, we found that cervical cancer cells undergo massive death by SIRT1 knockdown, but this effect is reversed by SIRT1 restoration. SIRT1-knocked-down cells showed representative features of pyroptosis, as well as highly expressed absent in melanoma 2 (AIM2) and its downstream genes related to the inflammasome response. Mechanistically, SIRT1 repressed the NF-κB-driven transcription of the AIM2 gene by destabilizing the RELB mRNA. Interestingly, pyroptotic death signaling in SIRT1-knocked-down cells was transmitted to naïve cervical cancer cells, which was mediated by extracellular vesicles carrying AIM2 inflammasome proteins. Furthermore, the growth of cervical cancer xenografts was significantly inhibited by either SIRT1-targeting siRNAs or SIRT1-knockdown-derived extracellular vesicles. Immunohistochemical analyses showed that SIRT1 expression correlated with poor clinical outcomes in cervical cancer. In conclusion, SIRT1 enabled HPV-infected cervical cancer cells to continue growing by nullifying AIM2 inflammasome-mediated immunity. Without SIRT1, cervical cancer cells could no longer survive because of the derepression of the AIM2 inflammasome. SIRT1 could therefore be a target for the effective treatment of cervical cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-018-0339-4DOI Listing
September 2018

NDRG3 lowers the metastatic potential in prostate cancer as a feedback controller of hypoxia-inducible factors.

Exp Mol Med 2018 05 14;50(5):1-13. Epub 2018 May 14.

Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea.

Expression of hypoxia-inducible factors (HIFs) and N-myc downstream-regulated gene 3 (NDRG3) are oxygen-dependently regulated by prolyl hydroxylase domain (PHD) enzymes. Little is known about the role of NDRG3 in the cellular adaptation to hypoxia, whereas the roles of HIFs are well understood. In this study, we investigated how NDRG3 affects the hypoxic response in prostate cancer cells. Compared with HIF-1α, hypoxic induction of NDRG3 was observed at a later phase. NDRG3 reduced hypoxic expression of HIF-1α by inhibiting AKT-driven translation of HIF1A mRNA. In addition, NDRG3 functionally inhibited HIF-1 by dissociating the coactivator p300 from HIF-1α. Accordingly, NDRG3 may fine-tune the HIF-1 signaling pathway to cope with long-term hypoxia. Of the diverse effects of HIF-1α on cancer progression, hypoxia-induced cell migration was investigated. In transwell chambers, NDRG3 negatively regulated the migration and invasion of prostate cancer cells under hypoxia. An informatics analysis using Gene Expression Omnibus (GEO) revealed that NDRG3 downregulation is associated with prostate cancer metastasis and high expression of HIF-1 downstream genes. In cancer tissue arrays, NDRG3 expression was lower in prostate cancer tissues with a Gleason score of 8 or greater and was inversely correlated with HIF-1α expression. Therefore, NDRG3 may have an anti-metastatic function in prostate cancer under a hypoxic microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s12276-018-0089-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951909PMC
May 2018

Epithelial cell-derived cytokines CST3 and GDF15 as potential therapeutics for pulmonary fibrosis.

Cell Death Dis 2018 05 1;9(5):506. Epub 2018 May 1.

Department of Biomedical Sciences, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, Korea.

While wound healing is completed, the epithelium functions to normalize the interstitial context by eliminating fibroblasts excited during matrix reconstruction. If not, tissues undergo pathologic fibrosis. Pulmonary fibrosis is a fatal and hardly curable disorder. We here tried to identify epithelium-derived cytokines capable of ameliorating pulmonary fibrosis. Human lung fibroblasts were inactivated in epithelial cell-conditioned media. Cystatin C (CST3) and growth differentiation factor 15 (GDF15) were found to be enriched in the conditioned media and to inhibit the growth and activation of lung fibroblasts by inactivating the TGF-Smad pathway. In mouse and human lungs with interstitial fibrosis, CST3 and GDF15 expressions were markedly reduced, and the restoration of these cytokines alleviated the fibrotic changes in mouse lungs. These results suggest that CST3 and GDF15 are bona fide regulators to prevent excessive proliferation and activation of fibroblasts in injured lungs. These cytokines could be potential therapeutics for ameliorating interstitial lung fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-018-0530-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938700PMC
May 2018

Wogonin attenuates nasal polyp formation by inducing eosinophil apoptosis through HIF-1α and survivin suppression.

Sci Rep 2018 04 18;8(1):6201. Epub 2018 Apr 18.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is an inflammatory sinonasal disorder characterized by eosinophilic inflammation and T-helper 2 skewing. Eosinophil accumulation in sinonasal mucosa comprises a major feature of CRSwNP. The study aimed to investigate the effect of the flavone wogonin in nasal polyposis by assessing its ability to induce eosinophil apoptosis in vitro and attenuate eosinophilic CRSwNP in mice. Double immunofluorescence, immunohistochemistry, flow cytometry, and immunoblotting were performed to evaluate hypoxia-inducible factor (HIF)-1α, survivin, and apoptotic markers in the human eosinophilic EoL-1 cell line or sinonasal tissues from patients with CRS with or without NPs. In sinonasal specimens from patients with CRS, HIF-1α and survivin were up-regulated in eosinophils from patients with NPs compared with levels in patients without NPs. Under hypoxia, HIF-1α and survivin expression was up-regulated in EoL-1 cells. Wogonin down-regulated both HIF-1α and survivin in EoL-1 cells. In addition, overexpression of survivin protected EoL-1 cells against apoptosis in response to wogonin. Moreover, wogonin attenuated nasal polyp formation in a murine model. Our findings suggest that wogonin could induce caspase-3 activation by suppressing HIF-1α and survivin expression in EoL-1 cells. Further studies regarding novel therapeutic options for CRSwNP targeting eosinophil apoptosis are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-24356-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906673PMC
April 2018

CST3 and GDF15 ameliorate renal fibrosis by inhibiting fibroblast growth and activation.

Biochem Biophys Res Commun 2018 06 13;500(2):288-295. Epub 2018 Apr 13.

Department of Biomedical Sciences, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, South Korea; Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, South Korea. Electronic address:

The final strategies to care patients with end-stage renal fibrosis rely on dialysis and kidney transplantation. Because such treatments are invasive and cause health problems eventually, it is necessary to develop new therapeutic strategies for delaying the disease progress. We here searched for cytokines showing an anti-fibrotic activity in cell-based experiments. Cystatin C (CST3) and Growth differentiation factor 15 (GDF15) were identified to have anti-fibrotic activities in a cytokine array screening. In primary fibroblasts isolated from the mouse kidneys subjected to ureteral obstruction-induced fibrosis, each cytokine induced apoptotic cell death and reduced collagen production. These anti-fibrotic effects were further augmented by co-administration of both cytokines. Mechanistically, CST3 and GDF15 were found to block the TGF-β receptor and the N-Myc signaling pathways, respectively. In mice with unilateral ureter obstruction, each cytokine and the combination of two cytokines effectively reduced the fibrotic burden in the subjected kidneys. Therefore, we propose that CST3 and GDF15 could be potential candidates for biopharmaceutics to ameliorate renal fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2018.04.061DOI Listing
June 2018