Publications by authors named "Seung-Hyun Shin"

30 Publications

  • Page 1 of 1

DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition.

J Allergy Clin Immunol 2021 May 4. Epub 2021 May 4.

Obstructive Upper airway Research Laboratory, the Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea. Electronic address:

Background: Diesel exhaust particles (DEPs) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear.

Objective: We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model.

Methods: Gene set enrichment and weighted gene coexpression network analyses were performed. Cytotoxicity, epithelial-to-mesenchymal transition (EMT) markers, and nasal polyposis were assessed. Effects of DEP exposure on EMT were determined using epithelial cells from normal people or patients with chronic rhinosinusitis with or without NPs. BALB/c mice were exposed to DEP through either a nose-only exposure system or nasal instillation, with or without house dust mite, followed by zinc finger E-box-binding homeobox (ZEB)2 small hairpin RNA delivery.

Results: Bioinformatics analyses revealed that DEP exposure triggered EMT features in airway epithelial cells. Similarly, DEP-exposed human nasal epithelial cells exhibited EMT characteristics, which were dependent on ZEB2 expression. Human nasal epithelial cells derived from patients with chronic rhinosinusitis presented more prominent EMT features after DEP treatment, when compared with those from control subjects and patients with NPs. Coexposure to DEP and house dust mite synergistically increased the number of NPs, epithelial disruptions, and ZEB2 expression. Most importantly, ZEB2 inhibition prevented DEP-induced EMT, thereby alleviating NP formation in mice.

Conclusions: Our data show that DEP facilitated NP formation, possibly via the promotion of ZEB2-induced EMT. ZEB2 may be a therapeutic target for DEP-induced epithelial damage and related airway diseases, including NPs.
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http://dx.doi.org/10.1016/j.jaci.2021.04.024DOI Listing
May 2021

Antenatal magnesium sulfate and intestinal morbidities in preterm infants with extremely low gestational age.

Pediatr Neonatol 2021 Mar 1;62(2):202-207. Epub 2021 Jan 1.

Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-ro Jongno-gu, Seoul 03080, Republic of Korea.

Background: Antenatal magnesium sulfate is widely used as a tocolytic, for maternal seizures, and for seizure prophylaxis in preeclampsia. Recent studies have suggested that antenatal magnesium sulfate use is associated with favorable neurodevelopmental outcomes in preterm infants. However, there are concerns regarding the effects of antenatal magnesium sulfate on neonates, especially regarding gastrointestinal morbidities. This study aims to explore the effects of antenatal magnesium sulfate on intestinal morbidities requiring surgery in preterm infants.

Methods: This was a retrospective cohort study of 181 preterm infants who were born at less than 28 weeks of gestational age. Subjects were categorized as infants exposed to antenatal magnesium sulfate and those not exposed to antenatal magnesium sulfate.

Results: Antenatal magnesium sulfate was associated with a decreased risk of surgical conditions of the intestine (OR 0.393, 95% CI 0.170-0.905). The multivariate analysis showed that the duration of antenatal magnesium sulfate use was associated with surgical conditions of the intestine (adjusted OR 0.766, 95% CI 0.589-0.997). In the <26 weeks of gestational age subgroup, the use of antenatal magnesium sulfate was significantly associated with decreased intestinal morbidities requiring surgery (adjusted OR 0.234, 95% CI 0.060-0.922).

Conclusion: Antenatal magnesium sulfate use appears to have a protective effect on intestinal morbidities requiring surgery in preterm infants in a duration-dependent manner. Association of antenatal magnesium sulfate use and decreased intestinal morbidities requiring surgery was more distinct in preterm infants <26 weeks of gestational age.
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http://dx.doi.org/10.1016/j.pedneo.2020.12.009DOI Listing
March 2021

Extrauterine growth restriction in extremely preterm infants based on the Intergrowth-21st Project Preterm Postnatal Follow-up Study growth charts and the Fenton growth charts.

Eur J Pediatr 2021 Mar 9;180(3):817-824. Epub 2020 Sep 9.

Department of Paediatrics, Seoul National University College of Medicine, Seoul, Korea.

Growth charts are essential for monitoring the postnatal growth of preterm infants. The preterm postnatal follow-up study (PPFS) of the Intergrowth-21st Project provides new growth standards based on a longitudinal study. This study was conducted to investigate the prevalence of extrautrine growth restriction (EUGR) and the associated factors of EUGR in preterm infants, using the PPFS charts and the Fenton charts. Data of 1,356 infants with gestational age (GA) less than 28 weeks from the Korean Neonatal Network were analysed. The prevalence of small for gestational age (SGA) of weight and length was higher with the Intergrowth charts than with the Fenton charts. EUGR in weight and length was more prevalent when using the Fenton charts. Multivariate analysis showed that low GA, high birthweight z score, male, treated patent ductus arteriosus (PDA), necrotizing enterocolitis, intraventricular haemorrhage and duration of parenteral nutrition (PN) were associated with EUGR in weight by the Intergrowth charts. High birthweight z score, treated PDA and PN duration were associated with EUGR defined by the Fenton charts.Conclusion: Compared to the Fenton charts, SGA was more defined and EUGR was less prevalent in extremely low gestational infants, while EUGR defined by the Intergrowth charts categorized infants with adverse clinical courses more elaborately. What is Known: • Preterm infants are at risk of postnatal growth restriction (PGR), although optimal postnatal growth is important for the long-term outcomes. • Growth charts are essential tools to monitor the postnatal growth of preterm infants. What is New: • PGR of weight and length were less defined with the Intergrowth charts than the Fenton charts. • PGR defined by the Intergrowth preterm postnatal follow-up study (PPFS) chart categorized preterm infants with morbidities more elaborately than the Fenton charts.
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http://dx.doi.org/10.1007/s00431-020-03796-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480632PMC
March 2021

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

The Association of Pregnancy-induced Hypertension with Bronchopulmonary Dysplasia - A Retrospective Study Based on the Korean Neonatal Network database.

Sci Rep 2020 03 27;10(1):5600. Epub 2020 Mar 27.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, South Korea.

The prevalence of pregnancy-induced hypertension (PIH) and preeclampsia (PE) are 5-10% and 2-4%, respectively. PIH might affect angiogenesis in preterm neonates, but its association with bronchopulmonary dysplasia (BPD) remains controversial. This study evaluated the association between PIH and BPD in very low-birth weight infants. We retrospectively analysed the maternal, perinatal, and neonatal data of preterm infants born before 30 weeks of gestation, selected from the nationwide registry of very low-birth weight infants, between January 2013 and December 2014. As a result, 1,624 infants without maternal PIH (gestational age: 27.3 ± 1.8 weeks) and 203 infants with maternal PIH (28.0 ± 1.4 weeks, p < 0.001) were included. Birth weight was higher in the non-PIH group, compared with the PIH group (1027.4 ± 250.2 vs. 876.4 ± 261.5 g, p < 0.001). Multivariate logistic regression showed that PIH was associated with BPD (adjusted OR 1.474, 95% confidence interval 1.025-2.121), after adjusting for confounders, including small-for-gestation age (SGA). The result of present study is consistent with the current concept of BPD as an early form of pulmonary vascular disease, for both PIH and BPD are attributed by abnormal vascular formation.
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http://dx.doi.org/10.1038/s41598-020-62595-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101434PMC
March 2020

Transduction of an SV40-Immortalized Normal Human Thyroid Cell Line Induces Dedifferentiated Thyroid Carcinogenesis in a Mouse Xenograft Model.

Thyroid 2020 04;30(4):487-500

Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Despite active studies of the clinical importance of BRAF, suitable research models to investigate the role of this mutation in the etiopathogenesis of human thyroid cancers are limited. Thus, we generated cell lines by transducing the simian virus (SV)-40 immortalized human thyroid cell line Nthy-ori 3-1 (Nthy) with lentiviral vectors expressing either (Nthy/WT) or . Nthy/WT and Nthy/V600E cells were then xenografted into mice to evaluate the carcinogenic role of BRAF. Each cell line was subcutaneously injected into NOD.Cg-Prkdc Il2rg/SzJ mice, and a pathological analysis was performed. The effects of the mutation were further verified by using a BRAF-selective inhibitor (PLX-4032, vemurafenib). The transcriptome was analyzed by RNA sequencing and compared with data from The Cancer Cell Line Encyclopedia and Gene Expression Omnibus. While Nthy/WT was not tumorigenic , Nthy/V600E formed tumors reaching 2784.343 mm in 4 weeks, on average. A pathological analysis indicated that Nthy/V600E tumors were dedifferentiated thyroid cancer. We found metastases in the lung, liver, and relevant lymph nodes. A transcriptomic analysis revealed 5512 differentially expressed genes (DEGs) between the mutant and wild-type cell lines, and more DEGs were shared with anaplastic thyroid cancer than with papillary thyroid cancer. BRAF activated the cell cycle mainly by regulating G1/S phases. PLX-4032 treatment significantly inhibited tumor growth and metastasis. Our data show that BRAF plays a pivotal role in the carcinogenic transformation of an SV40-transfected immortalized normal human thyroid cell line. This xenograft model is expected to contribute to studies of the etiopathogenesis and treatment of highly malignant thyroid cancers.
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http://dx.doi.org/10.1089/thy.2019.0301DOI Listing
April 2020

Early postnatal cardiac manifestations are associated with perinatal brain injury in preterm infants with twin to twin transfusion syndrome.

Sci Rep 2019 12 6;9(1):18505. Epub 2019 Dec 6.

Seoul National University College of Medicine, Department of Pediatrics, Seoul, 110-769, Republic of Korea.

Altered hemodynamics associated with twin to twin transfusion syndrome (TTTS) can be manifested in the fetal and neonatal heart. This study evaluated the association between cardiac manifestations immediately after birth and brain injury in preterm infants with TTTS. Medical records of preterm infants who were born at <35 weeks of gestation with TTTS and admitted to the neonatal intensive care unit at Seoul National University Children's Hospital between January 2011 and January 2018 were reviewed. TTTS was prenatally diagnosed and staged according to the Quintero criteria. Echocardiographic findings, brain ultrasound and MRI imaging findings were analyzed. Fifty-three infants were enrolled in this study. Thirty-two infants (60.3%) were treated by fetoscopic laser coagulation. Brain injury developed in 15 infants (28.3%). Hypotension within the first week and immediate postnatal cardiac manifestations were more prevalent in the brain injury group. In the multivariate analysis, acute kidney injury and cardiac manifestations, such as ventricular dysfunction and tricuspid regurgitation, were statistically associated with brain injury in the study population. Immediate postnatal cardiac manifestations, such as ventricular dysfunction and tricuspid regurgitation, can serve as surrogate markers for perinatal hemodynamic disturbance, which are associated with early neonatal brain injury in preterm infants with TTTS.
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http://dx.doi.org/10.1038/s41598-019-54951-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898644PMC
December 2019

High-performance and -stability graphene quantum dots-mixed conducting polymer/porous Si hybrid solar cells with titanium oxide passivation layer.

Nanotechnology 2020 Feb 15;31(9):095202. Epub 2019 Nov 15.

Department of Applied Physics and Institute of Natural Sciences, Kyung Hee University, Yongin 17104, Republic of Korea.

Recently, conducting polymer/Si hybrid solar cells (HSCs) based on simple fabrication processes have become highly attractive due to their low cost, but low conductivity of the polymer, high reflection index of Si, and large recombination loss on the Si back contact are major drawbacks that should be solved for the practical applications. Here, we first report HSCs composed of graphene quantum dots (GQDs)-mixed poly (3,4-ethylenedioxythiophene) (PEDOT:GQDs)/ porous Si (PSi)/n-Si/titanium oxide (TiO , back passivation layer). Maximum power conversion efficiency (PCE) of 10.49% is obtained from the HSCs at an active area of 5 mm, resulting from the enhanced conductivity of the PEDOT:GQDs, the reduced reflectivity of Si (the increased absorption) by the formation of PSi, and the prevented recombination loss at the Si backside due to the passivation. In addition, the HSCs of 16 mm active area maintain ∼78% (absolutely from 8.03% to 6.28%) of the initial PCE even while kept under ambient conditions for 15 d.
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http://dx.doi.org/10.1088/1361-6528/ab5838DOI Listing
February 2020

Fabrication and Comparison of Self-Organized Ag and Au Nanodots on Ti/MgO(001) Substrates.

J Nanosci Nanotechnol 2020 May;20(5):3231-3238

Department of Electronic Materials Engineering, Kwangwoon University, Seoul 01897, Korea.

We analyze and compare the differences in the dewetting phenomena and crystal structure between Ag(5.0 nm) and Au(5.0 nm) layers deposited on a Ti(1.0 nm) seed layer coated onto a MgO(001) substrate. The samples are deposited at room temperature and annealed at 350-450 °C for 5 h. The surfaces of both Ag/Ti and Au/Ti films exhibit a completely separated island structure, subsequently leading to the formation of a nanodot array after annealing. Based on atomic force microscopy (AFM) analysis, we conclude that the dewetting progression speed of Ag/Ti films is higher than that of Au/Ti films. Based on X-ray diffraction (XRD) results, the Ti thin film acts as a seed layer, assisting the epitaxial growth of fcc-Ag(001) nanodots on the MgO(001) substrate, whereas in the case of Au/Ti, the Au layer grows non-epitaxially on the MgO(001) substrate, which is related to the difference in the surface energies of Ag and Au. Furthermore, the optical absorbance spectra of the self-organized Ag and Au nanodots with the Ti seed layer are obtained in the visible light range and the optical properties of Ag and Au nanodots are compared.
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http://dx.doi.org/10.1166/jnn.2020.17385DOI Listing
May 2020

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.
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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.
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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.
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http://dx.doi.org/10.1038/s41388-019-0676-yDOI 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.
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http://dx.doi.org/10.1038/s41467-018-06606-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173745PMC
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.
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http://dx.doi.org/10.1038/s41388-018-0354-5DOI Listing
October 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.
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http://dx.doi.org/10.1038/s12276-018-0089-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951909PMC
May 2018

Astrocyte-derived CCL20 reinforces HIF-1-mediated hypoxic responses in glioblastoma by stimulating the CCR6-NF-κB signaling pathway.

Oncogene 2018 06 14;37(23):3070-3087. Epub 2018 Mar 14.

Department of Biomedical Sciences, BK21-plus education program, Seoul National University College of Medicine, Seoul, Korea.

During tumor development, stromal cells are co-opted to the tumor milieu and provide favorable conditions for the tumor. Hypoxia stimulates cancer cells to acquire a more malignant phenotype via activation of hypoxia-inducible factor 1 (HIF-1). Given that cancer cells and astrocytes in glioblastomas coexist in a hypoxic microenvironment, we examined whether astrocytes affect the adaptation of glioblastoma cells to hypoxia. Immunoblotting, reporter assays, quantitative RT-PCR, and chromatin immunoprecipitation were performed to evaluate HIF-1 signaling in glioblastoma cells. Astrocyte-derived chemokine C-C motif ligand 20 (CCL20) was identified using cytokine arrays, and its role in glioblastoma development was evaluated in orthotopic xenografts. Astrocytes augmented HIF-1α expression in glioblastoma cells under hypoxia. The expression of HIF-1 downstream genes, cancer colony formation, and Matrigel invasion of glioblastoma cells were stimulated by conditioned medium from astrocytes pre-exposed to hypoxia. CCL20 was secreted in a hypoxia-dependent manner from astrocytes and busted the hypoxic induction of HIF-1α in glioblastoma cells. Mechanistically, the CCL20/CCR6 signaling pathway upregulates HIF-1α by stimulating nuclear factor kappa B-driven transactivation of the HIF1A gene. Compared with the control tumors, CCR6-deficient glioblastoma xenografts grew more slowly, with poor vascularization, and expressed lower levels of HIF-1α and its downstream proteins. Furthermore, CCR6 expression was correlated with HIF-1α expression in GEO and TCGA datasets from human glioblastoma tissues. These results suggest that glioblastoma cells adapt well to hypoxic stress by virtue of CCL20 derived from neighboring astrocytes.
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http://dx.doi.org/10.1038/s41388-018-0182-7DOI Listing
June 2018

FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes.

Cancer Res 2018 03 19;78(5):1184-1199. Epub 2017 Dec 19.

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

The prolyl hydroxylase domain-containing proteins (PHD1-3) and the asparaginyl hydroxlyase factor inhibiting HIF (FIH) are oxygen sensors for hypoxia-inducible factor-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygen-dependent epigenetic regulation more broadly is not known. Here, we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. In clinical specimens of ovarian cancer, expression of FIH and G9a were reciprocally associated with patient outcomes. We also identified mutations of FIH target motifs in G9a and GLP, which exhibited excessive H3K9 methylation and facilitated cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen-dependent chromatin remodeling. It also implies that the FIH-G9a/GLP pathway could be a potential target for inhibiting hypoxia-induced cancer metastasis. These findings deepen understanding of oxygen-dependent gene regulation and cancer metastasis in response to hypoxia. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2506DOI Listing
March 2018

Hyponatremic Hypertensive Syndrome in a Preterm Infant with Twin Anemia-Polycythemia Sequence.

Pediatr Neonatol 2017 08 28;58(4):382-383. Epub 2016 Oct 28.

Department of Pediatrics, College of Medicine, Seoul National University, Seoul, South Korea.

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http://dx.doi.org/10.1016/j.pedneo.2016.08.003DOI Listing
August 2017

Baicalin, a flavonoid, affects the activity of human dermal papilla cells and promotes anagen induction in mice.

Naunyn Schmiedebergs Arch Pharmacol 2015 May 2;388(5):583-6. Epub 2014 Dec 2.

Department of Immunology, School of Medicine, Kyungpook National University, 101 Dongin-dong 2 Ga, Jung-gu, Daegu, 700-422, Republic of Korea.

Baicalin, a flavonoid isolated from Scutellaria baicalensis, is known to have multiple biological functions. Recent studies have demonstrated that baicalin treatment increases alkaline phosphatase activity (ALP) and osteoprotegerin secretion by osteoblasts. Furthermore, baicalin induces the differentiation of cultured osteoblasts via the activation of the Wnt/β-catenin signaling pathway. In this study, we evaluated the hair growth-promoting effects of baicalin in human follicular dermal papilla (DP) cells. A reporter assay and Western blotting were used to assess the effect of baicalin on β-catenin signaling in DP cells. ALP activity and messenger RNA (mRNA) expression were examined by ALP staining and real-time polymerase chain reaction (PCR), respectively. Growth factor expression levels were also evaluated using real-time PCR. Finally, the effect of baicalin on hair growth in vivo was examined by topical application of baicalin on the shaved dorsal skin of C57BL/6 mice. Our results indicate that baicalin activates Wnt/β-catenin signaling in a dose-dependent manner in human DP cells. ALP mRNA expression and activity were significantly induced in the presence of baicalin. In addition, treatment with baicalin induced the mRNA expression of growth factors, such as insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF). Moreover, compared to vehicle treatment, baicalin treatment induced an earlier conversion from telogen to anagen. Our results strongly suggest that baicalin promotes hair growth by regulating the activity of DP cells.
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http://dx.doi.org/10.1007/s00210-014-1075-0DOI Listing
May 2015

Differential roles of Sirt1 in HIF-1α and HIF-2α mediated hypoxic responses.

Biochem Biophys Res Commun 2014 Jan 11;444(1):36-43. Epub 2014 Jan 11.

Departments of Biomedical Sciences and Pharmacology, Ischemic/Hypoxic Disease Institute, Cancer Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea. Electronic address:

Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) determine cancer cell fate under hypoxia. Despite the similarities of their structures, HIF-1α and HIF-2α have distinct roles in cancer growth under hypoxia, that is, HIF-1α induces growth arrest whereas HIF-2α promotes cell growth. Recently, sirtuin 1 (Sirt1) was reported to fine-tune cellular responses to hypoxia by deacetylating HIF-1α and HIF-2α. Yet, the roles of Sirt1 in HIF-1α and HIF-2α functions have been controversial. We here investigated the precise roles of Sirt1 in HIF-1α and HIF-2α regulations. Immunological analyses revealed that HIF-1α K674 and HIF-2α K741 are acetylated by PCAF and CBP, respectively, but are deacetylated commonly by Sirt1. In the Gal4 reporter systems, Sirt1 was found to repress HIF-1α activity constantly in ten cancer cell-lines but to regulate HIF-2α activity cell type-dependently. Moreover, Sirt1 determined cell growth under hypoxia depending on HIF-1α and HIF-2α. Under hypoxia, Sirt1 promoted cell proliferation of HepG2, in which Sirt1 differentially regulates HIF-1α and HIF-2α. In contrast, such an effect of Sirt1 was not shown in HCT116, in which Sirt1 inactivates both HIF-1α and HIF-2α because conflicting actions of HIF-1α and HIF-2α on cell growth may be offset. Our results provide a better understanding of the roles of Sirt1 in HIF-mediated hypoxic responses and also a basic concept for developing anticancer strategy targeting Sirt1.
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http://dx.doi.org/10.1016/j.bbrc.2014.01.001DOI Listing
January 2014

In vivo monitoring of survival and proliferation of hair stem cells in a hair follicle generation animal model.

Mol Imaging 2013 Jul-Aug;12(5):310-7

Departments of Nuclear Medicine and Immunology, Kyungpook National University School of Medicine, Daegu, South Korea, 700-721.

The purpose of this study was to investigate in vivo monitoring of hair follicle stem cells (newborn mouse fibroblasts [NFs]) expressing enhanced firefly luciferase (effluc) (NF-effluc) using noninvasive bioluminescence imaging (BLI). Effluc gene transduction into NFs was performed by retroviral vector, and effluc messenger ribonucleic acid expression and function were evaluated by reverse transcription-polymerase chain reaction and luciferase assay. After in vivo transplantation of NF-effluc cells to generate hair follicles, BLI was performed on days 1, 3, 7, 14, and 21 after transplantation. Additionally, hair follicle generation by the implanted stem cells was investigated using microscopy. The luciferase activity of NF-effluc was 41,175-fold higher compared to that of untransfected NFs. Bioluminescence signals from the transplantation site decreased gradually over 2 weeks; then the signal plateaued. Hair follicles were confirmed at the NF-effluc cell implantation site on day 14 after transplantation. We successfully monitored hair generation by hair stem cell implantation noninvasively with optical molecular strategy in an in vivo model.
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April 2014

Extracellular histones inhibit hair shaft elongation in cultured human hair follicles and promote regression of hair follicles in mice.

Exp Dermatol 2012 Dec;21(12):956-8

Release of histone H4 in rat vibrissa dermal papilla (DP) cells exposed to sub-toxic dose of colchicines has been recently reported. In addition, exposure to histone H4 has been reported to result in inhibited proliferation and reduced alkaline phosphatase (ALP) activity of cultured vibrissa DP cells. These findings prompted us to investigate the role of extracellular histones in hair growth using cultured human hair follicles and hair cycling using back skin of mice. We report here that exposure of cultured hair follicles to histone H4 and H2A resulted in significant inhibition of elongation of hair shafts, decreased expression of IGF-1 and decreased expression and activity of ALP. Injection of histones into hypodermis of mice during anagen resulted in premature onset of catagen. Findings of the current study provide strong evidence suggesting the inhibitory role of extracellular histones in hair growth.
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http://dx.doi.org/10.1111/exd.12033DOI Listing
December 2012

Conditioned media obtained from human outer root sheath follicular keratinocyte culture activates signalling pathways that contribute to maintenance of hair-inducing capacity and increases trichogenicity of cultured dermal cells.

Exp Dermatol 2012 Oct 7;21(10):793-5. Epub 2012 Aug 7.

Findings from recent studies have demonstrated that hair-inducing capacity (trichogenicity) of cultured dermal cells can be maintained by addition of conditioned media obtained from culture of epidermal keratinocytes. In this study, we investigated the question of whether treatment with human follicular keratinocyte-conditioned media (FKCM) can result in activation of signalling pathways that contribute to trichogenicity and increase the trichogenicity of cultured dermal cells. Through conduct of hair reconstitution assays, we observed that treatment of cells with FKCM resulted in induction of a greater number of hair follicles, compared with control cells. Treatment of dermal cells with FKCM resulted in the activation of BMP and β-catenin signalling pathways. In addition, higher levels of IGFBP-7, IL-8, OPG and uPA were observed in FKCM. Altogether, our data suggest that a patient's own FKCM would be ideal for expansion of the patient's own follicular dermal cells for cell therapy for treatment of hair loss.
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http://dx.doi.org/10.1111/j.1600-0625.2012.01570.xDOI Listing
October 2012

Establishment and characterization of an immortalized human dermal papilla cell line.

BMB Rep 2011 Aug;44(8):512-6

Department of Immunology and Hair Research Center, School of Medicine, Kyungpook National University, Daegu, Korea.

Establishment of immortalized human dermal papilla cells (DPCs) retaining the characteristics of DPCs would be a great help for hair researchers. We recently established a simian virus 40T (SV40T)-transformed human DP cell line (SV40TDPC). However, the cell line senesced around passage 25 and ceased proliferation. In this study, we introduced the human telomerase reverse transcriptase (hTERT) gene into SV40T-DPC and established an immortalized human DP cell line. The cell line, SV40T-hTERT-DPC, did not induce tumors when inoculated into nude mice. SV40T-hTERT-DPC maintained morphology of early passage DPCs, expressed markers of DPCs, and retained responses to Wnt/β-catenin and bone morphogenic protein (BMP) signaling pathways known to be required for hair-inducing activity of DPCs. The data strongly suggest that SV40T-hTERT-DPC retains many characteristics of human DPCs in vivo without malignant transformation.
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http://dx.doi.org/10.5483/bmbrep.2011.44.8.512DOI Listing
August 2011

Erythropoietin promotes hair shaft growth in cultured human hair follicles and modulates hair growth in mice.

J Dermatol Sci 2010 Aug 19;59(2):86-90. Epub 2010 May 19.

Department of Immunology, School of Medicine, Kyungpook National University, 101 Dong-In-Dong, Jung-Gu, Daegu 700-422, Republic of Korea.

Background: Recent studies have shown that erythropoietin (EPO)/erythropoietin receptor (EPOR) signaling exist in both human and mouse hair follicles (HFs).

Objective: To investigate whether dermal papilla cells (DPCs) express functional EPOR and, if so, to investigate effects of EPO on hair shaft growth in cultured human scalp hair follicles and hair growth in mice.

Methods: EPOR expression in DPCs and follicular keratinocytes was examined by RT-PCR and immunoblot. Phosphorylation of EPOR signaling pathway mediators by EPO treatment was examined by immunoblot. MTT assay was employed to check cell viability after EPO treatment. Hair shaft growth was measured in the absence or presence of EPO and matrix keratinocyte proliferation was examined by Ki-67 immunostaining in cultured hair follicles. Agarose beads containing EPO were implanted into dorsal skin of C57BL/6 mice to examine effects of EPO on hair growth in vivo.

Results: EPOR mRNA and protein are expressed in cultured human DPCs. EPOR signaling pathway mediators such as EPOR and Akt are phosphorylated by EPO in DPCs. EPO significantly promoted the growth of DPCs and elongated hair shafts with increased proliferation of matrix keratinocytes in cultured human hair follicles. In addition, EPO not only promoted anagen induction from telogen but also prolonged anagen phase.

Conclusions: EPO may modulate hair growth by stimulating DPCs that express functional EPOR.
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http://dx.doi.org/10.1016/j.jdermsci.2010.04.015DOI Listing
August 2010

Identification of transcriptional targets of Wnt/beta-catenin signaling in dermal papilla cells of human scalp hair follicles: EP2 is a novel transcriptional target of Wnt3a.

J Dermatol Sci 2010 May 6;58(2):91-6. Epub 2010 Mar 6.

Department of Immunology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.

Background: Recent studies showed that Wnt signaling through the beta-catenin pathway (canonical Wnt signaling) act on mouse dermal papilla cells (DPCs) enabling hair follicles to keep growing.

Objective: To investigate whether human DPCs respond to canonical Wnt signaling and, if so, to identify target genes of Wnt/beta-catenin pathway.

Methods: Cultured human DPCs were transiently transfected with the beta-catenin responsive TCF reporter plasmid (pTopflash) and corresponding negative control reporter (pFopflash) to assess the activity of beta-catenin signaling by Wnt3a (one of the canonical Wnts). Immunofluorescence staining was also performed to localize beta-catenin in the presence or absence of Wnt3a. Microarray was carried out using Affymetrix gene chips. RT-PCR analysis and immunoblot were employed to verify microarray data. Cyclic AMP (cAMP) levels were measured using EIA assay after Wnt3a and PGE2 treatment in DPCs.

Results: Wnt3a significantly stimulated the transcriptional activity of pTopflash but not pFopflash. In line with this, we identified a number of genes that are regulated by Wnt3a. Some of the differently expressed genes including EP2 were confirmed by RT-PCR analysis. Immunoblot further confirmed that EP2 protein is indeed increased by Wnt3a. DPCs pretreated with Wnt3a showed higher responsiveness to PGE2 as measured by cAMP levels.

Conclusions: Elucidation of the role of Wnt3a-regulated genes identified in this study including EP2 would help our understanding of hair-induction and maintenance of anagen phase.
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http://dx.doi.org/10.1016/j.jdermsci.2010.02.011DOI Listing
May 2010

Slowed progression in models of Huntington disease by adipose stem cell transplantation.

Ann Neurol 2009 Nov;66(5):671-81

Department of Neurology, Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea.

Objective: Adipose-derived stem cells (ASCs) are readily accessible and secrete multiple growth factors. Here, we show that ASC transplantation rescues the striatal pathology of Huntington disease (HD) models.

Methods: ASCs were isolated from human subcutaneous adipose tissue. In a quinolinic acid (QA)-induced rat model of striatal degeneration, human ASCs (1 million cells) were transplanted into the ipsilateral striatal border immediately after the QA injection. In 60-day-old R6/2 mice transgenic for HD, ASCs (0.5 million cells) were transplanted into each bilateral striata. In in vitro experiments, we treated mutant huntingtin gene-transfected cerebral neurons with ASC-conditioned media.

Results: In the QA model, human ASCs reduced apomorphine-induced rotation behavior, lesion volume, and striatal apoptosis. In R6/2 transgenic mice, transplantation of ASCs improved Rota-Rod performance and limb clasping, increased survival, attenuated the loss of striatal neurons, and reduced the huntingtin aggregates. ASC-transplanted R6/2 mice expressed elevated levels of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and reactive oxygen defense enzymes and showed activation of the Akt/cAMP-response element-binding proteins. ASC-conditioned media decreased the level of N-terminal fragments of mutant huntingtin and associated apoptosis, and increased PGC-1alpha expression.

Interpretation: Collectively, ASC transplantation slowed striatal degeneration and behavioral deterioration of HD models, possibly via secreted factors.
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http://dx.doi.org/10.1002/ana.21788DOI Listing
November 2009