Seok-Yong Choi

Chonnam National University, Gwangju, Gwangju, South Korea

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Publications (14)73.45 Total impact

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    ABSTRACT: MicroRNAs are increasingly implicated in the modulation of the progression of various cancers. We previously observed that KITENIN (KAI1 C-terminal interacting tetraspanin) is highly expressed in sporadic human colorectal cancer (CRC) tissues and that the functional KITENIN complex acts to promote progression of CRC. However, it remains unknown which microRNAs target KITENIN and whether KITENIN-targeting microRNAs modulate CRC cell motility and colorectal tumorigenesis. Here, through bioinformatic analyses and functional studies, we showed that miR-124, miR-27a, and miR-30b negatively regulate KITENIN expression and suppress the migration and invasion of several CRC cell lines via modulation of KITENIN expression. Through in vitro and in vivo induction of mature microRNAs using a tetracycline-inducible system, miR-124 was found to effectively inhibit the invasion of CT-26 colon adenocarcinoma cells and tumor growth in a syngeneic mouse xenograft model. Constitutive overexpression of precursor miR-124 in CT-26 cells suppressed in vivo tumorigenicity and resulted in decreased expression of KITENIN as well as that of MYH9 and SOX9, which are targets of miR-124. Thus, our findings identify that KITENIN-targeting miR-124, miR-27a, and miR-30b function as endogenous inhibitors of CRC cell motility and demonstrate that miR-124 among KITENIN-targeting microRNAs plays a suppressor role in colorectal tumorigenesis.Molecular Therapy (2014); doi:10.1038/mt.2014.105.
    Molecular Therapy 06/2014; · 7.04 Impact Factor
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    ABSTRACT: Alexander disease (AxD) is an astrogliopathy that primarily affects the white matter of the central nervous system (CNS). AxD is caused by mutations in a gene encoding GFAP (glial fibrillary acidic protein). The GFAP mutations in AxD have been reported to act in a gain-of-function manner partly because the identified mutations generate practically full-length GFAP. We found a novel nonsense mutation (c.1000 G>T, p.(Glu312Ter); also termed p.(E312*)) within a rod domain of GFAP in a 67-year-old Korean man with a history of memory impairment and leukoencephalopathy. This mutation, GFAP p.(E312*), removes part of the 2B rod domain and the whole tail domain from the GFAP. We characterized GFAP p.(E312*) using western blotting, in vitro assembly and sedimentation assay, and transient transfection of human adrenal cortex carcinoma SW13 (Vim(+)) cells with plasmids encoding GFAP p.(E312*). The GFAP p.(E312*) protein, either alone or in combination with wild-type GFAP, elicited self-aggregation. In addition, the assembled GFAP p.(E312*) aggregated into paracrystal-like structures, and GFAP p.(E312*) elicited more GFAP aggregation than wild-type GFAP in the human adrenal cortex carcinoma SW13 (Vim(+)) cells. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of GFAP that is associated with AxD and paracrystal formation.European Journal of Human Genetics advance online publication, 23 April 2014; doi:10.1038/ejhg.2014.68.
    European journal of human genetics: EJHG 04/2014; · 3.56 Impact Factor
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    ABSTRACT: In response to microbial infection, expression of the defensin-like peptide hepcidin (encoded by Hamp) is induced in hepatocytes to decrease iron release from macrophages. To elucidate the mechanism by which Salmonella enterica var. Typhimurium (S. typhimurium), an intramacrophage bacterium, alters host iron metabolism for its own survival, we examined the role of nuclear receptor family members belonging to the NR3B subfamily in mouse hepatocytes. Here, we report that estrogen-related receptor γ (ERRγ, encoded by Esrrg) modulates the intramacrophage proliferation of S. typhimurium by altering host iron homeostasis, and we demonstrate an antimicrobial effect of an ERRγ inverse agonist. Hepatic ERRγ expression was induced by S. typhimurium-stimulated interleukin-6 signaling, resulting in an induction of hepcidin and eventual hypoferremia in mice. Conversely, ablation of ERRγ mRNA expression in liver attenuated the S. typhimurium-mediated induction of hepcidin and normalized the hypoferremia caused by S. typhimurium infection. An inverse agonist of ERRγ ameliorated S. typhimurium-mediated hypoferremia through reduction of ERRγ-mediated hepcidin mRNA expression and exerted a potent antimicrobial effect on the S. typhimurium infection, thereby improving host survival. Taken together, these findings suggest an alternative approach to control multidrug-resistant intracellular bacteria by modulating host iron homeostasis.
    Nature medicine 03/2014; · 27.14 Impact Factor
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    ABSTRACT: Loss-of-function mutations in angiopoietin-like 3 (ANGPTL3) cause familial hypobetalipoproteinemia type 2 (FHBL2) in humans. ANGPTL3 belongs to the angiopoietin-like family, the vascular endothelial growth factor family that is structurally similar to angiopoietins and is known for a regulator of lipid and glucose metabolism, although it is unclear how mutations in ANGPTL3 lead to defect in liver development in the vertebrates. We report here that angptl3 is primarily expressed in the zebrafish developing liver and that morpholino (MO) knockdown of Angptl3 reduces the size of the developing liver, which is caused by suppression of cell proliferation, but not by enhancement of apoptosis. However, MO knockdown of Angptl3 did not alter angiogenesis in the developing liver. Additionally, disruption of zebrafish Angptl3 elicits the hypocholesterolemia phenotype that is characteristic of FHBL2 in humans. Together, our findings propose a novel role for Angptl3 in liver cell proliferation and maintenance during zebrafish embryogenesis. Finally, angptl3 morphants will serve as a good model for understanding the pathophysiology of FHBL2.
    Biochemical and Biophysical Research Communications 01/2014; · 2.28 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are endogenous non-coding 21–23 nucleotide RNAs that are involved in post-transcriptional regulation. They control various cellular processes, one of which is tumorigenesis. miRNAs have been implicated in the pathogenesis of hepatocellular carcinoma (HCC), the most common primary liver cancer. To find yet-to-be-identified miRNAs associated with HCC tumorigenesis, we resected HCC and adjacent non-tumor liver tissues from patients and excluded liver tissues harboring fibrosis from further analysis. We then carried out miRNA microarray analysis with miRNAs extracted from the tissues. Sixteen miRNAs displayed a significant change in expression levels between non-tumor and HCC liver tissues. To validate the microarray findings, we transfected HEK293 cells with miR-128 alone or miR-128 and plasmid encoding luciferase fused to the 3′ untranslated region (UTR) of E2F3, a predicted target of miR-128. As expected, miR-128 downregulated luciferase activities of E2F3 3′UTR fused to luciferase, confirming that E2F3 is a target gene of miR-128. Identification of miRNAs dysregulated in non-cirrhotic HCC will further the understanding of the pathogenesis of non-cirrhotic HCC.
    Genes & genomics 12/2013; · 0.50 Impact Factor
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    ABSTRACT: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the unintentional byproduct of various industrial processes, is classified as human carcinogen and could disrupt reproductive, developmental and endocrine systems. Induction of cyp1a1 is used as an indicator of TCDD exposure. We sought to determine tissues that are vulnerable to TCDD toxicity using a transgenic zebrafish (Danio rerio) model. We inserted a nuclear enhanced green fluorescent protein gene (EGFP) into the start codon of a zebrafish cyp1a gene in a fosmid clone using DNA recombineering. The resulting recombineered fosmid was then used to generate cyp1a reporter zebrafish, embryos of which were exposed to TCDD. Expression pattern of EGFP in the reporter zebrafish mirrored that of endogenous cyp1a mRNA. In addition, exposure of the embryos to TCDD at as low as 10pM for 72h, which does not elicit morphological abnormalities of embryos, markedly increased GFP expression. Furthermore, the reporter embryos responded to other AhR ligands as well. Exposure of the embryos to TCDD revealed previously reported (the cardiovascular system, liver, pancreas, kidney, swim bladder and skin) and unreported target tissues (retinal bipolar cells, otic vesicle, lateral line, cloaca and pectoral fin bud) for TCDD. Transgenic cyp1a reporter zebrafish we have developed can further understanding of ecotoxicological relevance and human health risks by TCDD. In addition, they could be used to identify agonists of AhR and antidotes to TCDD toxicity.
    Aquatic toxicology (Amsterdam, Netherlands) 03/2013; 134-135C:57-65. · 3.12 Impact Factor
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    ABSTRACT: Human skeletal muscle channelopathies (HSMCs) are a group of heritable conditions with ion channel-related etiology and similar presentation. To create a comprehensive picture of the phenotypic spectrum for each condition and to devise a strategy that facilitates the differential diagnosis, we collected the genotype and phenotype information from more than 500 previously published HSMC studies. Using these records, we were able to identify clear correlations between particular clinical features and the underlying alteration(s) in the genes SCN4A, CACNA1S, KCNJ2, and CLCN1. This allowed us to develop a clinical, symptom-based, binary decision flow algorithm that predicts the proper genetic origin with high accuracy (0.88-0.93). The algorithm was implemented in a stand-alone online tool ("CGPS"- http://cgps.ddd.co.kr ) to assist with HSCM diagnosis in the clinical practice. The CGPS provides simple, symptom-oriented navigation that guides the user to the most likely molecular basis of the presentation, which permits highly targeted genetic screens and, upon confirmation, tailored pharmacotherapy based on the molecular origin.
    Journal of Neurology 03/2013; · 3.58 Impact Factor
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    ABSTRACT: While the etiology and clinical features of "EMG disease" - which is characterized by diffusely increased insertional activity on needle electromyography (EMG) in the absence of neuromuscular disease - are not well known, some authorities believe it may be a form of myotonia congenita (MC). The aims of this study were to determine the clinical features of EMG disease and its relationship with CLCN1 mutations in patients. The detailed clinical and electrophysiological features of EMG disease were evaluated in six patients. All 23 coding exons and exon-intron boundaries in CLCN1 gene were analyzed by direct sequencing to detect nucleotide changes. The common clinical symptoms of EMG disease were chronic muscle stiffness or generalized myalgia, which were aggravated in a cold environment. Four patients complained of action myotonia several times a year. Short trains of provoked positive sharp waves were documented on needle EMG, but myotonic discharges, fibrillation potentials, and fasciculations were not. Increased insertional activity was identified at the asymptomatic muscles studied. One novel heterozygous mutation was identified in one patient following genetic testing for CLCN1 mutations (c.1679T>C, p.Met560Thr). The clinical features of EMG disease might be quite similar to those of MC, but CLCN1 mutation was found in only one subject. It is thus difficult to accept that EMG disease lies within the phenotypic spectrum of MC. Additional testing is needed to verify the pathogenetic cause of the diffusely increased insertional activity associated with this condition.
    Journal of Clinical Neurology 09/2012; 8(3):212-7. · 1.69 Impact Factor
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    ABSTRACT: To electrophysiologically characterize the Na(v)1.4 mutant N440K found in a Korean family with a syndrome combining symptoms of paramyotonia congenita, hyperkalemic periodic paralysis, and potassium-aggravated myotonia. We characterized transiently expressed wild-type and mutant Na(v)1.4 using whole-cell voltage-clamp analysis. N440K produced a significant depolarizing shift in the voltage dependence of fast inactivation and increased persistent current and acceleration in fast inactivation recovery, which gave rise to a 2-fold elevation in the dynamic availability of the mutant channels. In addition, the mutant channels required substantially longer and stronger depolarization to enter the slow-inactivated state. N440K causes a gain of function consistent with skeletal muscle hyperexcitability as observed in individuals with the mutation. How the same mutation results in distinct phenotypes in the 2 kindreds remains to be determined.
    Neurology 08/2012; 79(10):1033-40. · 8.30 Impact Factor
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    ABSTRACT: The development of a relatively simple, reliant and cost-effective animal test will greatly facilitate drug development. In this study, our goal was the establishment of a rapid, simple, sensitive and reproducible zebrafish xenograft model for anti-cancer drug screening. We optimized the conditions for the cancer cell xenograft in terms of injected cell numbers, incubation temperature and time. A range of human carcinoma cell types were stained with a fluorescent dye prior to injection into the fish larvae. Subsequent cancer cell dissemination was observed under fluorescent microscopy. Differences in injected cell numbers were reflected in the rate of dissemination from the xenograft site. Paclitaxel, known as a microtubule stabilizer, dose-dependently inhibited cancer cell dissemination in our zebrafish xenograft model. An anti-migratory drug, LY294002 (phosphatidylinositol 3-kinase inhibitor) also decreased the cancer cell dissemination. Chemical modifications to increase cancer drug pharmacokinetics, such as increased solubility (17-DMAG compared to geldanamycin) could also be assessed in our xenograft model. In addition to testing our new model using known anti-cancer drugs, we carried out further validation by screening a tagged triazine library. Two novel anti-cancer drug candidates were discovered. Therefore, our zebrafish xenograft model provides a vertebrate animal system for the rapid screening and pre-clinical testing of novel anti-cancer agents, prior to the requirement for testing in mammals. Our model system should greatly facilitate drug development for cancer therapy because of its speed, simplicity and reproducibility.
    Molecular BioSystems 05/2012; 8(7):1930-9. · 3.35 Impact Factor
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    ABSTRACT: Histone lysine methylation, as one of the most important factors in transcriptional regulation, is associated with a various physiological conditions. Using a bioinformatics search, we identified and subsequently cloned mouse SET domain containing 3 (SETD3) with SET (Su(var)3-9, Enhancer-of-zeste and Trithorax) and Rubis-subs-bind domains. SETD3 is a novel histone H3K4 and H3K36 methyltransferase with transcriptional activation activity. SETD3 is expressed abundantly in muscular tissues and, when overexpressed, activates transcription of muscle-related genes, myogenin, muscle creatine kinase (MCK), and myogenic factor 6 (Myf6), thereby inducing muscle cell differentiation. Conversely, knockdown of SETD3 by shRNA significantly retards muscle cell differentiation. In this study, SETD3 was recruited to the myogenin gene promoter along with MyoD where it activated transcription. Together, these data indicate that SETD3 is a H3K4/K36 methyltransferase and plays an important role in the transcriptional regulation of muscle cell differentiation.
    Journal of Biological Chemistry 08/2011; 286(40):34733-42. · 4.65 Impact Factor
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    ABSTRACT: When expression of more than one gene is required in cells, bicistronic or multicistronic expression vectors have been used. Among various strategies employed to construct bicistronic or multicistronic vectors, an internal ribosomal entry site (IRES) has been widely used. Due to the large size and difference in expression levels between genes before and after IRES, however, a new strategy was required to replace IRES. A self-cleaving 2A peptide could be a good candidate to replace IRES because of its small size and high cleavage efficiency between genes upstream and downstream of the 2A peptide. Despite the advantages of the 2A peptides, its use is not widespread because (i) there are no publicly available cloning vectors harboring a 2A peptide gene and (ii) comprehensive comparison of cleavage efficiency among various 2A peptides reported to date has not been performed in different contexts. Here, we generated four expression plasmids each harboring different 2A peptides derived from the foot-and-mouth disease virus, equine rhinitis A virus, Thosea asigna virus and porcine teschovirus-1, respectively, and evaluated their cleavage efficiency in three commonly used human cell lines, zebrafish embryos and adult mice. Western blotting and confocal microscopic analyses revealed that among the four 2As, the one derived from porcine teschovirus-1 (P2A) has the highest cleavage efficiency in all the contexts examined. We anticipate that the 2A-harboring cloning vectors we generated and the highest efficiency of the P2A peptide we demonstrated would help biomedical researchers easily adopt the 2A technology when bicistronic or multicistronic expression is required.
    PLoS ONE 01/2011; 6(4):e18556. · 3.53 Impact Factor
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    ABSTRACT: Elaeagnus glabra (Thunb.), an evergreen shrub with alternate leaves, has been used as a medicinal plant in Korea. Since many plant-derived molecules have inhibitory effects on tumor cell invasion, primarily via suppression of the activity of matrix metalloproteinases (MMPs), we investigated the effect of the methanol extract of E. glabra on tumor cell invasion. The invasiveness of HT1080 human fibrosarcoma cells were reduced in a dose-dependent manner following 24 h treatment of up to 200 microg/ml of the E. glabra extract, at which concentration no cytotoxicity occurred. Furthermore, gelatinolytic activities, and the protein and mRNA levels of MMP-2 and MMP-9 were also suppressed with increasing concentrations of the extract. Given that MMP-2 and MMP-9 are instrumental in tumor cell invasion, it is very likely that the reduction in tumor cell invasion by E. glabra extract is a consequence, at least in part, of suppressed expression of both MMP-2 and MMP-9. Isolation of a molecule(s) responsible for the extract inhibition of tumor cell invasion would pave the way for the development of a new generation of metastasis inhibitors.
    Oncology Reports 03/2009; 21(2):559-63. · 2.30 Impact Factor
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    ABSTRACT: Mitochondria maintain a web-shaped network in cells through a balance between fusion and fission. Under certain physiological and pathological conditions, this balance is breached, and as a result, change in mitochondrial morphology ensues. Real-time monitoring of such change is of significant importance for studying mitochondrial physiology and pathology, such as apoptosis, aging, and neurodegeneration. Numerous studies have been conducted in animal cell culture systems concerning mitochondrial morphology change. However, very little is known to date about the real-time changes in mitochondrial morphology at the organism level due to difficulties in observation and administration of mitochondria-disrupting drugs. Here we report the generation of transgenic zebrafish (Danio rerio) expressing mitochondrially targeted green fluorescent protein (GFP). The transparency of transgenic zebrafish embryos make it possible to monitor mitochondrial morphology in real time and in vivo. Since zebrafish inhabit fresh water, incubating zebrafish in drug-dissolved water sufficed to administer drugs to the zebrafish. We observed real-time and in vivo fragmentation of mitochondria in the transgenic embryos upon incubation in water with the following apoptosis-inducing drugs: valinomycin, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), and staurosporine. Thus, the transgenic zebrafish we generated could provide a platform for research on apoptosis and mitochondrial physiology and a screen for apoptosis-modulating drugs. It could also facilitate study of the pathogenesis of apoptosis-related diseases.
    BioTechniques 10/2008; 45(3):331-4. · 2.40 Impact Factor