Yangsik Jeong

Yonsei University Hospital, Sŏul, Seoul, South Korea

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Publications (19)118.45 Total impact

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    ABSTRACT: Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.
    Full-text · Article · Aug 2015 · PLoS ONE
  • Ai N. H. Phan · Yangsik Jeong

    No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: Licochalcone (lico) F is a novel synthetic retrochalcone. In this study, we investigated the anti-inflammatory effects of lico F in vitro, and its effects on obesity-induced chronic inflammation, glucose intolerance, and fatty liver in vivo. The inhibitory effects of lico F on TNFα-induced inflammation were investigated using NF-κB luciferase reporter assay and RT-PCR. Diet-induced obese mice were treated orally, once per day, with vehicle or lico F (10 mg/kg/day), for 3 weeks, and blood, liver, and adipose tissues were analyzed. Lico F inhibited TNFα-induced NF-κB activation and mRNA expression of TNFα, COX-2, IL-6, IL-1β, and NOS2. In obese mice, lico F administration significantly alleviated glucose tolerance without changes in body weight gain and food intake. Lico F reduced adipocyte size and macrophage infiltration into white adipose tissue and improved hepatic lesions, by decreasing fat droplets and glycogen deposition. The mRNA expression levels of TNFα, MCP-1, and CD68 in white adipose tissue also decreased markedly. Moreover, lico F enhanced Akt signaling, but reduced p38 MAPK signaling in white adipose tissue. Lico F had anti-inflammatory effects and showed beneficial effects on glucose metabolism, which could be partially caused by activation of the Akt signal pathway and obesity-induced chronic inflammation, probably by downregulating p38 signal pathway. Moreover, lico F could be used as a potential novel therapeutic compound against type 2 diabetes and obesity-induced chronic inflammation without the deleterious effects of body weight gain and fatty liver. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
    No preview · Article · Mar 2015 · Clinical nutrition (Edinburgh, Scotland)
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    ABSTRACT: Diabetes is a risk factor for breast cancer development and is associated with poor prognosis for breast cancer patients. However, the molecular and biochemical mechanisms underlying the association between diabetes and breast cancer have not been fully elucidated. Here, we investigated estradiol response in MCF-7 breast cancer cells with or without chronic exposure to insulin. We found that insulin priming is necessary and specific for estradiol-induced cancer cell growth, and induces anaplerotic shunting of glucose into macromolecule biosynthesis in the estradiol treated cells. Treatment with ERK or Akt specific inhibitors, U0126 or LY294002, respectively, suppressed estradiol-induced growth. Interestingly, molecular analysis revealed that estradiol treatment markedly increases expression of cyclin A and B, and decreases p21 and p27 in the insulin-primed cells. In addition, estradiol treatment activated metabolic genes in pentose phosphate (PPP) and serine biosynthesis pathways in the insulin-primed cells while insulin priming decreased metabolic gene expression associated with glucose catabolism in the breast cancer cells. Finally, we found that anti-diabetic drug metformin and AMPK ligand AICAR, but not thiazolidinediones (TZDs), specifically suppress the estradiol-induced cellular growth in the insulin-primed cells. These findings suggest that estrogen receptor (ER) activation under chronic hyperinsulinemic condition increases breast cancer growth through the modulation of cell cycle and apoptotic factors and nutrient metabolism, and further provide a mechanistic evidence for the clinical benefit of metformin use for ER-positive breast cancer patients with diabetes.
    Full-text · Article · Feb 2015 · Cancer biology & therapy
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    ABSTRACT: Gallic acid [3,4,5-trihydroxybenzoic acid (GA)], a natural phytochemical, is known to have a variety of cellular functions including beneficial effects on metabolic syndromes. However, the molecular mechanism by which GA exerts its beneficial effects is not known. Here we report that GA plays its role through the activation of AMP-activated protein kinase (AMPK) and by regulating mitochondrial function via the activation of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Sirtuin 1 (Sirt1) knockdown significantly blunted GA's effect on PGC1α activation and downstream genes, suggesting a critical role of the AMPK/Sirt1/PGC1α pathway in GA's action. Moreover, diet-induced obese mice treated with GA showed significantly improved glucose and insulin homeostasis. In addition, the administration of GA protected diet-induced body weight gain without a change in food intake. Biochemical analyses revealed a marked activation of AMPK in the liver, muscle, and interscapular brown adipose tissue of the GA-treated mice. Moreover, uncoupling protein 1 together with other genes related to energy expenditure was significantly elevated in the interscapular brown adipose tissue. Taken together, these results indicate that GA plays its beneficial metabolic roles by activating the AMPK/Sirt1/PGC1α pathway and by changing the interscapular brown adipose tissue genes related to thermogenesis. Our study points out that targeting the activation of the AMPK/Sirt1/PGC1α pathway by GA or its derivatives might be a potential therapeutic intervention for insulin resistance in metabolic diseases.
    Full-text · Article · Oct 2014 · Endocrinology
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    ABSTRACT: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.
    Full-text · Article · Apr 2014 · Biochemical and Biophysical Research Communications
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    ABSTRACT: Human induced pluripotent stem (hiPS) cells are an alternative cell source of regenerative medicine for liver disease. Since variations in hepatic differentiation efficacy among hiPS cells exist, it is important to select a hiPS cell line with hepaticdifferentiation propensity. In addition, nuclear receptors (NRs)regulate essential biological processes including differentiation and development.In this study, we identified the hiPS cell line with hepatic differentiation propensity and examined expression levels of 48 NRs during this process. We screened28hiPS cell lines, which are established from various tissues of healthy persons with variousreprogramming methods, using 3 step differentiation method,and examined expression levels of 48 NRs by quantitative real-time PCR during differentiation process in the selected cells. HiPS-RIKEN-2B and HiPS-RIKEN-2F cells have hepatic differentiation propensity. Differentiation propensity toward endoderm was affected by donor origin but not byreprogramming methods or cell type of origins. Expression levels of NRs were closely associated with those of hepatic differentiation markers. Furthermore, expression patterns of NRs were categorized as five patterns. In particular, seven NRssuch as COUP-TF1, RARα, PPARγ, PR, PNR, TLX and GRwere identified as the genes of which expression gradually goes up with differentiation. These findings will be useful for not only elucidating mechanisms of hepatic differentiation of hiPS cells but also cell based therapy for liver diseases.
    Full-text · Article · Mar 2014 · Hepatology Research
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    ABSTRACT: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.
    Full-text · Article · Jan 2014 · Biochemical and Biophysical Research Communications
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    ABSTRACT: Lung cancer is a major cause of cancer-related death worldwide. It is believed that obesity-related malignancies such as breast, endometrial, colorectal, and kidney carcinomas have lower plasma level and/or tissue expression of adiponectin receptors. However, the association between adiponectin receptors and lung cancer, a non obesity-related malignancy, is still unknown. We evaluated the tissue expression of adiponectin receptor (AdipoR) 1 and AdipoR2 in 83 cases of non-small cell lung carcinoma (NSCLC) and matched non-neoplastic lung tissues by immunohistochemistry and real-time polymerase chain reaction (PCR). Clinicopathological data, including smoking history, smoker's bronchiolitis, emphysema, lymph node metastasis, and T-stage were collected and evaluated. Expression of immunohistochemically stained AdipoR1 and AdipoR2 was observed in all samples of non-neoplastic lung tissues. Both receptors showed higher mRNA expression in non-neoplastic than neoplastic tissues (p < 0.05). In NSCLC tissues, AdipoR1 immunohistochemical expression was not observed in most of patients with squamous cell carcinoma and current smoking history (31/42, p = 0.04 and 25/29, p = 0.003, respectively). Additionally, AdipoR1 mRNA expression was significantly lower in patients with lymph node metastasis (p = 0.05). Meanwhile, AdipoR2 immunohistochemical stain expression was inversely correlated with T-stage (p = 0.05) and AdipoR2 mRNA expression was significantly lower in patients with smoker's bronchiolitis (p = 0.01) and emphysema (p = 0.03). Patients with expression of AdipoR1 had longer overall survival. AdipoR2 expression was not correlated with patients' survival. In conclusion, we suggest that expression of AdipoR1 is indicative of favorable prognosis and may be used as prognostic marker in NSCLC.
    Full-text · Article · Feb 2013 · The Tohoku Journal of Experimental Medicine
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    ABSTRACT: Oxysterol binding protein related protein 1S (ORP1S) is a member of a family of sterol transport proteins. Here we present evidence that ORP1S translocates from the cytoplasm to the nucleus in response to sterol binding. The sterols that best promote nuclear import of ORP1S also activate the liver X receptor (LXR) transcription factors and we show that ORP1S binds to LXRs, promotes binding of LXRs to LXR response elements (LXREs) and specifically enhances LXR-dependent transcription via the ME.1 and ME.2 enhancer elements of the apoE gene. We propose that ORP1S is a cytoplasmic sterol sensor, which transports sterols to the nucleus and promotes LXR-dependent gene transcription through select enhancer elements.
    No preview · Article · Jun 2012 · Experimental Cell Research
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    ABSTRACT: Lung cancer is the leading cause of cancer-related death. Despite a number of studies that have provided prognostic biomarkers for lung cancer, a paucity of reliable markers and therapeutic targets exist to diagnose and treat this aggressive disease. In this study we investigated the potential of nuclear receptors (NRs), many of which are well-established drug targets, as therapeutic markers in lung cancer. Using quantitative real-time PCR, we analyzed the expression of the 48 members of the NR superfamily in a human panel of 55 normal and lung cancer cell lines. Unsupervised cluster analysis of the NR expression profile segregated normal from tumor cell lines and grouped lung cancers according to type (i.e. small vs. non-small cell lung cancers). Moreover, we found that the NR signature was 79% accurate in diagnosing lung cancer incidence in smokers (n = 129). Finally, the evaluation of a subset of NRs (androgen receptor, estrogen receptor, vitamin D receptor, and peroxisome proliferator-activated receptor-γ) demonstrated the therapeutic potential of using NR expression to predict ligand-dependent growth responses in individual lung cancer cells. Preclinical evaluation of one of these receptors (peroxisome proliferator activated receptor-γ) in mouse xenografts confirmed that ligand-dependent inhibitory growth responses in lung cancer can be predicted based on a tumor's receptor expression status. Taken together, this study establishes NRs as theragnostic markers for predicting lung cancer incidence and further strengthens their potential as therapeutic targets for individualized treatment.
    No preview · Article · Jun 2012 · Molecular Endocrinology
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    ABSTRACT: The liver X receptor α (LXRα) is a nuclear receptor that is involved in regulation of lipid metabolism, cellular proliferation and apoptosis, and immunity. In this report, we characterize three human LXRα isoforms with variation in the ligand-binding domain (LBD). While examining the expression of LXRα3, which lacks 60 amino acids within the LBD, we identified two novel transcripts that encode LXRα-LBD variants (LXRα4 and LXRα5). LXRα4 has an insertion of 64 amino acids in helix 4/5, and LXRα5 lacks the C-terminal helices 7 to 12 due to a termination codon in an additional exon that encodes an intron in the LXRα1 mRNA. LXRα3, LXRα4, and LXRα5 were expressed at lower levels compared with LXRα1 in many human tissues and cell lines. We also observed weak expression of LXRα3 and LXRα4 in several tissues of mice. LXR ligand treatment induced differential regulation of LXRα isoform mRNA expression in a cell type-dependent manner. Whereas LXRα3 had no effect, LXRα4 has weak transactivation, retinoid X receptor (RXR) heterodimerization, and coactivator recruitment activities. LXRα5 interacted with a corepressor in a ligand-independent manner and inhibited LXRα1 transactivation and target gene expression when overexpressed. Combination of LXRα5 cotransfection and LXRα antagonist treatment produced additive effects on the inhibition of ligand-dependent LXRα1 activation. We constructed structural models of the LXRα4-LBD and its complexes with ligand, RXR-LBD, and coactivator peptide. The models showed that the insertion in the LBD can be predicted to disrupt RXR heterodimerization. Regulation of LXRα pre-mRNA splicing may be involved in the pathogenesis of LXRα-related diseases.
    Full-text · Article · Mar 2012 · Molecular pharmacology

  • No preview · Article · Apr 2011 · Cancer Research
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    Dataset: Table S3
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    ABSTRACT: Clinical information on individual patients. (0.06 MB PDF)
    Preview · Dataset · Dec 2010
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    Dataset: Figure S2
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    ABSTRACT: Expression profiles of the NR superfamily in lung tissues. Quantitative real-time PCR analysis was performed for 48 NRs (including two common splice variants each for PPARγ and PPARδ) in 30 pair-matched tissues (normal and tumor) from patients with lung cancer. Relative expression values were obtained as described in Methods. Ct>34 was scored as below detection. Open and filled bars represent normal and pair-matched tumor tissues from each patient, respectively. The patients are numbered from 1 to 30 (see Table S3) and grouped according to gender and survival status, with each patient being in the same position for each NR dataset. (0.92 MB PDF)
    Preview · Dataset · Dec 2010
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    Dataset: Figure S9
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    ABSTRACT: Identification of NRs as prognostic biomarkers in normal lung tissue from patients with lung cancer. Kaplan-Meier plots of time to recurrence and survival are shown for NGFIB3 and MR, respectively. Note that these two plots are identical to those obtained when using the entire 48-NR gene set. (A) LOOCV of recursive partitioning tree model of the MDACC QPCR data in normal tissues shows that NGFIB3 is the single gene left in the predictive model for disease progression (HR = 4.61, 95% CI, 1.74–12.3; p = 0.00099). (B) Similar LOOCV analysis shows MR is a single gene predictor of the entire 48-NR gene set as associated with patient survival (HR = 2.22, 95% CI, 0.85–5.81; p = 0.094). Red and black lines represent high- and low-risk groups, respectively. Open circles indicate censored samples. (0.13 MB PDF)
    Preview · Dataset · Dec 2010
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    Dataset: Figure S7
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    ABSTRACT: Kaplan-Meier estimates of survival time based on NR expression when clinical variables are included in the analysis. The analysis for survival time was performed for clinical variables in the absence (A) or presence (B) of NR expression. The microarray dataset from the four-institute Consortium was divided into two groups, one for the training cohort and the other for the testing cohort. The analysis included the two principal component sets of 48 NR expression variables and clinical variables. The clinical variables included gender, age, stage, and treatments (i.e., those receiving adjuvant chemotherapy or not, and those receiving adjuvant radiation therapy or not) as co-variables in classification tree model. The final predictive tree structure can be seen in the Sweave report (Text S2). The predictive model was built in the training cohort and then validated in the testing cohort. In the testing cohort, patients in the predicted high-risk group live for a significantly shorter time than patients in the predicted low-risk group, (HR = 2.71, p = 1.02×10−5 for using clinical variables only; HR = 3.21, p = 2.43×10−7 for using clinical and NR signature). p-values were obtained by log-rank test. Red and black lines represent predicted high- and low-risk groups, respectively. Open circles indicate censored samples. (0.14 MB PDF)
    Preview · Dataset · Dec 2010
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    Dataset: Table S2
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    ABSTRACT: Summary of patient clinical information. (0.04 MB PDF)
    Preview · Dataset · Dec 2010
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    Dataset: Table S1
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    ABSTRACT: Comparison of patient characteristics between the selected 30 samples and the whole 379 samples of the MDACC lung tumor collection. (0.04 MB PDF)
    Preview · Dataset · Dec 2010
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    Dataset: Text S1
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    ABSTRACT: Supplementary methods. (0.02 MB PDF)
    Preview · Dataset · Dec 2010

Publication Stats

730 Citations
118.45 Total Impact Points

Institutions

  • 2015
    • Yonsei University Hospital
      Sŏul, Seoul, South Korea
  • 2012-2015
    • Yonsei University
      • Department of Biochemistry
      Sŏul, Seoul, South Korea
  • 2006-2012
    • University of Texas Southwestern Medical Center
      • • Department of Cell Biology
      • • Department of Pharmacology
      Dallas, Texas, United States
  • 2009
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States