Seon-Kyu Kim

Korea Research Institute of Bioscience and Biotechnology KRIBB, Anzan, Gyeonggi-do, South Korea

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Publications (26)159.96 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Previous study identified E2F1 as a key mediator of NMIBC progression. The aim of this study is to identify the E2F1-related genes associated with poor prognosis and aggressive characteristics of bladder cancer. Microarray analysis was performed to find E2F1-related genes associated with tumor progression and aggressiveness in the gene expression data from 165 primary bladder cancer patients. The biological activity of E2F1-related genes in tumor progression and aggressiveness was confirmed with experimental assays using bladder cancer cells and tumor xenograft assay. The expression of E2F1 was significantly associated with EZH2 and SUZ12. The overexpression of E2F1, EZH2 and SUZ12 enhanced cancer progression including cell colony formation, migration and invasiveness. Knockdown of these genes reduced motility, blocked invasion and decreased tumor size in vivo. E2F1 bound the proximal EZH2 and SUZ12 promoter to activate transcription, suggesting that E2F1 and its downstream effectors, EZH2 and SUZ12, could be important mediators for the cancer progression. Additionally, we confirmed an association between these genes and aggressive characteristics. Interestingly, the treatment of anticancer drugs to the cells overexpressing E2F1, EZH2 and SUZ12 induced the expression of CD44, KLF4, OCT4 and ABCG2 known as CSC-related genes. The link between E2F1, EZH2 and/or SUZ12 revealed that E2f1 directly regulates transcription of the EZH2 and SUZ12 genes. The signature of E2F1-EZH2-SUZ12 shows a predictive value for prognosis in bladder tumors and the E2F1-EZH2-SUZ12-driven transcriptional events may regulate the cancer aggressiveness and chemo-resistance, which may provide opportunity for development of new treatment modalities. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 08/2015; DOI:10.1158/1078-0432.CCR-14-2680 · 8.72 Impact Factor
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    ABSTRACT: Previous studies have shown that c-MET is overexpressed in cases of aggressive bladder cancer (BCa). Identification of crosstalk between c-MET and other RTKs such as AXL and PDGFR suggest that c-MET network genes (c-MET-AXL-PDGFR) may be clinically relevant to BCa. Here, we examine whether expression of c-MET network genes can be used to identify BCa patients at increased risk of developing aggressive disease. In vitro analysis, c-MET knockdown suppressed cell proliferation, invasion, and migration, and increased sensitivity to cisplatin-induced apoptosis. In addition, c-MET network gene (c-MET, AXL, and PDGFR) expression allowed discrimination of BCa tissues from normal control tissues and appeared to predict poor disease progression in non-muscle invasive BCa patients and poor overall survival in muscle invasive BCa patients. These results suggest that c-MET network gene expression is a novel prognostic marker for predicting which BCa patients have an increased risk of developing aggressive disease. These genes might be a useful marker for co-targeting therapy, and are expected to play an important role in improving both response to treatment and survival of BCa patients.
    PLoS ONE 08/2015; 10(7):e0134552. DOI:10.1371/journal.pone.0134552 · 3.23 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):592-592. DOI:10.1158/1538-7445.AM2015-592 · 9.33 Impact Factor
  • In-Sun Chu · Seon-Kyu Kim · Yun-Gil Roh · Sun-Hee Leem
    Cancer Research 08/2015; 75(15 Supplement):4794-4794. DOI:10.1158/1538-7445.AM2015-4794 · 9.33 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):4351-4351. DOI:10.1158/1538-7445.AM2015-4351 · 9.33 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) in biological fluids are potential biomarkers for the diagnosis and assessment of urological diseases such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The aim of the study was to identify and validate urinary cell-free miRNAs that can segregate patients with PCa from those with BPH. In total, 1,052 urine, 150 serum, and 150 prostate tissue samples from patients with PCa or BPH were used in the study. A urine-based miRNA microarray analysis suggested the presence of differentially expressed urinary miRNAs in patients with PCa, and these were further validated in three independent PCa cohorts, using a quantitative reverse transcriptionpolymerase chain reaction analysis. The expression levels of hsa-miR-615-3p, hsv1-miR-H18, hsv2-miR-H9-5p, and hsa-miR-4316 were significantly higher in urine samples of patients with PCa than in those of BPH controls. In particular, herpes simplex virus (hsv)-derived hsv1-miR-H18 and hsv2-miR-H9-5p showed better diagnostic performance than did the serum prostate-specific antigen (PSA) test for patients in the PSA gray zone. Furthermore, a combination of urinary hsv2-miR-H9-5p with serum PSA showed high sensitivity and specificity, providing a potential clinical benefit by reducing unnecessary biopsies. Our findings showed that hsv-encoded hsv1-miR-H18 and hsv2-miR-H9-5p are significantly associated with PCa and can facilitate early diagnosis of PCa for patients within the serum PSA gray zone.
    International neurourology journal 06/2015; 19(2):74-84. DOI:10.5213/inj.2015.19.2.74 · 1.06 Impact Factor
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    Seon-Kyu Kim · Wun-Jae Kim
    Korean journal of urology 02/2015; 56(2):87. DOI:10.4111/kju.2015.56.2.87
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    ABSTRACT: Colorectal cancer (CRC) patients frequently experience disease recurrence and distant metastasis. This study aimed to identify prognostic indicators, including individual responses to chemotherapy, in CRC patients. RNA-seq data was generated using 54 samples (normal colon, primary CRC, and liver metastases) from 18 CRC patients and genes associated with CRC aggressiveness were identified. A risk score based on these genes was developed and validated in four independent CRC patient cohorts (n = 1,063). Diverse statistical methods were applied to validate the risk scoring system, including a generalized linear model likelihood ratio test, Kaplan-Meier curves, a log-rank test, and the Cox model. TREM1 and CTGF were identified as two activated regulators associated with CRC aggressiveness. A risk score based on 19 genes regulated by TREM1 or CTGF activation (TCA19) was a significant prognostic indicator. In multivariate and subset analyses based on pathological staging, TCA19 was an independent risk factor (HR = 1.894, 95% CI = 1.227 – 2.809, P = 0.002). Subset stratification in stage III patients revealed that TCA19 had prognostic potential and identified patients who would benefit from adjuvant chemotherapy, regardless of age. The TCA19 predictor represents a novel diagnostic tool for identifying high-risk CRC patients and possibly predicting the response to adjuvant chemotherapy.
    Molecular Oncology 12/2014; 8(8). DOI:10.1016/j.molonc.2014.06.016 · 5.33 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):51-51. DOI:10.1158/1538-7445.AM2014-51 · 9.33 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):3830-3830. DOI:10.1158/1538-7445.AM2014-3830 · 9.33 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):3408-3408. DOI:10.1158/1538-7445.AM2014-3408 · 9.33 Impact Factor
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    ABSTRACT: Because cancer has heterogeneous clinical behaviors due to the progressive accumulation of multiple genetic and epigenetic alterations, the identification of robust molecular signatures for predicting cancer outcome is profoundly important. Here, we introduce the APPEX Web-based analysis platform as a versatile tool for identifying prognostic molecular signatures that predict cancer diversity. We incorporated most of statistical methods for survival analysis and implemented seven survival analysis workflows, including CoxSingle, CoxMulti, IntransSingle, IntransMulti, SuperPC, TimeRoc and multivariate. A total of 236 publicly available datasets were collected, processed and stored to support easy independent validation of prognostic signatures. Two case studies including disease recurrence and bladder cancer progression were described using different combinations of the seven workflows. Availability and implementation: APPEX is freely available at Contact: Supplementary information: Supplementary data are available at Bioinformatics online.
    Bioinformatics 08/2014; 30(22). DOI:10.1093/bioinformatics/btu521 · 4.98 Impact Factor
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    ABSTRACT: Although standard treatment with transurethral resection and intravesical therapy (IVT) is known to be effective to address the clinical behavior of non-muscle-invasive bladder cancer (NMIBC), many patients fail to respond to the treatment and frequently experience disease recurrence. Here, we aim to identify a prognostic molecular signature that predicts the NMIBC heterogeneity and response to IVT. We analyzed the genomic profiles of 102 NMIBC patients to identify a signature associated with disease recurrence. The validity of the signature was verified in three independent patient cohorts (n = 658). Various statistical methods, including a leave-one-out cross-validation and multivariate Cox regression analyses, were applied to identify a signature. We confirmed an association between the signature and tumor aggressiveness with experimental assays using bladder cancer cell lines. Gene expression profiling in 102 NMIBC patients identified a CCNB1 signature associated with disease recurrence, which was validated in another three independent cohorts of 658 patients. The CCNB1 signature was shown to be an independent risk factor by a multivariate analysis and subset stratification according to stage and grade (HR 2.93, 95% CI = 1.302 to 6.594, P = 0.009). The subset analysis also revealed that the signature could identify patients who would benefit from IVT. Lastly, gene network analyses and experimental assays indicated that NMIBC recurrence could be mediated by FOXM1-CCNB1-Fanconi anemia pathways. The CCNB1 signature represents a promising diagnostic tool to identify NMIBC patients who have a high risk of recurrence and to predict response to IVT.
    Clinical Cancer Research 04/2014; 20(12). DOI:10.1158/1078-0432.CCR-13-2761 · 8.72 Impact Factor
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    ABSTRACT: DNA methylation patterns are associated with the development and prognosis of cancer. The aim of the present study was to identify novel methylation markers for the prediction of patient outcomes using microarray analysis of DNA methylation and RNA expression patterns in samples from long-term follow-up patients with non-muscle invasive bladder cancer (NMIBC). A total of 187 human bladder specimens were used for microarray array or pyrosequencing (PSQ) analyses: 6 normal controls (NC) and 181 NMIBC. Tumor-specific hypermethylated genes were selected from a data set comprising 24 matched microarray-based DNA methylation and gene expression profiles (6 controls and 18 NMIBC), and their clinical relevance was verified by quantitative PSQ analysis. The methylation status of Homeobox A9 (HOXA9), ISL LIM homeobox 1 (ISL1), and Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) was significantly associated with decreased gene expression levels and aggressive clinicopathological characteristics. Multivariate regression analyses showed that hypermethylation of these genes was an independent predictor of disease recurrence (HOXA9, ISL1, and ALDH1A3, either alone or in combination) and progression (ISL1 and ALDH1A3, either alone or in combination) (each p < 0.05). The results of the present study suggest that these novel methylation markers are independent prognostic indicators in NMIBC patients, which may facilitate the assessment of disease recurrence and progression in NMIBC patients and inform clinical decision making regarding treatment. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 09/2013; 133(5). DOI:10.1002/ijc.28121 · 5.09 Impact Factor
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    ABSTRACT: Long intergenic non-coding RNAs (lincRNAs) have historically been ignored in cancer biology. However, thousands of lincRNAs have been identified in mammals using recently developed genomic tools, including microarray and high-throughput RNA sequencing (RNA-seq). Several of the lincRNAs identified have been well characterized for their functions in carcinogenesis. Here we performed RNA-seq experiments comparing gastric cancer with normal tissues to find differentially expressed transcripts in intergenic regions. By analyzing our own RNA-seq and public microarray data, we identified 31 transcripts, including a known expressed sequence tag, BM742401. BM742401 was downregulated in cancer, and its downregulation was associated with poor survival in gastric cancer patients. Ectopic overexpression of BM742401 inhibited metastasis-related phenotypes and decreased the concentration of extracellular MMP9. These results suggest that BM742401 is a potential lincRNA marker and therapeutic target.
    07/2013; 45(7):e31. DOI:10.1038/emm.2013.59
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    ABSTRACT: We used gene expression profiling to identify inflammatory cytokines that correlate with bladder cancer development. Gene expression profiles of the tissue samples were investigated using cDNA microarrays that contained 103 non-muscle invasive bladder cancers (NMIBC), 62 muscle invasive bladder cancers (MIBC), 58 samples of histologically normal-looking surrounding tissues, and 10 normal, healthy subjects who served as the control cohort for comparison. We grouped the data-sets according to biological characterizations and focused on immune response genes with at least 2-fold differential expression in MIBC vs. controls. The experimental data-set identified 36 immune-related genes that were significantly altered in MIBC samples. In addition, 10 genes were up-regulated and 26 genes were down-regulated in MIBC samples compared with the normal tissues. Among the 10 up-regulated molecules examined, the capacity for both wound-healing migration and invasion was enhanced in response to IL-5, IL-20, and IL-28A in bladder cancer cell lines (253J and EJ cells), compared with untreated cells. The expression levels of IL-5, IL-20, and IL-28A were increased in patients with MIBC. All 3 cytokines and their receptors were produced in bladder cancer cell lines, as determined by real-time PCR, immunoblot analysis and confocal immunofluorescence. Up-regulation of MMP-2 and MMP-9 was found after IL-5, IL-20, and IL-28A stimulation in both cell types. Moreover, an EMSA assay showed that treatment with IL-5, IL-20, and IL-28A induced activation of the transcription factors NF-κB and AP-1 that regulate the MMP-9 promoter. Finally, activation of MAPK and Jak-Stat signaling was observed after the addition of IL-5, IL-20, and IL-28A to bladder cancer cells. This study suggests the presence of specific inflammatory cytokine (IL-5, IL-20, and IL-28A)-mediated association in bladder cancer development. All 3 cytokines may be important new molecular targets for the modulation of migration and invasion in bladder cancer.
    PLoS ONE 09/2012; 7(9):e40267. DOI:10.1371/journal.pone.0040267 · 3.23 Impact Factor
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    ABSTRACT: A total of 149 human prostate tissues obtained from our institute were assessed: 52 specimens of benign prostate hyperplasia (BPH) and 97 specimens of prostate cancer (PCa). The methylation status of the genes of Adenomatous polyposis coli (APC) and glutathione-S-transferase-P1 (GSTP1) was analyzed by quantitative pyrosequencing. A methylation score (M score) was calculated to capture the combined methylation level of both genes. The methylation level of each single gene and that of both genes combined was significantly higher in PCa specimens than in BPH (each p < 0.001). The value of APC methylation, GSTP1 methylation, and M score for predicting PCa was measured by the area under the receiver operating characteristic (ROC) curve and reached 0.954, 0.942, and 0.983, respectively. The sensitivity and specificity of the M score in discriminating between PCa and BPH reached 92.8% and 100.0%, respectively. The M score was positively associated with the serum prostate-specific antigen (PSA) level (p trend < 0.001). Our study demonstrates that the quantitative measurement of two methylation markers might drastically improve the ability to discriminate PCa from BPH.
    Journal of Biomolecular Screening 04/2012; 17(7):987-92. DOI:10.1177/1087057112444445 · 2.42 Impact Factor
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    ABSTRACT: Urinary bladder cancer is often a result of exposure to chemical carcinogens such as cigarette smoking. Because of histological similarity, chemically-induced rodent cancer model was largely used for human bladder cancer studies. Previous investigations have suggested that nicotinamide, water-soluble vitamin B3, may play a key role in cancer prevention through its activities in cellular repair. However, to date, evidence towards identifying the genetic alterations of nicotinamide in cancer prevention has not been provided. Here, we search for the molecular signatures of cancer prevention by nicotinamide using a N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced urinary bladder cancer model in mice. Via microarray gene expression profiling of 20 mice and 233 human bladder samples, we performed various statistical analyses and immunohistochemical staining for validation. The expression patterns of 893 genes associated with nicotinamide activity in cancer prevention were identified by microarray data analysis. Gene network analyses of these 893 genes revealed that the Myc and its associated genes may be the most important regulator of bladder cancer prevention, and the gene expression signature correlated well with protein expression data. Comparison of gene expression between human and mouse revealed that BBN-induced mouse bladder cancers exhibited gene expression profiles that were more similar to those of invasive human bladder cancers than to those of non-invasive human bladder cancers. This study demonstrates that nicotinamide plays an important role as a chemo-preventive and therapeutic agent in bladder cancer through the regulation of the Myc oncogenic signature. Nicotinamide may represent a promising therapeutic modality in patients with muscle-invasive bladder cancer.
    PLoS ONE 10/2011; 6(10):e26131. DOI:10.1371/journal.pone.0026131 · 3.23 Impact Factor
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    ABSTRACT: Abnormal DNA methylation is associated with many human cancers. The aim of the present study was to identify novel methylation markers in prostate cancer (PCa) by microarray analysis and to test whether these markers could discriminate normal and PCa cells. Microarray-based DNA methylation and gene expression profiling was carried out using a panel of PCa cell lines and a control normal prostate cell line. The methylation status of candidate genes in prostate cell lines was confirmed by real-time reverse transcriptase-PCR, bisulfite sequencing analysis, and treatment with a demethylation agent. DNA methylation and gene expression analysis in 203 human prostate specimens, including 106 PCa and 97 benign prostate hyperplasia (BPH), were carried out. Further validation using microarray gene expression data from the Gene Expression Omnibus (GEO) was carried out. Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) was identified as a lead candidate methylation marker for PCa. The gene expression level of EFEMP1 was significantly higher in tissue samples from patients with BPH than in those with PCa (P < 0.001). The sensitivity and specificity of EFEMP1 methylation status in discriminating between PCa and BPH reached 95.3% (101 of 106) and 86.6% (84 of 97), respectively. From the GEO data set, we confirmed that the expression level of EFEMP1 was significantly different between PCa and BPH. Genome-wide characterization of DNA methylation profiles enabled the identification of EFEMP1 aberrant methylation patterns in PCa. EFEMP1 might be a useful indicator for the detection of PCa.
    Clinical Cancer Research 05/2011; 17(13):4523-30. DOI:10.1158/1078-0432.CCR-10-2817 · 8.72 Impact Factor
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    ABSTRACT: There are no reliable criteria to handle disease progression of muscle invasive bladder cancer (MIBC), which strongly influences patient survival. Therefore, an accurate predicting method to identify progressive MIBC patients is greatly needed. The aim of this study was to identify a genetic signature associated with disease progression in MIBC. To address this issue, we analyzed three independent cohorts (a training set, test set 1 and test set 2) comprising a total of 128 MIBC patients. Microarray gene expression profiling, including gene network analysis, was performed in the training set to identify a gene expression signature associated with disease progression. The prognostic value of the signature was validated in test set 1 and test set 2 by microarray and real-time reverse transcriptase polymerase chain reaction (RT-PCR), respectively. The determination of gene expression patterns by microarray data analysis identified 1,320 genes associated with disease progression. Gene network analysis of the 1,320 genes suggested that IL1B, S100A8, S100A9 and EGFR were important mediators of MIBC progression. We validated this putative four-gene signature in two independent cohorts (log-rank test, P < 0.05 each, respectively) and estimated the predictive value of the signature by multivariate Cox regression analysis (hazard ratio [HR], 6.24; 95% confidence interval [CI], 1.58-24.61; P = 0.009). Finally, signature-based stratification demonstrated that the four-gene signature was an independent predictor of MIBC progression. In conclusion, a molecular signature defined by four genes represents a promising diagnostic tool for the identification of MIBC patients at high risk of progression.
    Molecular Medicine 02/2011; 17(5-6):478-85. DOI:10.2119/molmed.2010.00274 · 4.51 Impact Factor

Publication Stats

329 Citations
159.96 Total Impact Points


  • 2006–2015
    • Korea Research Institute of Bioscience and Biotechnology KRIBB
      • • Medical Genomics Research Center
      • • Korean BioInformation Center
      Anzan, Gyeonggi-do, South Korea
  • 2010–2011
    • Chungbuk National University
      • • Department of Medicine
      • • Department of Urology
      Chinsen, Chungcheongbuk-do, South Korea