• 생명과학회지
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• 제22권11호
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• pp.1500-1506
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• 2012

Transforming growth factor-${\beta}$ (TGF-${\beta}$)에 의해 유도되는 세포사멸 과정은 간에서 손상 받은 조직이나 비정상적인 조직을 제거하는데 중요한 역할을 담당한다. 간세포에서 TGF-${\beta}$에 의해 유도되는 세포사멸 과정 동안 중요한 기능을 담당하는 유전자를 탐색하고자 쥐의 간세포인 AML12 세포를 이용하여 TGF-${\beta}$ 처리 전후에 발현이 변화되는 유전자를 microarray analysis를 통해 확인하였다. TGF-${\beta}$에 의해 여러 가지 유전자들의 발현이 변화됨을 확인하였는데, 그 가운데 여러 가지 세포사멸 인자들의 활성을 억제하여 세포사멸을 억제한다고 알려져 있는 SGK1의 발현 감소를 확인하였다. TGF-${\beta}$에 의해 SGK1의 mRNA와 단백질 level이 모두 감소함을 확인하였고, 항상 active한 형태의 SGK1 (CA-SGK1)을 발현시켰을 때 TGF-${\beta}$에 의한 세포사멸이 억제됨을 확인하였다. 이러한 결과들은 간세포에서 SGK1의 발현 감소가 TGF-${\beta}$에 의한 세포사멸을 유도하는데 중요한 기능을 담당할 가능성이 높음을 의미하는 것이다.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.239-244
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• 2014

Several recent studies have showed that the n-myc downstream regulated gene 2 (NDRG2) is a new tumor suppressor gene, and that it plays an important role in tumor suppression in several cancers or cancer cell lines. However, few studies focused on its function in neuroblastoma cells. In the present investigation, we demonstrated that NDRG2 overexpression inhibited their proliferation. Using a cDNA microarray, we found that overexpression of NDRG2 inhibited the expression of cysteine-rich protein 61 (CYR61), a proliferation related gene. From our research, CYR61 may partially hinder NDRG2-mediated inhibition of cell proliferation. Overexpression of NDRG2 resulted in accumulation of cells in the G1 phase, which was accompanied by upregulation of p21 and p27 and downregulation of CDK4 and cyclin D1. Taken together, these data indicate that NDRG2 inhibits the proliferation of neuroblastoma cells partially through suppression of CYR61. Our findings offer novel insights into the physiological roles of NDRG2 in neuroblastoma cell proliferation, and NDRG2 may prove to be effective candidate for the treatment of children with neuroblastoma.

• Environmental Analysis Health and Toxicology
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• 제21권1호
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• pp.71-79
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• 2006

Epidemiologic studies have showed a close correlation between arsenic exposure and heart disease such as, cardiovascular problem, ischemic heart disease, infarction, atherosclerosis and hypertension in human. It may increase the mortality of high risk group with heart disease. Regarding the mechanism studies of heart failure, blood vessel, vascular smooth muscle cells and endothelial cells have long been focused as the primary targets in arsenic exposure but there are only a few studies on the cardiomyocytes. In this study, the generation of oxidative stress by low dose of arsenic trioxide was investigated in rat cardiomyocytes. By direct measurement of reactive oxygen species and fluorescent microscopic observation using fluorescent dye 2',7'-dichlorofluorescin diacetate, reactive oxygen species were found to be generated without cell death, where cells are treated with 0.1 ppm arsenic for 24 hours. With the induction of reactive oxygen species, GSH level was decreased by the same treatment. However, DNA damage did not seem to be serious by DAPI staining, while high dose of arsenic (2 ppm for 24 hrs) caused fragmentation of DNA. To identify the molecular biomarkers of low-dose arsenic exposure, gene expression was also investigated with whole genome microarray. As results, 9,022 genes were up-regulated including heme oxygenase-l and glutathione S-transrerase, which are well-known biomarkers of oxidative stress. 9,404 genes were down-regulated including endothelial type gp 91-phox gene by the treatment of 0.1 ppm arsenic for 24 hours. This means that biological responses of cardiomyocytes may be altered by ROS induced by low level arsenic without cell death, and this alteration may be detected clearly by molecular biomarkers such as heme oxygenase-1.

• Journal of Gastric Cancer
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• 제16권4호
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• pp.221-229
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• 2016

Purpose: Dysregulated microRNAs (miRNAs) can contribute to cancer development by leading to abnormal proliferation of cells, apoptosis, and differentiation. Although several miRNAs that are related to gastric cancer have been identified, the reported results have been inconsistent. The aim of this study was to determine miRNA expression profiles and validate miRNAs up- and down-regulated in gastric cancer. Materials and Methods: We evaluated 34 primary gastric cancer tissues and paired adjacent nontumorous gastric tissues. Total RNA was extracted, and low-molecular-weight RNAs (<200 nucleotides) were isolated for further analysis. Two pairs of tissues were processed for GeneChip microarray analysis, and the identified up- and down-regulated miRNAs were validated by real-time quantitative polymerase chain reaction (qPCR). Results: In the set of differentially expressed miRNAs, 5 were overexpressed by more than 2 fold, and 5 were reduced by 2 fold or less in gastric cancer tissues compared with normal gastric tissues. Four of these miRNAs (miR-196b-5p, miR-375, miR-483-5p, and miR-486-5p) were then validated by qPCR, and the relative expression levels of 2 miRNAs (miR-196b-5p and miR-375) were significantly different between cancer and normal tissues. Conclusions: Our results revealed that the expression of miR-196b-5p and miR-375 significantly correlates with gastric cancer. These miRNAs could therefore serve as diagnostic biomarkers of gastric cancer.

• Molecular & Cellular Toxicology
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• 제4권4호
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• pp.318-322
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• 2008

Obesity is an increasing worldwide health problem that is strongly related to the imbalance of food intake and energy metabolism. It was well-known that several substances in the hypothalamus regulate food intake and energy metabolism. We planned an integrative study to elucidate the mechanism of the development of obesity. Firstly, to find candidate genes with the marvelous effect, the different expression in the hypothalamus between ob/ob and 48-h fasting mice was investigated by using DNA microarray technology. As a result, we found 3 genes [peroxisome proliferator activated receptor, gamma, coactivator 1 alpha (Ppargc1a), calmodulin 1 (Calm1), and complexin 2 (Cplx2)] showing the different hypothalamic expression between ob/ob and 48-h fasting mice. Secondly, a genetic approach on PPARGC1A gene was performed, because PPARGC1A acts as a transcriptional coactivator and a metabolic regulator. Two hundred forty three obese female patients with body mass index (BMI)${\geq}$25 and 285 control female subjects with BMI 18 to<23 were recruited according to the Classification of Korean Society for the Study of Obesity. Among the coding single nucleotide polymorphisms (cSNPs) of PPARGC1A, 2 missense SNPs (rs8192678, Gly482Ser; rs3736265, Thr612Met) and 1 synonymous SNP (rs3755863, Thr528Thr) were selected, and analyzed by PCR-RFLP and pyrosequencing. For the analysis of genetic data, chi-square ($X^2$) test and EH program were used. The rs8192678 was significantly associated with obese women (P<0.0006; odds ratio, 1.5327; 95% confidence interval, 1.2006-1.9568). Haplotypes also showed significant association with obese women ($X^2$=33.28, P<0.0008). These results suggest that PPARGC1A might be related to the development of obesity.

• BMB Reports
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• 제51권8호
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• pp.412-417
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• 2018

Homotypic cell-in-cell (CIC) structures forming between cancer cells were proposed to promote tumor evolution via entosis, a nonapoptotic cell death process. However, the mechanisms underlying their formation remained poorly understood. We performed a microarray analysis to identify genes associated with homotypic CIC formation. Cancer cells differing in their ability to form homotypic CIC structures were selected for the study. Association analysis identified 73 probe sets for 62 candidate genes potentially involved in CIC formation. Among them, twenty-one genes were downregulated while 41 genes were upregulated. Pathway analysis identified a gene interaction network centered on IL-8, which was upregulated in high CIC cells. Remarkably, CIC formation was significantly inhibited by IL-8 knockdown and enhanced upon recombinant IL-8 treatment, which correlated with altered cell-cell adhesion and expression of adhesive molecules such as P-cadherin and ${\gamma}$-catenin. Together, our work identified IL-8 as a positive regulator of homotypic CIC formation via enhancing intercellular adhesion.

• Molecular & Cellular Toxicology
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• 제5권4호
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• pp.310-316
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• 2009

Some environmental chemicals have been shown to cause liver-toxicity as the result of bioaccumulation. Particularly, fungicides have been shown to cause varying degrees of hepatictoxicity and to disrupt steroid hormone homeostasis in in vivo models. The principal objective of this study was to evaluate the liver-toxic responses of environmental chemicals-in this case selected fungicides and parasiticides-in order to determine whether or not this agent differentially affected its toxicogenomic activities in hepatic tumor cell lines. To determine the gene expression profiles of 3 fungicides (triadimefon, myclobutanil, vinclozolin) and 1 parasiticide (dibutyl phthalate), we utilized a modified HazChem human array V2. Additionally, in order to observe the differential alterations in its time-dependent activities, we conducted two time (3 hr, 48 hr) exposures to the respective IC20 values of four chemicals. As a result, we analyzed the expression profiles of a total of 1638 genes, and we identified 70 positive significant genes and 144 negative significant genes using four fungicidic and parasiticidic chemicals, using SAM (Significant Analysis of Microarray) methods (q-value<0.5%). These genes were analyzed and identified as being related to apoptosis, stress responses, germ cell development, cofactor metabolism, and lipid metabolism in GO functions and pathways. Additionally, we found 120 genes among those time-dependently differentially expressed genes, using 1-way ANOVA (P-value<0.05). These genes were related to protein metabolism, stress responses, and positive regulation of apoptosis. These data support the conclusion that the four tested chemicals have common toxicogenomic effects and evidence respectively differential expression profiles according to exposure time.

• Biomolecules & Therapeutics
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• 제21권3호
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• pp.190-195
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• 2013

Cisplatin is a member of platinum-containing anti-cancer drugs that causes cross-linking of DNA and ultimately cancer cell apoptosis. The therapeutic function of cisplatin on various types of cancers has been widely reported but the side effects have been discovered together and nephrotoxicity has been regarded as major side effect of cisplatin. To select candidates for new sensitive nephrotoxicity biomarker, we performed proteomic analysis using 2-DE/MALDI-TOF-MS followed by cisplatin treatment in human kidney cell line, HK-2 cells, and compared the results to the gene profile from microarray composed of genes changed in expression by cisplatin from formerly reported article. Annexin A5 has been selected to be the most potential candidate and it has been identified using Western blot, RT-PCR and cell viability assay whether annexin A5 is available to be a sensitive nephrotoxic biomarker. Treatment with cisplatin on HK-2 cells caused the increase of annexin A5 expression in protein and mRNA levels. Over-expression of annexin A5 blocked HK-2 cell proliferation, indicating correlation between annexin A5 and renal cell toxicity. Taken together, these results suggest the possibility of annexin A5 as a new biomarker for cisplatin-mediated nephrotoxicity.

• Bulletin of the Korean Chemical Society
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• 제31권6호
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• pp.1555-1560
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• 2010

Quantum dots (QDs) are extensively employed for biomedical research as a fluorescence reporter and their use for various labeling applications will continue to increase as they are preferred over conventional labeling methods for various reasons. However, concerns have been raised over the toxicity of these particles in the biological system. Till date no thorough investigation has been carried out to identify the molecular signatures of QD mediated toxicity. In this study we evaluated the toxicity of CdSe, $Cd_{1-x}Zn_xS$/ZnS and CdSe/ZnS quantum dots having different spectral properties (red, blue, green) using human embryonic kidney fibroblast cells (HEK293). Cell viability assay for both short and long duration exposure show concentration material dependent toxicity, in the order of CdSe > $Cd_{1-x}Zn_xS$/ZnS > CdSe/ZnS. Genome wide changes in the expression of genes upon QD exposure was also analyzed by wholegenome microarray. All the three QDs show increase in the expression of genes related to apoptosis, inflammation and response towards stress and wounding. Further comparison of coated versus uncoated CdSe QD-mediated cell death and molecular changes suggests that ZnS coating could reduce QD mediated cytotoxicity to some extent only.

• International Journal of Oral Biology
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• 제36권4호
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• pp.179-185
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• 2011

MicroRNAs (miRNAs) are small non-coding RNAs that mediate gene expression at the post-transcriptional level by degrading or repressing targeted mRNAs. These molecules are about 21-25 nucleotides in length and exert their effects by binding to partially complementary sites in mRNAs, predominantly in the 3'-untranslated region (3'-UTR). Recent evidence has demonstrated that miRNAs can function as oncogenes or tumor suppressors through the modulation of multiple oncogenic cellular processes in cancer development, including initiation, cell proliferation, apoptosis, invasion and metastasis. In our present study, we examined the expression profile of miRNAs related to oral cancer cell growth inhibition using normal human oral keratinocytes (NHOK) and YD-38 human oral cancer cells. By miRNA microassay analysis, 40 and 31 miRNAs among the 1,769 examined were found to be up- and down-regulated in YD-38 cells compared with NHOK cells, respectively. Using qRT-PCR analysis, the expression levels of miR-30a and miR-1246 were found to be increased in YD-38 cells compared with NHOK cells, whereas miR-203 and miR-125a were observed to be decreased. Importantly, the overexpression of miR-203 and miR-125a significantly inhibited the growth of YD-38 cells. This finding and the microarray data indicate the involvement of specific miRNAs in the development and progression of oral cancer.