• Asian Pacific Journal of Cancer Prevention
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• 제16권10호
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• pp.4215-4218
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• 2015

Gastric cancer (GC) is one of the most common malignancies in the world. It is the first cause of cancer deaths in both sexes In Iranian population. Circulating insulin-like growth factor-one (IGF-1) levels have been associated for gastric cancer. IGF-1 protein has central roles involved in the regulation of epithelial cell growth, proliferation, transformation, apoptosis and metastasis. Single nucleotide polymorphism in IGF-1 regulatory elements may lead to alter in IGF-1expression level and GC susceptibility. The aim of this study was to investigate the influence of IGF-1 gene polymorphism (rs5742612) on risk of GC and clinicopathological features for the first time in Iranian population. In total, 241 subjects including 100 patients with GC and 141 healthy controls were recruited in our study. Genotypes were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay with DNA from peripheral blood. The polymorphism was statistically analyzed to investigate the relationship with the risk of GC and clinicopathological properties. Logistic regression analysis revealed that there was no significant association between rs5742612 and the risk of GC. In addition, no significant association between genotypes and clinicopathological features was observed (p value>0.05). The frequencies of the CC, CT, and TT genotypes were 97%, 3%, and 0%, respectively, among the cases, and 97.9%, 2.1%, and 0%, respectively, among the controls. CC genotype was more frequent in cases and controls. The frequencies of C and T alleles were 98.9% and 1.1% in controls and 98.5% and 1.5% in patient respectively. Our results provide the first evidence that this variant is rare in Iranian population and it may not be a powerful genetic predisposing biomarker for prediction GC clinicopathological features in an Iranian population.

• 환경영향평가
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• 제14권5호
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• pp.347-353
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• 2005

The risk assessment is the qualitative or quantitative evaluation of the risk posed to human health and the environment by the actual or potential presence or release of hazardous substances, pollutants or contaminants. The environmental impact assessment (EIA) is assessed by the environmental criteria, and risk assessment is assessed by the risk rate. Risk rate based on dose-response values may not be easy to apply on regulatory basis like EIA for uncertainty. Internationally there is an example of OECD program. Risk assessment of High Production Volume (HPV) Chemicals has started since the OECD Program with the 1990 Council Act on the Co-operative Investigation and Risk Reduction of Existing Chemicals. These HPV chemicals include all chemicals produced or imported at levels greater than 1,000 tonnes per year in at least one Member country or in the European Union region. The SIDS called the Screening Information Data Set is regarded as the minimum information needed to assess an HPV chemical to determine whether any further work should be carried out or not. All the data elements of SIDS including assessment for environment and health are prepared as three formats of the full SIDS Dossier, the SIDS Initial Assessment Report (SIAR), and the SIDS Initial Assessment Profile (SIAP) of an HPV chemical. In 1998 the global chemical industry through the International Council of Chemical Associations (ICCA) has joined to work with OECD. The OECD has assessed approximately 1,000 chemicals from 1991 through 2004 with ICCA. Till the February of 2005, 592 chemicals of those chemicals completed SIDS reports. Member countries have been targeted the goal of 1,000 new chemicals from 2005 to 2010 and Korea shared 36 chemicals from the 1,000 new chemicals. Currently Korea has completed SIDS reports of 7 chemicals among sponsored 24 chemicals. In conclusion SIDS project will be linked to national program for outputs application with more reliable production. Both the OECD and industry will carry out their commitment to complete assessments for more and the remaining chemicals assessment. The major outputs will contribute to cope with international chemical management.

• 생명과학회지
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• 제26권1호
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• pp.140-145
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• 2016

다세포 생물의 유전자들은 발생 및 분화 그리고 조직 특이적으로 전사되며, 이러한 유전자 전사는 게놈 상에서 멀리 떨어져 존재하는 인핸서(enhancer) 부위에 의해 조절된다. 최근의 연구들은 활성화된 인핸서에서 RNA Polymerase II (Pol II)에 의해 noncoding RNA가 전사된다고 보고하고 있으며, 이들은 인핸서 RNA (eRNA)라 불리고 있다. eRNA는 인핸서 중심으로부터 양방향으로 합성되며, 5’ capping은 일어나지만, splicing이나 3’ tailing은 되지 않는다. eRNA의 전사는 전사 활성자의 결합에 의해 일어나며, 표적 유전자의 전사 수준과 비례하게 일어난다. 인위적으로 eRNA의 전사를 억제하거나 합성된 eRNA를 제거하면 표적 유전자의 전사는 억제된다. eRNA의 전사 과정은 인핸서 부분의 활성 히스톤 변형을 유도하며, 합성된 eRNA는 인핸서와 프로모터 사이의 크로마틴 고리 구조 형성을 매개한다. 또한 표적 유전자의 프로모터에 RNA Pol II를 모집하고 이들의 신장을 촉진하는 것도 eRNA의 역할로 보인다. 본 총설은 인핸서 유래 eRNA의 특징에 대해 살펴보고, eRNA의 합성 기작 및 표적 유전자의 전사 조절을 위한 eRNA의 역할을 정리해보고자 한다.

• Molecules and Cells
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• 제38권11호
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• pp.991-997
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• 2015

Tristetraprolin (TTP) is an AU-rich elements (AREs)-binding protein, which regulates the decay of ARE-scontaining mRNAs such as proto-oncogenes, anti-apoptotic genes and immune regulatory genes. Despite the low expression of TTP in various human cancers, the mechanism involving suppressed expression of TTP is not fully understood. Here, we demonstrate that Resveratrol (3,5,4'-trihydroxystilbene, Res), a naturally occurring compound, induces glioma cell apoptosis through activation of tristetraprolin (TTP). Res increased TTP expression in U87MG human glioma cells. Res-induced TTP destabilized the urokinase plasminogen activator and urokinase plasminogen activator receptor mRNAs by binding to the ARE regions containing the 3' untranslated regions of their mRNAs. Furthermore, TTP induced by Res suppressed cell growth and induced apoptosis in the human glioma cells. Because of its regulation of TTP expression, these findings suggest that the bioactive dietary compound Res can be used as a novel anti-cancer agent for the treatment of human malignant gliomas.

• 한국생물정보학회:학술대회논문집
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• 한국생물정보시스템생물학회 2006년도 Principles and Practice of Microarray for Biomedical Researchers
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• pp.83-89
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• 2006

Cellular functions are carried out by a concerted action of biochemical pathways whose components have genetic interactions. Abnormalities in the activity of the genes that constitute or modulate these pathways frequently have oncogenic implications. Therefore, identifying the upstream regulatory genes for major biochemical pathways and defining their roles in carcinogenesis can have important consequences in establishing an effective target-oriented antitumor strategy We have analyzed the gene expression profiles of human liver cancer samples using cDNA microarray chips enriched in liver and/or stomach-expressed cDNA elements, and identified groups of genes that can tell tumors from non-tumors or normal liver, or classify tumors according to clinical parameters such as tumor grade, age, and inflammation grade. We also set up a high-throughput cell-based assay system (cell chip) that can monitor the activity of major biochemical pathways through a reporter assay. Then, we applied the cell chip platform for the analysis of the HCC-associated genes discovered from transcriptome profiling, and found a number of cancer marker genes having a potential of modulating the activity of cancer-related biochemical pathways such as E2F, TCF, p53, Stat, Smad, AP-1, c-Myc, HIF and NF-kB. Some of these marker genes were previously blown to modulate these pathways, while most of the others not. Upon a fast-track phenotype analysis, a subset of the genes showed increased colony forming abilities in soft agar and altered cell morphology or adherence characteristics in the presence of purified matrix proteins. We are currently analyzing these selected marker genes in more detail for their effects on various biological Processes and for Possible clinical roles in liver cancer development.

• BMB Reports
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• 제53권6호
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• pp.323-328
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• 2020

Matrix metalloproteinase 1 (MMP-1), a calcium-dependent zinccontaining collagenase, is involved in the initial degradation of native fibrillar collagen. Tissue necrosis factor-alpha (TNFα) is a pro-inflammatory cytokine that is rapidly produced by dermal fibroblasts, monocytes/macrophages, and keratinocytes and regulates inflammation and damaged-tissue remodeling. MMP-1 is induced by TNFα and plays a critical role in tissue remodeling and skin aging processes. However, the regulation of the MMP1 gene by TNFα is not fully understood. We aimed to find additional cis-acting elements involved in the regulation of TNFα-induced MMP1 gene transcription in addition to the nuclear factor-kappa B (NF-κB) and activator protein 1 (AP1) sites. Assessments of the 5'-regulatory region of the MMP1 gene, using a series of deletion constructs, revealed the requirement of the early growth response protein 1 (EGR-1)-binding sequence (EBS) in the proximal region for proper transcription by TNFα. Ectopic expression of EGR-1, a zinc-finger transcription factor that binds to G-C rich sequences, stimulated MMP1 promoter activity. The silencing of EGR-1 by RNA interference reduced TNFα-induced MMP-1 expression. EGR-1 directly binds to the proximal region and transactivates the MMP1 gene promoter. Mutation of the EBS within the MMP1 promoter abolished EGR-1-mediated MMP-1 promoter activation. These data suggest that EGR-1 is required for TNFα-induced MMP1 transcriptional activation. In addition, we found that all three MAPKs, ERK1/2, JNK, and p38 kinase, mediate TNFα-induced MMP-1 expression via EGR-1 upregulation. These results suggest that EGR-1 may represent a good target for the development of pharmaceutical agents to reduce inflammation-induced MMP-1 expression.

• Molecules and Cells
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• 제41권7호
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• pp.653-664
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• 2018

The RNA-binding protein tristetraprolin (TTP) binds to adenosine-uridine AU-rich elements in the 3'-untranslated region of messenger RNAs and facilitates rapid degradation of the target mRNAs. Therefore, it regulates the expression of multiple cancer and immunity-associated transcripts. Furthermore, a lack of TTP in cancer cells influences cancer progression and predicts poor survival. Although the functions of TTP on cancer cells have previously been researched, the mechanism of TTP on the interaction between cancer cells with their micro-environment remains undiscovered. In this study, we admed to determine the role of cancer cell TTP during the interaction between tumor and immune cells, specifically regulatory T cells (Tregs). We evaluate the capability of TTP to modulate the antitumor immunity of GC and explored the underlying mechanism. The overexpression of TTP in GC cells dramatically increased peripheral blood mononuclear lymphocyte (PBML) -mediated cytotoxicity against GC cells. Increased cytotoxicity against TTP-overexpressed GC cells by PBMLs was determined by Treg development and infiltration. Surprisingly, we found the stabilization of programmed death-ligand 1 (PD-L1) mRNA was declining while TTP was elevated. The PD-L1 protein level was reduced in TTP-abundant GC cells. PD-L1 gas been found to play a pivotal role in Treg development and functional maintenance in immune system. Taken together, our results suggest the overexpression of TTP in GC cells not only affects cell survival and apoptosis but also increases PBMLs -mediated cytotoxicity against GC cells to decelerate tumor progression. Moreover, we identified PD-L1 as a critical TTP-regulated factor that contributes to inhibiting antitumor immunity.

• Applied Biological Chemistry
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• 제37권5호
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• pp.361-369
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• 1994

Ribulose-1,5-bisphosphate carboxylase small subunit(rbcS)의 광유도 발현과 엽록체로의 단백질 이동 메카니즘을 연구하기 위해 벼의 게놈으로부터 rbcS 유전자를 분리하여(GrbcS) 그의 염기서열을 결정하였다. GrbcS의 유전자 염기서열 결정 결과, 단백질 암호부위는 한 개의 intron과 두 개의 exon으로 이루어져 있고 이들은 47개의 transit peptide를 포함하는 175개의 아미노산을 암호화하는 것으로 밝혀졌다. GrbcS의 이러한 구조적인 성질은 다른 단자엽 식물의 그것과 비교적 일치하고 genomic Southern blot analysis 결과 rbcS 유전자는 벼의 게놈상에 상대적으로 적은 규모의 multigene family로 존재한다는 것이 밝혀졌다. GrbcS의 유전자 염기서열과 그로부터 유추된 아미노산의 염기서열은 벼로부터 분리된 다른 rbcS와 매우 유사함을 보였고 다른 식물체로부터 분리된 그것과도 높은 유사성을 보였다. GrbcS의 5’ 앞쪽 부분에는 G-box, 3AF1-binding site, GATA site와 같은 광유도 발현 유전자에 공통적으로 존재하는 염기서열을 지니고 있었다.

• Molecules and Cells
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• 제44권9호
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• pp.658-669
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• 2021

Enhancers have been conventionally perceived as cis-acting elements that provide binding sites for trans-acting factors. However, recent studies have shown that enhancers are transcribed and that these transcripts, called enhancer RNAs (eRNAs), have a regulatory function. Here, we identified putative eRNAs by profiling and determining the overlap between noncoding RNA expression loci and eRNA-associated histone marks such as H3K27ac and H3K4me1 in hepatocellular carcinoma (HCC) cell lines. Of the 132 HCC-derived noncoding RNAs, 74 overlapped with the eRNA loci defined by the FANTOM consortium, and 65 were located in the proximal regions of genes differentially expressed between normal and tumor tissues in TCGA dataset. Interestingly, knockdown of two selected putative eRNAs, THUMPD3-AS1 and LINC01572, led to downregulation of their target mRNAs and to a reduction in the proliferation and migration of HCC cells. Additionally, the expression of these two noncoding RNAs and target mRNAs was elevated in tumor samples in the TCGA dataset, and high expression was associated with poor survival of patients. Collectively, our study suggests that noncoding RNAs such as THUMPD3-AS1 and LINC01572 (i.e., putative eRNAs) can promote the transcription of genes involved in cell proliferation and differentiation and that the dysregulation of these noncoding RNAs can cause cancers such as HCC.

• Molecules and Cells
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• 제37권2호
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• pp.178-186
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• 2014

Differential transcription of the clusterin (CLU) gene yields two CLU isoforms, a nuclear form (nCLU) and a secretory form (sCLU), which play crucial roles in prostate tumorigenesis. Pro-apoptotic nCLU and anti-apoptotic sCLU have opposite effects and are differentially expressed in normal and cancer cells; however, their regulatory mechanisms at the transcriptional level are not yet known. Here, we examined the transcriptional regulation of nCLU in response to hypoxia. We identified three putative hypoxia response elements (HREs) in the human CLU promoter between positions -806 and +51 bp. Using a luciferase reporter, electrophoretic gel mobility shift, and chromatin immunoprecipitation assays, we further showed that hypoxia-inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) bound directly to these sites and activated transcription. Exposure to the hypoxia-mimetic compound $CoCl_2$, incubation under 1% $O_2$ conditions, or overexpression of HIF-$1{\alpha}$ enhanced nCLU expression and induced apoptosis in human prostate cancer PC3M cells. However, LNCaP prostate cancer cells were resistant to hypoxia-induced cell death. Methylation-specific PCR analysis revealed that the CLU promoter in PC3M cells was not methylated; in contrast, the CLU promoter in LNCap cells was methylated. Co-treatment of LNCaP cells with $CoCl_2$ and a demethylating agent promoted apoptotic cell death through the induction of nCLU. We conclude that nCLU expression is regulated by direct binding of HIF-$1{\alpha}$ to HRE sites and is epigenetically controlled by methylation of its promoter region.