Biomedical subjects

Young Il Yeom

Publications and source records attributed to Young Il Yeom.

At least 19 recordsLinked to original sources

PubMed2007

Up-regulation of Mac-2 binding protein by hTERT in gastric cancer.

Mac-2 binding protein (Mac-2BP) is a secreted tumor antigen that is elevated in many cancers and implicated in tumor metastasis, as well as cell adhesion and immune functions. We focused on the human telomerase reverse transcriptase (hTERT) induced Mac-2BP expression and the relationship between Mac-2BP expression and the progression of gastric cancer. A cDNA expression array analysis was performed on the telomerase-negative cell line, SW13, which was engineered to overexpress hTERT when compared with the parental SW13 cell. hTERT-induced Mac-2BP expression was confirmed via RT-PCR and Northern blotting. ELISA and flow cytometric analyses revealed that Mac-2BP protein was increased by 2- to 4-fold in hTERT-overexpressing cells compared with the mock control. Mac-2BP expression was significantly reduced when the overexpressed hTERT was neutralized by the introduction of hTERT-specific siRNA. These results suggest that Mac-2BP expression is modulated by hTERT. Mac-2BP levels in both gastric cancer cells and tumor tissues were determined via Northern blot analysis and immunohistochemistry. Mac-2BP protein was highly expressed in most gastric cancer cell lines, and gastric tumor tissues were stained more densely than normal tissues. The intracellular and secreted Mac-2BP levels were also evaluated via ELISA, indicating that Mac-2BP was expressed and secreted more abundantly in gastric cancer patients than in healthy donors. The elevated serum Mac-2BP level in gastric tumor patients was also significantly associated with distant metastasis (p = 0.05) and higher tumor stage (p = 0.04). Our findings suggest that Mac-2BP is induced by hTERT, and that it may prove to be a useful prognostic marker for the detection of malignant progression of metastatic stomach cancers.

Adult↗

PubMed2006

The expression of estrogen receptors in hepatocellular carcinoma in Korean patients.

Expression of estrogen receptors (ER)-alpha and -beta, as well as androgen receptor (AR), in hepatocellular carcinoma (HCC) is thought to be correlated with prognosis, survival, and male prevalence of HCC. These hypotheses are based on investigations of European patients; however the expression patterns of these receptors in Asian patients are largely unknown. In this study, we collected liver carcinoma and peritumor tissues from 32 patients (9 females and 23 males) in South Korea. The expression of ERs and ARs was studied using RT-PCR. Wild-type ER-alpha and AR were expressed in all of the samples investigated, and their expression was independent of the causal virus or patient sex. Expression of the ER-alpha variant was independent of sex (100% female vs. 91.3% male) and HCV and HBV status (91.3% vs. 100%). Wild-type ER-beta was expressed more often in HCV patients than in HBV patients (95.7% vs. 44.4%; p < 0.05). In conclusion, the stronger ER-alpha variant expression in HCC tissues implies that this variant has an important role in HCC development. However, at least in Korean patients, expression of the ER-alpha variant (vER-alpha) is not related to male HCC prevalence. In addition, the predominant expression of ER-beta in HCV patients suggests that it plays an important role in HCV-induced liver disease.

Aged↗

PubMed2006

The suppression of zfpm-1 accelerates the erythropoietic differentiation of human CD34+ cells.

Erythropoiesis is a complex multistage process for the differentiation of mature erythrocytes from hematopoietic stem cells. The function of several transcription factors has been reported in hematopoietic stem cell differentiation. However, the molecular basis governing its functional behavior is unclear. In this study, we characterized the role of Zfpm-1 during the erythropoietic differentiation of human hematopoietic stem cells. To verify the function of Zfpm-1 during erythropoietic differentiation, we established human CD34+ cell culture system by using human umbilical cord blood. At day 7 of the human CD34+ cell differentiation process to proerythocytes, Zfpm-1 was initially up-regulated and then dramatically down-regulated at day 9. The Zfpm-1 siRNA transfected HSCs contained 20% more GPA+ cells than the mock transfected cells, and showed repressed expression of the hematopoietic transcription factors, c-myc and c-myb, but increased expression of GATA-1. In contrast, the Zfpm-1 gain-of-function is the opposite of loss-of-function results above.

Antigens, CD34↗

PubMed2006

Novel candidate targets of Wnt/beta-catenin signaling in hepatoma cells.

The activity of beta-catenin/TCF, the key component of Wnt signaling pathway, is frequently deregulated in HCC, resulting in the activation of genes whose dysregulation has significant consequences on tumor development. Therefore, identifying the target genes of Wnt signaling is important for understanding beta-catenin-mediated carcinogenesis. We analyzed the transcriptome profile of human hepatoma cell lines using cDNA microarrays representing 15,127 unique, liver-enriched gene loci to identify the target genes of beta-catenin-mediated transcription (p<0.005). This analysis yielded 130 potential Wnt-associated classifier genes, and we found 33 of them contain consensus TCF-binding sites in presumptive transcriptional regulatory sequences. These genes were, then, tested for their Wnt-dependence of expression in experimental models of Wnt activation. Genes such as RPL29, NEDD4L, FUT8, LYZ, STMN2, STARD7 and KIAA0998 were proven to be up-regulated upon Wnt/beta-catenin activation. Gene ontology analysis of the 33 candidate genes indicated the presence of functional categories relevant to Wnt pathway such as cell growth, proliferation, adhesion and signal transduction. In conclusion, we identified a number of candidate Wnt/beta-catenin target genes that can be useful for studying the role of altered Wnt signaling in liver cancer development, and showed that some of them might be direct targets of Wnt signaling in hepatoma cells.

Carcinoma, Hepatocellular↗

PubMed2006

Enhanced specificity of the p53 family proteins-based adenoviral gene therapy in uterine cervical cancer cells with E2F1-responsive promoters.

p63 and p73, the p53 family proteins, are similar to p53 in many aspects: structural homology, transactivation of p53-downstream genes, and induction of apoptosis. Interestingly, they also differ from p53; in particular, they are not inhibited by viral oncoproteins such as HPV E6. This feature would be an advantage over p53 in HPV-associated cancers and therefore, we evaluated the therapeutic potentials of various p53 family proteins (p73alpha, p73beta, p63alpha and p63gamma) against HPV-infected cervical cancers. In clonogenic assay, exogenous expression of p73alpha, p73beta and p63gamma inhibited the colony formation of HPV-positive cervical cancer cells under G418- selection while p53 could not. Recombinant adenoviruses Ad/CMVp73alpha, Ad/CMVp73beta and Ad/CMVp63gamma induced potent apoptosis in all infected cervical cancers (CasKi, SiHa, HeLa, C33A, SNU682, SNU17, SNU1005, SNU703), irrespective of their HPV-infection status. Unfortunately however, Ad/CMVp73alpha, Ad/CMVp73beta, and Ad/CMVp63gamma inhibited also normal cells such as endothelial cells, fibroblasts, and keratinocytes thus, tumorspecific promoter was indispensable to the p53 family proteins-based therapy. Here we report a stringent tumor killing by p73beta in combination with ESM6, a synthetic promoter targeting the DNA tumor virusassociated cancers. Recombinant adenoviruses encoding p73beta by ESM6 (Ad/ESM6p73beta and Ad/ESM6p73bENH) expressed p73beta and induced apoptosis only in the cancer cells but not in normal cells. Collectively, we suggest that the p53 family proteins are potent therapeutic agents for HPV-associated uterine cervical cancers and ESM6 mediated expression of the p53 family proteins would be a safe and strong tumor targeting strategy.

Adenoviridae↗

PubMed2006

Hormonal activity of AIMP1/p43 for glucose homeostasis.

AIMP1/p43 is known as a cytokine working in the control of angiogenesis, inflammation, and wound healing. Here we report its enrichment in pancreatic alpha cells and glucagon-like hormonal activity. AIMP1 is secreted from the pancreas upon glucose starvation. Exogenous infusion of AIMP1 increased plasma levels of glucose, glucagon, and fatty acid, and AIMP1-deficient mice showed reduced plasma glucose levels compared with the wild-type mice under fasting conditions. Thus, AIMP1 plays a glucagon-like role in glucose homeostasis.

3T3-L1 Cells↗

PubMed2006

Role of E2F1 in endoplasmic reticulum stress signaling.

The transcription factor E2F1 coordinates cell cycle progression and induces apoptosis in response to DNA damage stress. Aside from DNA damage, the role of E2F1 in the endoplasmic reticulum (ER) stress signaling pathways is unclear. We found that E2F1-/- murine embryonic fibroblasts (MEFs) are resistant to apoptosis triggered by the ER stress inducer thapsigargin. In addition, E2F1 deficiency results in enhanced phosphorylation of eukaryotic translation initiation factor 2a (eIF2a). These results therefore indicate that E2F1 deficiency increases phosphorylation of eIF2a in response to ER stress triggered by thapsigargin, and suggest that the reduction in ER stress-induced apoptosis in E2F1-deficient cells is related to the high level of eIF2a phosphorylation.

Animals↗

PubMed2006

HCNet: a database of heart and calcium functional network.

SUMMARY: The Heart and Calcium functional Network (HCNet) database is a collection of functional gene modules calculated from the microarray data compendium available from the GEO database. It is a specialized database designed to assist experimentalists for cardiac calcium signaling research by providing the pre-calculated gene clusters and their potential correlation network in heart. In the current release of HCNet, 57 functional modules from 786 target genes obtained by a bi-clustering analysis of 381 microarray datasets are available. Detailed information of the clusters such as expression profiles, network diagrams is provided in two categories, heart-specific genes and heart-specific genes along with calcium toolkit genes. Overrepresented gene ontological categories and transcription factors in each cluster are also provided to infer the biological implications of the detected functional modules. AVAILABILITY: HCNet is available at http://sbrg2.gist.ac.kr/hcnet.

Algorithms↗

PubMed2006

Hepatocellular carcinoma model cell lines with two distinct migration modes.

Migration is an essential feature of metastatic cancer cells. To understand how motility is regulated in hepatocellular carcinoma, we analyzed gene expression profiles of mouse model cell lines we established from transgenic mice carrying SV40 large T antigen. A non-motile HC9 cell line was isolated from mouse liver tumors, and two additional cell lines, HCM1 and HCM4, were derived from HC9 cells. We found that both HCM1 and HCM4 cells were substantially more migratory than HC9, and that HCM1 generated tumor nodules in nude mice. In contrast to HCM4 cells that exhibited mesenchymal cell-type gene expression similar to HC9 cells, HCM1 cells appeared to have undergone a mesenchymal-amoeboidal transition. Thus, HCM1 and HCM4 cells have distinct migration and gene expression patterns, and together with HC9 cells, they can serve as model cell lines for understanding how migration is acquired and controlled in hepatocellular carcinoma.

Animals↗

PubMed2006

STMN2 is a novel target of beta-catenin/TCF-mediated transcription in human hepatoma cells.

The activity of beta-catenin/TCF, the key component of Wnt signaling pathway, is frequently deregulated in human cancers, resulting in the activation of genes whose dysregulation has significant consequences on tumor development. Therefore, identifying the target genes of Wnt signaling is important for understanding beta-catenin-mediated carcinogenesis. Here, we report STMN2, a gene implicated in the regulation of microtubule dynamics, as a novel target of beta-catenin-mediated transcription. STMN2 was up-regulated in hepatoma and cirrhotic liver tissues compared to normal liver and also in cell lines where beta-catenin/TCF is constitutively activated. Transient activation of beta-catenin/TCF either by transfection of a constitutively active form of beta-catenin or by LiCl treatment induced the STMN2 mRNA expression in PLC/PRF/5 cells. Of the four members of STMN gene family, only STMN2 showed a Wnt-dependent expression pattern. Through promoter mapping and chromatin immunoprecipitation assays, we found that STMN2 is a direct target of beta-catenin/TCF-mediated transcription and that the TCF binding site at -1713 of STMN2 promoter is critical for beta-catenin/TCF-dependent expression regulation. siRNA-mediated knock-down of STMN2 expression indicated that STMN2 is required for maintaining the anchorage-independent growth state of beta-catenin/TCF-activated hepatoma cells. Our results suggest that STMN2 might be a novel player of beta-catenin/TCF-mediated carcinogenesis in the liver.

Carcinoma, Hepatocellular↗

PubMed2006

Confirmation of a linkage between H-Ras and MMP-13 expression as well as MMP-9 by chemical genomic approach.

As farnesylation of the Ras protein by farnesyl transferase is a critical step for the Ras functional activity, the farnesyl transferase inhibitor could affect H-Ras functions and the inhibitors such as arteminolide, SCH66336 and LB42908 completely inhibited Ras-farnesylation. However, they did not induce apoptosis of H-Ras-transformed cells with concentration for blocking H-Ras farnesylation. To determine the antitumor effects of the inhibitors, it was analyzed through the expression profile of genes, regulated by activated H-Ras or FTIs by using cDNA microarray. On the basis of the results, the relationship between H-Ras and MMPs expression was confirmed by RT-PCR, Western bolt, zymographic analysis and angiogenesis assay. Our results suggested that activation of MMP-13 as well as MMP-9 induced by H-Ras is involved in angiogenesis and with farnesyl transferase inhibitors, in part, exerts their anticancer effects. We confirmed that MMP-13 is a critical H-Ras target gene through chemical genomic approaches with farnesyl transferase inhibitors.

Animals↗

PubMed2006

Diagnostic accuracy of serum asialo-alpha1-acid glycoprotein concentration for the differential diagnosis of liver cirrhosis and hepatocellular carcinoma.

BACKGROUND: Serum asialoglycoproteins concentration are increased in patients with hepatic disease. We developed an antibody-lectin sandwich assay that is sensitive and specific to measure asialo-alpha(1)-acid glycoprotein (AsAGP) concentration in human serum and evaluated it as a biochemical marker for hepatic disease. METHODS: Serum AsAGP concentration was measured by antibody-lectin sandwich assay with 610 serum specimens of patients with hepatic disease. Serum from 41 healthy donors and 155 patients with non-hepatic disease served as negative controls. The AsAGP values were analyzed by receiver operator characteristics (ROC) curve analysis. The diagnostic accuracy of AsAGP value was compared with those of the conventional biochemical markers in the liver function test. RESULTS: Serum AsAGP concentration in 83% of patients with liver cirrhosis (LC) and 89% of patients with hepatocellular carcinoma (HCC) was increased over the cutoff value (1.33 microg/ml), indicating that an increase of serum AsAGP concentration is restricted to LC or HCC cases. The area under curve (AUC) in the ROC curve was 0.919 for LC and 0.946 for HCC. CONCLUSIONS: Serum AsAGP concentration exhibited good diagnostic accuracy as a biochemical marker for LC and HCC. The addition of AsAGP to conventional liver function tests may significantly improve the diagnosis and prognosis.

Adolescent↗

PubMed2006

Targeted therapy of DNA tumor virus-associated cancers using virus-activated transcription factors.

DNA tumor virus-mediated tumorigenic processes typically involve functional inactivation of cellular tumor suppressors pRB and p53 by viral oncoproteins, with concomitant activation of oncogenic transcription factors such as E2Fs. This feature could be exploited to design a treatment for corresponding malignancies. Here, we report a gene therapy strategy for DNA tumor virus-associated cancers using a synthetic, E2F-regulated gene expression system named pESM6. This system contains multimerized E2F-responsive elements in combination with the binding sites for ubiquitous transcription factors Sp1 and CTF/NF1. pESM6 could drive a high-level transgene expression comparable to that of the CMV IE promoter and exert constitutive activity in cells expressing DNA tumor viral oncogenes. In contrast, it was effectively repressed by pRB and thus only minimally active in nontransformed cells. Expression of cytosine deaminase from pESM6 resulted in a highly efficient and specific killing of HPV-transformed fibroblasts (C3) after treatment with the prodrug 5-fluorocytosine. Also, an effective tumor mass reduction was observed when the vector was injected directly into C3 tumors implanted in C57BL/6 mice. pESM6 showed a superior performance throughout these experiments compared to the previously known E2F-regulated gene vector. These results clearly demonstrate the potential usability of pESM6 for the gene therapy of DNA tumor virus-associated cancers.

Adenoviridae↗

PubMed2006

Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo.

The pituitary tumor transforming (PTTG) gene family comprises PTTG1, 2, and 3. Forced expression of PTTG1 (securin) induces cellular transformation and promotes tumor development in animal models. PTTG1 is overexpressed in various human cancers. However, the expression and pathogenic implications of the PTTG gene family in hepatocellular carcinoma are largely unknown. Gene silencing using short interfering RNA (siRNA) has become an efficient means to study the functions of genes and has been increasingly used for cancer gene therapy approaches. We report that PTTG1, but not PTTG2 and 3, was highly and frequently expressed in liver cancer tissues from patients and highly in SH-J1, SK-Hep1, and Huh-7 hepatoma cell lines. Adenoviral vector encoding siRNA against PTTG1 (Ad.PTTG1-siRNA) depleted PTTG1 specifically and efficiently in SH-J1 hepatoma cells, which resulted in activation of p53 that led to increased p21 expression and induction of apoptosis. The depletion of PTTG1 in HCT116 colorectal cancer cells exhibited a cytotoxic effect in a p53-dependent manner. Ad.PTTG1-siRNA-mediated cytotoxic effect was dependent on expression levels of PTTG1 and p53 in hepatoma cell lines. Huh-7 hepatoma cells, once transduced with Ad.PTTG1-siRNA, displayed markedly attenuated growth potential in nude mice. Intra-tumor delivery of Ad.PTTG1-siRNA led to significant inhibition of tumor growth in SH-J1 tumor xenograft established in nude mice. In conclusion, PTTG1 overexpressed in hepatoma cell lines negatively regulates the ability of p53 to induce apoptosis. PTIG1 gene silencing using siRNA may be an effective modality to treat liver cancer, in which PTTG1 is abundantly expressed. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/ suppmat/index.html).

Adenoviridae↗

PubMed2006

A composite gene delivery system consisting of polyethylenimine and an amphipathic peptide KALA.

BACKGROUND: Animal viruses such as enveloped virus carry multi-functional proteins in the virion that can mediate more than two distinct steps of a gene delivery process during the transfer of viral genome into host cells. We tested if the aspects of the viral gene delivery mechanism could be mimicked by forming composite formulae from multi-functional synthetic gene carriers having complementary action modes. METHODS: Polyethylenimine (PEI) was chosen as the component responsible for endosome escape and DNA condensation and KALA for cellular entry and DNA condensation. Compact DNA-carrier particles consisting of the core part where DNA chains were tightly condensed by PEI and the outer layer lined with KALA were formulated, characterized and compared with monolithic cationic formulae in terms of gene delivery efficiency and mechanism. RESULTS: High-level gene expression was observed when C2C12 cells were transfected with DNA that was first partially condensed with PEI and, then, fully with KALA. In these formulae KALA mediated enhanced cellular entry of DNA by facilitating endocytic vesicle formation, while PEI provided an effective endosomolytic capacity. An optimal PEI/KALA formula showed transfection efficiencies better than or comparable to the commercial cationic liposome in various cell types in culture and in vivo. CONCLUSIONS: Gene delivery by combining the membrane-active property of KALA with the endosomolytic activity of PEI can be more efficient than that by either of the properties alone. It appears that, in these formulae, the predominant role of KALA is to facilitate cellular entry of DNA by providing a fusogenic capability, rather than an endosomolytic activity.

Animals↗

PubMed2005

Doxorubicin prevents endoplasmic reticulum stress-induced apoptosis.

Several cellular stress signaling pathways initiate apoptosis in eukaryotic cells, but the interactions and coordination between the pathways have not been elucidated. In this study, apoptosis was triggered in MCF7 human breast carcinoma cells using doxorubicin, a topoisomerase inhibitor, and an endoplasmic reticulum (ER) stress inducer, thapsigargin, the latter causing the unfolded protein response (UPR). Interestingly, compared to treatment with doxorubicin or thapsigargin alone, cell death was reduced by treatment with both stress inducers. In contrast to another topoisomerase inhibitor, etoposide, doxorubicin markedly decreased apoptosis induced by thapsigargin; this doxorubicin effect was accompanied by reduced expression of the UPR-specific proapoptotic protein, C/EBP-homologous protein, and its upstream transcription factor, ATF4. We further found that doxorubicin downregulates the expression of ATF4 mRNA, indicating that doxorubicin interferes with the UPR at the level of ATF4 transcription. Taken together, the data suggest that ER stress-initiated cell death might be regulated by doxorubicin.

Activating Transcription Factor 4↗

PubMed2004

Feature genes of hepatitis B virus-positive hepatocellular carcinoma, established by its molecular discrimination approach using prediction analysis of microarray.

Recent introduction of a learning algorithm for cDNA microarray analysis has permitted to select feature set to accurately distinguish human cancers according to their pathological judgments. Here, we demonstrate that hepatitis B virus-positive hepatocellular carcinoma (HCC) could successfully be identified from non-tumor liver tissues by supervised learning analysis of gene expression profiling. Through learning and cross-validating HCC sample set, we could identify an optimized set of 44 genes to discriminate the status of HCC from non-tumor liver tissues. In an analysis of other blind-tested HCC sample sets, this feature set was found to be statistically significant, indicating the reproducibility of our molecular discrimination approach with the defined genes. One prominent finding was an asymmetrical distribution pattern of expression profiling in HCC, in which the number of down-regulated genes was greater than that of up-regulated genes. In conclusion, the present findings indicate that application of learning algorithm to HCC may establish a reliable feature set of genes to be useful for therapeutic target of HCC, and that the asymmetric expression pattern may emphasize the importance of suppressed genes in HCC.

Carcinoma, Hepatocellular↗

PubMed2004

Integrative analysis of multiple gene expression profiles applied to liver cancer study.

A statistical method for combining multiple microarray studies has been previously developed by the authors. Here, we present the application of the method to our hepatocellular carcinoma (HCC) data and report new findings on gene expression changes accompanying HCC. From the cross-verification result of our studies and that of published studies, we found that single microarray analysis might lead to false findings. To avoid those pitfalls of single-set analyses, we employed our effect size method to integrate multiple datasets. Of 9982 genes analyzed, 477 significant genes were identified with a false discovery rate of 10%. Gene ontology (GO) terms associated with these genes were explored to validate our method in the biological context with respect to HCC. Furthermore, it was demonstrated that the data integration process increases the sensitivity of analysis and allows small but consistent expression changes to be detected. These integration-driven discoveries contained meaningful and interesting genes not reported in previous expression profiling studies, such as growth hormone receptor, erythropoietin receptor, tissue factor pathway inhibitor-2, etc. Our findings support the use of meta-analysis for a variety of microarray data beyond the scope of this specific application.

Carcinoma, Hepatocellular↗