Background: The aim of this study is to evaluate the associations between vascular endothelial gr... more Background: The aim of this study is to evaluate the associations between vascular endothelial growth factor (VEGF) Single-nucleotide polymorphisms (SNPs) and clinical outcome in advanced gastric cancer patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX).
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
To investigate the clinical utility of targeted next-generation sequencing (NGS) for predicting t... more To investigate the clinical utility of targeted next-generation sequencing (NGS) for predicting the responsiveness to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy, we compared the efficacy with conventional sequencing in never-smokers with lung adenocarcinoma (NSLAs). We obtained DNA from 48 NSLAs who received gefitinib or erlotinib for their recurrent disease after surgery. Sanger sequencing and peptide nucleic acid clamp polymerase chain reaction (PCR) were used to analyze EGFR, KRAS, BRAF, and PIK3CA mutations. We analyzed ALK, RET, and ROS1 rearrangements by fluorescent in situ hybridization or reverse transcriptase-PCR and quantitative real-time PCR. After molecular screening, Ion Torrent NGS was performed in 31 cases harboring only EGFR exon 19 deletions (19DEL), an L858R mutation, or none of the above mutations. The 31 samples were divided into four groups: (1) responders to EGFR-TKIs with only 19DEL or L858R (n=15); (2) primary resistance to EGFR-TKI with only 19DEL or L858R (n=4); (3) primary resistance to EGFR-TKI without any mutations (n=8); (4) responders to EGFR-TKI without any mutations (n=4). With NGS, all conventionally detected mutations were confirmed except for one L858R in group 2. Additional uncovered predictive mutations with NGS included one PIK3CA E542K in group 2, two KRAS (G12V and G12D), one PIK3CA E542K, one concomitant PIK3CA and EGFR L858R in group 3, and one EGFR 19DEL in group 4. Targeted NGS provided a more accurate and clinically useful molecular classification of NSLAs. It may improve the efficacy of EGFR-TKI therapy in lung cancer.
Reproductive System and Sexual Disorders, Mar 2, 2016
Objective: To investigate the association of genetic variants of nerve injury-induced protein 1 (... more Objective: To investigate the association of genetic variants of nerve injury-induced protein 1 (NINJ1) with risk of prostate cancer in Korean men, we performed this association study using single nucleotide polymorphism (SNP). Materials and methods: We enrolled 383 patients with prostate cancer and 373 healthy controls. Twentysix candidate SNPs of the NINJ1 gene were selected for genotype analysis. The distribution of each genotype and haplotype was analyzed, and their association with the incidence of prostate cancer was evaluated. Results: None of the SNPs and haplotypes showed significant associations with prostate cancer risk in our subjects. In relation to the genotype frequency, 14 out of the 24 characterized SNPs revealed monomorphic features in cases and controls. Conclusions: Although no association was observed between SNPs of the NINJ1 gene and prostate cancer risk, this study is meaningful because it is the first report to investigate the genetic epidemiology of the NINJ1 gene in relation to the development of prostate cancer. In addition, we observed monomorphic features of several SNPs of the NINJ1 gene in Korean men,and this finding was similar to that observed in Chinese and Japanese men based on the review of SNP database.
Background: Stomach cancer is the third deadliest among all cancers worldwide. Although incidence... more Background: Stomach cancer is the third deadliest among all cancers worldwide. Although incidence of the intestinal-type gastric cancer has decreased, the incidence of diffuse-type is still increasing and its progression is notoriously aggressive. There is insufficient information on genome variations of diffuse-type gastric cancer because its cells are usually mixed with normal cells, and this low cellularity has made it difficult to analyze the genome. Results: We analyze whole genomes and corresponding exomes of diffuse-type gastric cancer, using matched tumor and normal samples from 14 diffuse-type and five intestinal-type gastric cancer patients. Somatic variations found in the diffuse-type gastric cancer are compared to those of the intestinal-type and to previously reported variants. We determine the average exonic somatic mutation rate of the two types. We find associated candidate driver genes, and identify seven novel somatic mutations in CDH1, which is a well-known gastric cancer-associated gene. Three-dimensional structure analysis of the mutated E-cadherin protein suggests that these new somatic mutations could cause significant functional perturbations of critical calcium-binding sites in the EC1-2 junction. Chromosomal instability analysis shows that the MDM2 gene is amplified. After thorough structural analysis, a novel fusion gene TSC2-RNF216 is identified, which may simultaneously disrupt tumor-suppressive pathways and activate tumorigenesis. Conclusions: We report the genomic profile of diffuse-type gastric cancers including new somatic variations, a novel fusion gene, and amplification and deletion of certain chromosomal regions that contain oncogenes and tumor suppressors.
Asian Pacific Journal of Cancer Prevention, Nov 28, 2014
A growing body of evidence suggests that the peroxisome proliferator-activated receptor-gamma (PP... more A growing body of evidence suggests that the peroxisome proliferator-activated receptor-gamma (PPARγ) gene may harbor targets for the chemoprevention of breast cancer. However, it is unclear whether polymorphisms in the PPARγ gene are associated with the susceptibility of breast cancer. We performed a candidate gene association study between PPARγ polymorphisms and breast cancer and a meta-analysis on the association of breast cancer with selected PPARγ variants. Six single nucleotide polymorphisms (SNPs) in the PPARγ gene were analyzed among 456 breast cancer patients and 461 controls from the National Cancer Center in Korea. Association between the polymorphisms and breast cancer risk were assessed using the Cochrane-Armitage test for trend and a multivariate logistic regression model. Two SNPs, rs3856806 and rs1801282, had been previously analyzed, thus enabling us to perform pooled analyses on their associations with breast cancer susceptibility. Our findings from the candidate gene association study showed no association between the PPARγ gene polymorphisms and breast cancer risk. A meta-analysis combining existing studies and our current study also refuted an association of the PPARγ gene with breast cancer. Our findings suggest that the PPARγ gene may not harbor variants that alter breast cancer susceptibility, although a moderate sample size might have precluded a decisive conclusion.
Tumorigenesis and tumor growth are accomplished through the crosstalk between intra- and extracel... more Tumorigenesis and tumor growth are accomplished through the crosstalk between intra- and extracellular molecules, which is often mediated by phosphorylation, and research on intracellular signal transduction has made great progress. Despite the significance of the tumor microenvironment (TME) for tumor progression, relatively few kinome studies have been conducted on phosphorylation cascade in the TME of oral squamous cell carcinoma (OSCC). OSCC is an aggressive cancer with a high recurrence rate of 40-60%, but there are uncertain molecular classification and no identifiable driver mutation genes to be a druggable target. As the presence of extranodal extension (ENE) is currently the most significant risk factor for locoregional recurrence or distant metastasis, differences in molecular profiles between patients with and without ENE may provide insight into regulatory mechanisms that are critical for the recurrence and progression of OSCC. Using LC-MS-based secretome analysis, we ex...
Elucidation of the interplay between viruses and host cells is crucial for taming viruses to bene... more Elucidation of the interplay between viruses and host cells is crucial for taming viruses to benefit human health. Cancer therapy using adenovirus, called oncolytic virotherapy, is a promising treatment option but is not robust in all patients. In addition, inefficient replication of human adenovirus in mouse hampered the development of an in vivo model for preclinical evaluation of therapeutically engineered adenovirus. nc886 is a human non-coding RNA that suppresses Protein Kinase R (PKR), an antiviral protein. In this study, we have found that nc886 greatly promotes adenoviral gene expression and replication. Remarkably, the stimulatory effect of nc886 is not dependent on its function to inhibit PKR. Rather, nc886 facilitates the nuclear entry of adenovirus via modulating the kinesin pathway. nc886 is not conserved in mouse and, when xenogeneically expressed in mouse cells, promotes adenovirus replication. Our investigation has discovered a novel mechanism of how a host ncRNA plays a pro-adenoviral role. Given that nc886 expression is silenced in a subset of cancer cells, our study highlights that oncolytic virotherapy might be inefficient in those cells. Furthermore, our findings open future possibilities of harnessing nc886 to improve the efficacy of oncolytic adenovirus and to construct nc886-expressing transgenic mice as an animal model.
Background: This study was aimed at investigating the functional significance of heparan sulfate ... more Background: This study was aimed at investigating the functional significance of heparan sulfate (glucosamine) 3-Osulfotransferase 2 (HS3ST2) hypermethylation in non-small cell lung cancer (NSCLC). Methodology/ Principal Findings : HS3ST2 hypermethylation was characterized in six lung cancer cell lines, and its clinical significance was analyzed using 298 formalin-fixed paraffin-embedded tissues and 26 fresh-frozen tissues from 324 NSCLC patients. MS-HRM (methylation-specific high-resolution melting) and EpiTYPER TM assays showed substantial hypermethylation of CpG island at the promoter region of HS3ST2 in six lung cancer cell lines. The silenced gene was demethylated and re-expressed by treatment with 5-aza-2′-deoxycytidine (5-Aza-dC). A promoter assay also showed the core promoter activity of HS3ST2 was regulated by methylation. Exogenous expression of HS3ST2 in lung cancer cells H460 and H23 inhibited cell migration, invasion, cell proliferation and whereas knockdown of HS3ST2 in NHBE cells induced cell migration, invasion, and cell proliferation in vitro. A negative correlation was observed between mRNA and methylation levels of HS3ST2 in 26 fresh-frozen tumors tissues (ρ =-0.51, P = 0.009; Spearman's rank correlation). HS3ST2 hypermethylation was found in 95 (32%) of 298 primary NSCLCs. Patients with HS3ST2 hypermethylation in 193 node-negative stage I-II NSCLCs with a median follow-up period of 5.8 years had poor overall survival (hazard ratio = 2.12, 95% confidence interval = 1.25-3.58, P = 0.005) compared to those without HS3ST2 hypermethylation, after adjusting for age, sex, tumor size, adjuvant therapy, recurrence, and differentiation. Conclusions/ Significance: The present study suggests that HS3ST2 hypermethylation may be an independent prognostic indicator for overall survival in node-negative stage I-II NSCLC.
Objective: To investigate the association of genetic variants of nerve injury-induced protein 1 (... more Objective: To investigate the association of genetic variants of nerve injury-induced protein 1 (NINJ1) with risk of prostate cancer in Korean men, we performed this association study using single nucleotide polymorphism (SNP). Materials and methods: We enrolled 383 patients with prostate cancer and 373 healthy controls. Twentysix candidate SNPs of the NINJ1 gene were selected for genotype analysis. The distribution of each genotype and haplotype was analyzed, and their association with the incidence of prostate cancer was evaluated. Results: None of the SNPs and haplotypes showed significant associations with prostate cancer risk in our subjects. In relation to the genotype frequency, 14 out of the 24 characterized SNPs revealed monomorphic features in cases and controls. Conclusions: Although no association was observed between SNPs of the NINJ1 gene and prostate cancer risk, this study is meaningful because it is the first report to investigate the genetic epidemiology of the NIN...
308 Background: Reliable biomarkers are required to predict patient response to sorafenib. We att... more 308 Background: Reliable biomarkers are required to predict patient response to sorafenib. We attempted to investigate genomic variations associated with responsiveness to sorafenib treatment in patients with unresectable hepatocellular carcinoma (HCC) and their functional relevance. Methods: We obtained blood samples from 4 strong and 3 poor responders to sorafenib treatment and subjected these samples to whole-genome analysis. Next, we performed validation tests for candidate single-nucleotide polymorphisms (SNPs) in the samples of 174 HCC patients who were treated with sorafenib, followed by in vitro functional analysis and in silico analyses of candidate SNPs. Results: On average, 90 gigabases/sample was generated at ~34X sequencing depth. In total, 1813 genomic variations were perfectly matched to sorafenib responses in the clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes—3...
Background: Single-nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEG... more Background: Single-nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) gene may have an impact on tumor progression, and response to chemotherapy. The aim of this study is to evaluate the associations between VEGF SNPs and clinical outcome in advanced gastric cancer patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). Methods: One hundred ninety recurrent or metastatic gastric cancer patients were enrolled in this study and treated with FOLFOX regimen. Genomic DNA was isolated from whole blood, and six VEGF (-2578C/A, –2489C/T, –1498T/C, –634G/C, 936C/T, and 1612G/A) gene polymorphisms were analyzed by PCR. Results: Patients genotyped G/G for –634G/C gene polymorphism had lower response rate (22.2%) than those G/C or C/C (32.3%, 51.1%; p = 0.034). The median serum levels of VEGF was higher in G/G genotypes than G/C + C/C (724.1 pg/ml vs. 462.4 pg/ml, p = 0.041). Patients with the VEGF –634CG/C polymorphism G/C + C/C genotype had a ...
AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4489 Alterations of the PI3K/AKT and MAPK ... more AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4489 Alterations of the PI3K/AKT and MAPK pathways occur in many human cancers. Phosphatase protein homologue to tesin (PTEN) and phsphatidlylinositol-3 phosphate kinase (PI3K) regulate activation of PI3K/AKT pathways. The K- ras and BRAF genes play an important role in the MAPK pathway. It has been reported that BRAF mutations, hMLH1 hypermethylation, and microsatellite instability (MSI) were frequently found in colorectal cancers. Recently, it was reported that PIK3CA mutation and PTEN protein deregulation were mutually exclusive in colorectal cancer. To identify relationship of PIK3CA , PTEN , K- ras and BRAF mutations in 204 colorectal cancer samples, we investigated mutation status of hot spot regions of PIK3CA (exon9 and exon20), K-ras (exon1), BRAF (exon11 and exon15) genes, and all exons of PTEN using direct sequencing. Additionally, we investigated MSI status and hMLH1 methylation. We identified 24 (13%) PIK3CA , 12 (6%) PTEN , 51 (25%) K- ras , 9 (4%) BRAF mutations, 43 (21%) MSI, and 48 (24%) hMLH1 hypermethylation. PTEN mutations were found only in the proximal CRC ( p =0.0003) and associated with MSI ( p =0.021). All cases with PTEN mutation had no PIK3CA mutation. PTEN mutations were mutually exclusive with PIK3CA mutations and showed an inverse correlation with K- ras mutations. Only one sample showed mutations in both PTEN and K- ras . PTEN mutations also exhibited an inverse correlation with hMLH1 promoter hypermethylation. Only one showed both PTEN mutation and hMLH1 promoter hypermethylation. PIK3CA mutations were associated with K-ras mutations ( p =0.041). Taken together, we investigated the relationship in several genes in PI3K/AKT pathway and colorectal cancer development and we identified a mutually exclusive relationship between PTEN and PIK3CA mutations.
Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Andr... more Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Androgen-receptor (AR) signaling has been targeted by several investigational agents in luminal AR subtype TNBCs. Bromodomain (BRD) and extra-terminal motif (BET) protein inhibitors have been shown to attenuate AR signaling in metastatic castration-resistant prostate cancer and to overcome enzalutamide resistance. We demonstrated potent anti-tumor effects of the BET inhibitor JQ1 against AR-positive TNBC cell lines using cell viability and cell cycle analysis. To reveal the mechanisms of JQ1 effects, multiplex gene expression analysis and immunoblotting assays were used. We examined in vivo effects of JQ1 in a xenograft model of AR expressing TNBC. JQ1 exhibited its anti-proliferative activity by inducing apoptosis and cell cycle arrest. JQ1 activity was not mediated by MYC downregulation. Instead, JQ1 blocked the interactions among the ATPase-family AAA-domain-containing 2 protein (ATAD2), ...
Transforming growth factor-β (TGF-β) signaling and microRNAs (miRNAs) are important gene regulato... more Transforming growth factor-β (TGF-β) signaling and microRNAs (miRNAs) are important gene regulatory components in cancer. Usually in advanced malignant stages, TGF-β signaling is elevated but global miRNA expression is suppressed. Such a gene expression signature is well illustrated in a fibrosis (or mesenchymal) subtype of ovarian cancer (OC) that is of poor prognosis. However, the interplay between the two pathways in the OC subtype has not yet been elucidated. nc886 is a recently identified non-coding RNA implicated in several malignancies. The high expression of nc886 is associated with poor prognosis in 285 OC patients. Herein, we find that in OC nc886 expression is induced by TGF-β and that nc886 binds to Dicer to inhibit miRNA maturation. By preventing the miRNA pathway, nc886 emulates TGF-β in gene expression patterns and potentiates cell adhesion, migration, invasion, and drug resistance. Here we report nc886 to be a molecular link between the TGF-β and miRNA pathways.
nc886 is a recently identified cellular non-coding RNA and its depletion leads to acute cell deat... more nc886 is a recently identified cellular non-coding RNA and its depletion leads to acute cell death via PKR (Protein Kinase RNA-activated) activation. nc886 expression is increased in some malignancies, but silenced in others. However, the precise role of nc886/PKR is controversial: is it a tumor suppressor or an oncogene? In this study, we have clarified the role of nc886 in thyroid cancer by sequentially generating PKR knockout (KO) and PKR/nc886 double KO cell lines from Nthy-ori 3-1, a partially transformed thyroid cell line. Compared to the wildtype, PKR KO alone does not exhibit any significant phenotypic changes. However, nc886 KO cells are less proliferative, migratory, and invasive than their parental PKR KO cells. Importantly, the requirement of nc886 in tumor phenotypes is totally independent of PKR. In our microarray data, nc886 KO suppresses some genes whose elevated expression is associated with poor survival confirmed by data from total of 505 thyroid cancer patients i...
Background: The aim of this study is to evaluate the associations between vascular endothelial gr... more Background: The aim of this study is to evaluate the associations between vascular endothelial growth factor (VEGF) Single-nucleotide polymorphisms (SNPs) and clinical outcome in advanced gastric cancer patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX).
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
To investigate the clinical utility of targeted next-generation sequencing (NGS) for predicting t... more To investigate the clinical utility of targeted next-generation sequencing (NGS) for predicting the responsiveness to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy, we compared the efficacy with conventional sequencing in never-smokers with lung adenocarcinoma (NSLAs). We obtained DNA from 48 NSLAs who received gefitinib or erlotinib for their recurrent disease after surgery. Sanger sequencing and peptide nucleic acid clamp polymerase chain reaction (PCR) were used to analyze EGFR, KRAS, BRAF, and PIK3CA mutations. We analyzed ALK, RET, and ROS1 rearrangements by fluorescent in situ hybridization or reverse transcriptase-PCR and quantitative real-time PCR. After molecular screening, Ion Torrent NGS was performed in 31 cases harboring only EGFR exon 19 deletions (19DEL), an L858R mutation, or none of the above mutations. The 31 samples were divided into four groups: (1) responders to EGFR-TKIs with only 19DEL or L858R (n=15); (2) primary resistance to EGFR-TKI with only 19DEL or L858R (n=4); (3) primary resistance to EGFR-TKI without any mutations (n=8); (4) responders to EGFR-TKI without any mutations (n=4). With NGS, all conventionally detected mutations were confirmed except for one L858R in group 2. Additional uncovered predictive mutations with NGS included one PIK3CA E542K in group 2, two KRAS (G12V and G12D), one PIK3CA E542K, one concomitant PIK3CA and EGFR L858R in group 3, and one EGFR 19DEL in group 4. Targeted NGS provided a more accurate and clinically useful molecular classification of NSLAs. It may improve the efficacy of EGFR-TKI therapy in lung cancer.
Reproductive System and Sexual Disorders, Mar 2, 2016
Objective: To investigate the association of genetic variants of nerve injury-induced protein 1 (... more Objective: To investigate the association of genetic variants of nerve injury-induced protein 1 (NINJ1) with risk of prostate cancer in Korean men, we performed this association study using single nucleotide polymorphism (SNP). Materials and methods: We enrolled 383 patients with prostate cancer and 373 healthy controls. Twentysix candidate SNPs of the NINJ1 gene were selected for genotype analysis. The distribution of each genotype and haplotype was analyzed, and their association with the incidence of prostate cancer was evaluated. Results: None of the SNPs and haplotypes showed significant associations with prostate cancer risk in our subjects. In relation to the genotype frequency, 14 out of the 24 characterized SNPs revealed monomorphic features in cases and controls. Conclusions: Although no association was observed between SNPs of the NINJ1 gene and prostate cancer risk, this study is meaningful because it is the first report to investigate the genetic epidemiology of the NINJ1 gene in relation to the development of prostate cancer. In addition, we observed monomorphic features of several SNPs of the NINJ1 gene in Korean men,and this finding was similar to that observed in Chinese and Japanese men based on the review of SNP database.
Background: Stomach cancer is the third deadliest among all cancers worldwide. Although incidence... more Background: Stomach cancer is the third deadliest among all cancers worldwide. Although incidence of the intestinal-type gastric cancer has decreased, the incidence of diffuse-type is still increasing and its progression is notoriously aggressive. There is insufficient information on genome variations of diffuse-type gastric cancer because its cells are usually mixed with normal cells, and this low cellularity has made it difficult to analyze the genome. Results: We analyze whole genomes and corresponding exomes of diffuse-type gastric cancer, using matched tumor and normal samples from 14 diffuse-type and five intestinal-type gastric cancer patients. Somatic variations found in the diffuse-type gastric cancer are compared to those of the intestinal-type and to previously reported variants. We determine the average exonic somatic mutation rate of the two types. We find associated candidate driver genes, and identify seven novel somatic mutations in CDH1, which is a well-known gastric cancer-associated gene. Three-dimensional structure analysis of the mutated E-cadherin protein suggests that these new somatic mutations could cause significant functional perturbations of critical calcium-binding sites in the EC1-2 junction. Chromosomal instability analysis shows that the MDM2 gene is amplified. After thorough structural analysis, a novel fusion gene TSC2-RNF216 is identified, which may simultaneously disrupt tumor-suppressive pathways and activate tumorigenesis. Conclusions: We report the genomic profile of diffuse-type gastric cancers including new somatic variations, a novel fusion gene, and amplification and deletion of certain chromosomal regions that contain oncogenes and tumor suppressors.
Asian Pacific Journal of Cancer Prevention, Nov 28, 2014
A growing body of evidence suggests that the peroxisome proliferator-activated receptor-gamma (PP... more A growing body of evidence suggests that the peroxisome proliferator-activated receptor-gamma (PPARγ) gene may harbor targets for the chemoprevention of breast cancer. However, it is unclear whether polymorphisms in the PPARγ gene are associated with the susceptibility of breast cancer. We performed a candidate gene association study between PPARγ polymorphisms and breast cancer and a meta-analysis on the association of breast cancer with selected PPARγ variants. Six single nucleotide polymorphisms (SNPs) in the PPARγ gene were analyzed among 456 breast cancer patients and 461 controls from the National Cancer Center in Korea. Association between the polymorphisms and breast cancer risk were assessed using the Cochrane-Armitage test for trend and a multivariate logistic regression model. Two SNPs, rs3856806 and rs1801282, had been previously analyzed, thus enabling us to perform pooled analyses on their associations with breast cancer susceptibility. Our findings from the candidate gene association study showed no association between the PPARγ gene polymorphisms and breast cancer risk. A meta-analysis combining existing studies and our current study also refuted an association of the PPARγ gene with breast cancer. Our findings suggest that the PPARγ gene may not harbor variants that alter breast cancer susceptibility, although a moderate sample size might have precluded a decisive conclusion.
Tumorigenesis and tumor growth are accomplished through the crosstalk between intra- and extracel... more Tumorigenesis and tumor growth are accomplished through the crosstalk between intra- and extracellular molecules, which is often mediated by phosphorylation, and research on intracellular signal transduction has made great progress. Despite the significance of the tumor microenvironment (TME) for tumor progression, relatively few kinome studies have been conducted on phosphorylation cascade in the TME of oral squamous cell carcinoma (OSCC). OSCC is an aggressive cancer with a high recurrence rate of 40-60%, but there are uncertain molecular classification and no identifiable driver mutation genes to be a druggable target. As the presence of extranodal extension (ENE) is currently the most significant risk factor for locoregional recurrence or distant metastasis, differences in molecular profiles between patients with and without ENE may provide insight into regulatory mechanisms that are critical for the recurrence and progression of OSCC. Using LC-MS-based secretome analysis, we ex...
Elucidation of the interplay between viruses and host cells is crucial for taming viruses to bene... more Elucidation of the interplay between viruses and host cells is crucial for taming viruses to benefit human health. Cancer therapy using adenovirus, called oncolytic virotherapy, is a promising treatment option but is not robust in all patients. In addition, inefficient replication of human adenovirus in mouse hampered the development of an in vivo model for preclinical evaluation of therapeutically engineered adenovirus. nc886 is a human non-coding RNA that suppresses Protein Kinase R (PKR), an antiviral protein. In this study, we have found that nc886 greatly promotes adenoviral gene expression and replication. Remarkably, the stimulatory effect of nc886 is not dependent on its function to inhibit PKR. Rather, nc886 facilitates the nuclear entry of adenovirus via modulating the kinesin pathway. nc886 is not conserved in mouse and, when xenogeneically expressed in mouse cells, promotes adenovirus replication. Our investigation has discovered a novel mechanism of how a host ncRNA plays a pro-adenoviral role. Given that nc886 expression is silenced in a subset of cancer cells, our study highlights that oncolytic virotherapy might be inefficient in those cells. Furthermore, our findings open future possibilities of harnessing nc886 to improve the efficacy of oncolytic adenovirus and to construct nc886-expressing transgenic mice as an animal model.
Background: This study was aimed at investigating the functional significance of heparan sulfate ... more Background: This study was aimed at investigating the functional significance of heparan sulfate (glucosamine) 3-Osulfotransferase 2 (HS3ST2) hypermethylation in non-small cell lung cancer (NSCLC). Methodology/ Principal Findings : HS3ST2 hypermethylation was characterized in six lung cancer cell lines, and its clinical significance was analyzed using 298 formalin-fixed paraffin-embedded tissues and 26 fresh-frozen tissues from 324 NSCLC patients. MS-HRM (methylation-specific high-resolution melting) and EpiTYPER TM assays showed substantial hypermethylation of CpG island at the promoter region of HS3ST2 in six lung cancer cell lines. The silenced gene was demethylated and re-expressed by treatment with 5-aza-2′-deoxycytidine (5-Aza-dC). A promoter assay also showed the core promoter activity of HS3ST2 was regulated by methylation. Exogenous expression of HS3ST2 in lung cancer cells H460 and H23 inhibited cell migration, invasion, cell proliferation and whereas knockdown of HS3ST2 in NHBE cells induced cell migration, invasion, and cell proliferation in vitro. A negative correlation was observed between mRNA and methylation levels of HS3ST2 in 26 fresh-frozen tumors tissues (ρ =-0.51, P = 0.009; Spearman's rank correlation). HS3ST2 hypermethylation was found in 95 (32%) of 298 primary NSCLCs. Patients with HS3ST2 hypermethylation in 193 node-negative stage I-II NSCLCs with a median follow-up period of 5.8 years had poor overall survival (hazard ratio = 2.12, 95% confidence interval = 1.25-3.58, P = 0.005) compared to those without HS3ST2 hypermethylation, after adjusting for age, sex, tumor size, adjuvant therapy, recurrence, and differentiation. Conclusions/ Significance: The present study suggests that HS3ST2 hypermethylation may be an independent prognostic indicator for overall survival in node-negative stage I-II NSCLC.
Objective: To investigate the association of genetic variants of nerve injury-induced protein 1 (... more Objective: To investigate the association of genetic variants of nerve injury-induced protein 1 (NINJ1) with risk of prostate cancer in Korean men, we performed this association study using single nucleotide polymorphism (SNP). Materials and methods: We enrolled 383 patients with prostate cancer and 373 healthy controls. Twentysix candidate SNPs of the NINJ1 gene were selected for genotype analysis. The distribution of each genotype and haplotype was analyzed, and their association with the incidence of prostate cancer was evaluated. Results: None of the SNPs and haplotypes showed significant associations with prostate cancer risk in our subjects. In relation to the genotype frequency, 14 out of the 24 characterized SNPs revealed monomorphic features in cases and controls. Conclusions: Although no association was observed between SNPs of the NINJ1 gene and prostate cancer risk, this study is meaningful because it is the first report to investigate the genetic epidemiology of the NIN...
308 Background: Reliable biomarkers are required to predict patient response to sorafenib. We att... more 308 Background: Reliable biomarkers are required to predict patient response to sorafenib. We attempted to investigate genomic variations associated with responsiveness to sorafenib treatment in patients with unresectable hepatocellular carcinoma (HCC) and their functional relevance. Methods: We obtained blood samples from 4 strong and 3 poor responders to sorafenib treatment and subjected these samples to whole-genome analysis. Next, we performed validation tests for candidate single-nucleotide polymorphisms (SNPs) in the samples of 174 HCC patients who were treated with sorafenib, followed by in vitro functional analysis and in silico analyses of candidate SNPs. Results: On average, 90 gigabases/sample was generated at ~34X sequencing depth. In total, 1813 genomic variations were perfectly matched to sorafenib responses in the clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes—3...
Background: Single-nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEG... more Background: Single-nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) gene may have an impact on tumor progression, and response to chemotherapy. The aim of this study is to evaluate the associations between VEGF SNPs and clinical outcome in advanced gastric cancer patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). Methods: One hundred ninety recurrent or metastatic gastric cancer patients were enrolled in this study and treated with FOLFOX regimen. Genomic DNA was isolated from whole blood, and six VEGF (-2578C/A, –2489C/T, –1498T/C, –634G/C, 936C/T, and 1612G/A) gene polymorphisms were analyzed by PCR. Results: Patients genotyped G/G for –634G/C gene polymorphism had lower response rate (22.2%) than those G/C or C/C (32.3%, 51.1%; p = 0.034). The median serum levels of VEGF was higher in G/G genotypes than G/C + C/C (724.1 pg/ml vs. 462.4 pg/ml, p = 0.041). Patients with the VEGF –634CG/C polymorphism G/C + C/C genotype had a ...
AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4489 Alterations of the PI3K/AKT and MAPK ... more AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4489 Alterations of the PI3K/AKT and MAPK pathways occur in many human cancers. Phosphatase protein homologue to tesin (PTEN) and phsphatidlylinositol-3 phosphate kinase (PI3K) regulate activation of PI3K/AKT pathways. The K- ras and BRAF genes play an important role in the MAPK pathway. It has been reported that BRAF mutations, hMLH1 hypermethylation, and microsatellite instability (MSI) were frequently found in colorectal cancers. Recently, it was reported that PIK3CA mutation and PTEN protein deregulation were mutually exclusive in colorectal cancer. To identify relationship of PIK3CA , PTEN , K- ras and BRAF mutations in 204 colorectal cancer samples, we investigated mutation status of hot spot regions of PIK3CA (exon9 and exon20), K-ras (exon1), BRAF (exon11 and exon15) genes, and all exons of PTEN using direct sequencing. Additionally, we investigated MSI status and hMLH1 methylation. We identified 24 (13%) PIK3CA , 12 (6%) PTEN , 51 (25%) K- ras , 9 (4%) BRAF mutations, 43 (21%) MSI, and 48 (24%) hMLH1 hypermethylation. PTEN mutations were found only in the proximal CRC ( p =0.0003) and associated with MSI ( p =0.021). All cases with PTEN mutation had no PIK3CA mutation. PTEN mutations were mutually exclusive with PIK3CA mutations and showed an inverse correlation with K- ras mutations. Only one sample showed mutations in both PTEN and K- ras . PTEN mutations also exhibited an inverse correlation with hMLH1 promoter hypermethylation. Only one showed both PTEN mutation and hMLH1 promoter hypermethylation. PIK3CA mutations were associated with K-ras mutations ( p =0.041). Taken together, we investigated the relationship in several genes in PI3K/AKT pathway and colorectal cancer development and we identified a mutually exclusive relationship between PTEN and PIK3CA mutations.
Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Andr... more Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Androgen-receptor (AR) signaling has been targeted by several investigational agents in luminal AR subtype TNBCs. Bromodomain (BRD) and extra-terminal motif (BET) protein inhibitors have been shown to attenuate AR signaling in metastatic castration-resistant prostate cancer and to overcome enzalutamide resistance. We demonstrated potent anti-tumor effects of the BET inhibitor JQ1 against AR-positive TNBC cell lines using cell viability and cell cycle analysis. To reveal the mechanisms of JQ1 effects, multiplex gene expression analysis and immunoblotting assays were used. We examined in vivo effects of JQ1 in a xenograft model of AR expressing TNBC. JQ1 exhibited its anti-proliferative activity by inducing apoptosis and cell cycle arrest. JQ1 activity was not mediated by MYC downregulation. Instead, JQ1 blocked the interactions among the ATPase-family AAA-domain-containing 2 protein (ATAD2), ...
Transforming growth factor-β (TGF-β) signaling and microRNAs (miRNAs) are important gene regulato... more Transforming growth factor-β (TGF-β) signaling and microRNAs (miRNAs) are important gene regulatory components in cancer. Usually in advanced malignant stages, TGF-β signaling is elevated but global miRNA expression is suppressed. Such a gene expression signature is well illustrated in a fibrosis (or mesenchymal) subtype of ovarian cancer (OC) that is of poor prognosis. However, the interplay between the two pathways in the OC subtype has not yet been elucidated. nc886 is a recently identified non-coding RNA implicated in several malignancies. The high expression of nc886 is associated with poor prognosis in 285 OC patients. Herein, we find that in OC nc886 expression is induced by TGF-β and that nc886 binds to Dicer to inhibit miRNA maturation. By preventing the miRNA pathway, nc886 emulates TGF-β in gene expression patterns and potentiates cell adhesion, migration, invasion, and drug resistance. Here we report nc886 to be a molecular link between the TGF-β and miRNA pathways.
nc886 is a recently identified cellular non-coding RNA and its depletion leads to acute cell deat... more nc886 is a recently identified cellular non-coding RNA and its depletion leads to acute cell death via PKR (Protein Kinase RNA-activated) activation. nc886 expression is increased in some malignancies, but silenced in others. However, the precise role of nc886/PKR is controversial: is it a tumor suppressor or an oncogene? In this study, we have clarified the role of nc886 in thyroid cancer by sequentially generating PKR knockout (KO) and PKR/nc886 double KO cell lines from Nthy-ori 3-1, a partially transformed thyroid cell line. Compared to the wildtype, PKR KO alone does not exhibit any significant phenotypic changes. However, nc886 KO cells are less proliferative, migratory, and invasive than their parental PKR KO cells. Importantly, the requirement of nc886 in tumor phenotypes is totally independent of PKR. In our microarray data, nc886 KO suppresses some genes whose elevated expression is associated with poor survival confirmed by data from total of 505 thyroid cancer patients i...
Uploads
Papers by Jung-Ah Hwang