So-Young Seol

A novel resveratrol derivative, HS1793, overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells

The chemopreventive and chemotherapeutic properties associated with resveratrol offer promise for the design of new chemotherapeutic agents. However, resveratrol is not a potent cytotoxic compound when compared with other chemotherapeutic drugs. Thus, several studies were undertaken to obtain synthetic analogues of resveratrol with potent activity. The present study was undertaken to examine whether four resveratrol analogues (HS-1784, -1792, -1791 and -1793) that we had designed and synthesized show antitumor activity. Here, we observed that all of these resveratrol analogues displayed stronger antitumor effects than resveratrol in most cancer cells tested. We further examined whether HS-1793, showing potent antitumor effects in most cancer cells tested, overcomes the resistance conferred by Bcl-2, since overcoming the resistance conferred by Bcl-2 represents an attractive therapeutic strategy against cancer. Our viability assay showed that HS-1793 overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells. Various apoptosis assessment assays demonstrated that HS-1793 overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells by inducing apoptosis. Noticeably, we elucidated the marked downregulation of 14-3-3 protein by HS-1793, indicating that HS-1793 overcomes the resistance conferred by Bcl-2 in U937 cells via 14-3-3. We also observed that HS-1793 exerts its antitumor activity via Bad. However, overall data obtained from methylation specific PCR, RT-PCR and real-time PCR suggest that HS-1793 plays a role in the downregulation of 14-3-3 at a post-transcriptional level. Further understanding exactly how HS-1793 overcomes the resistance conferred by Bcl-2 via 14-3-3 may guide the development of future anticancer agents.

Rare Exonic Minisatellite Alleles in MUC2 Influence Susceptibility to Gastric Carcinoma

Background Mucins are the major components of mucus and their genes share a common, centrally-located region of sequence that encodes tandem repeats. Mucins are well known genes with respect to their specific expression levels; however, their genomic levels are unclear because of complex genomic properties. In this study, we identified eight novel minisatellites from the entire MUC2 region and investigated how allelic variation in these minisatellites may affect susceptibility to gastrointestinal cancer. Methodology/Principle Findings We analyzed genomic DNA from the blood of normal healthy individuals and multi-generational family groups. Six of the eight minisatellites exhibited polymorphism and were transmitted meiotically in seven families, following Mendelian inheritance. Furthermore, a case-control study was performed that compared genomic DNA from 457 cancer-free controls with DNA from individuals with gastric (455), colon (192) and rectal (271) cancers. A statistically significant association was identified between rare exonic MUC2-MS6 alleles and the occurrence of gastric cancer: odds ratio (OR), 2.56; 95% confidence interval (CI), 1.31–5.04; and p = 0.0047. We focused on an association between rare alleles and gastric cancer. Rare alleles were divided into short (40, 43 and 44) and long (47, 50 and 54), according to their TR (tandem repeats) lengths. Interestingly, short rare alleles were associated with gastric cancer (OR = 5.6, 95% CI: 1.93–16.42; p = 0.00036). Moreover, hypervariable MUC2 minisatellites were analyzed in matched blood and cancer tissue from 28 patients with gastric cancer and in 4 cases of MUC2-MS2, minisatellites were found to have undergone rearrangement. Conclusions/Significance Our observations suggest that the short rare MUC2-MS6 alleles could function as identifiers for risk of gastric cancer. Additionally, we suggest that minisatellite instability might be associated with MUC2 function in cancer cells.

Minisatellite polymorphisms of the SLC6A19 : Susceptibility in hypertension

The SLC6A19 is a human homolog of B(0)AT1 that encodes a neutral amino acid transporter. We examined the distribution of VNTR (variable number of tandem repeats; minisatellites) and conducted polymorphic analysis of SCL6A19 isolated from the genomic DNA of controls and multi-generational families. The SLC6A19 was found to contain seven blocks of minisatellites, 3 of which (SLC6A19-MS1, -MS4, and -MS7) showed polymorphism and were found to be transmitted through meiosis following Mendelian inheritance in seven families. These minisatellite polymorphisms may be useful markers for paternity mapping and DNA fingerprinting. Furthermore, we conducted a case-control study in which genomic DNA from 400 controls and 205 cases with essential hypertension was compared. A statistically significant association was identified between rare SLC6A19-MS7 alleles and the occurrence of hypertension (odds ratio, 7.87; 95% confidence interval, 0.88-70.66; and p=0.028). These findings suggest that the rare SLC6A19-MS7 allele may be a risk factor for hypertension.

Short rare MUC6 minisatellites-5 alleles influence susceptibility to gastric carcinoma by regulating gene.

The human MUC6 gene, which is reported to be expressed in the stomach and gall bladder, is clustered on chromosome 11p15.5 with other secreted mucins. In this study, the genomic structure of MUC6 has been analyzed and five VNTR (minisatellites; MS1–MS5) were identified. These minisatellites were analyzed in genomic DNA extracted from 1,103 controls, 470 gastric cancer patients, and multigenerational families. Five novel minisatellites were found to be polymorphic and transmitted through meiosis by Mendelian inheritance in families. We evaluated allelic variation in these minisatellites to determine if such variation affected the susceptibility to gastric cancer. A significant association (odds ratio [OR]=7.08) between short rare MUC6–MS5 alleles and relative risks were observed for gastric cancer (95% confidence interval [CI], 1.43–35.19; P=0.005). To investigate the function of minisatellite alleles of MUC6–MS5, we examined the effects on gene expression from luciferase reporters when inserted with minisatellites. Interestingly, when the shortest allele (7TR) was inserted in the promoter, the expression level decreased over 20‐fold (P<0.001) in normal and cancer cell lines. Furthermore, the cancer‐specific rare allele (TR8) also showed decreased expression levels in cancer cells. Therefore, we suggest that the short rare MUC6–MS5 alleles may be related to cancer development by the regulation of MUC6 expression. Hum Mutat 31:1–8, 2010.

Analysis of VNTRs in the solute carrier family 6, member 18 (SLC6A18) and lack of association with hypertension.

We report here the distribution of VNTRs (variable number of tandem repeats; minisatellites) and polymorphic analysis of SLC6A18, which is a member of the SLC6 Na(+)- and Cl(-)-dependent neurotransmitter transporter family. In this study, DNA was obtained from 300 unrelated individuals and 205 patients with essential hypertension (EH). We then analyzed the VNTRs in the genomic DNA by searching for minisatellites of SLC6A18 using the Tandem Repeat Finder program. Eight novel VNTRs were identified: five of which were polymorphic minisatellites (SLC6A18-MS1, -MS2, -MS4, -MS5, and -MS6) and three of which were monomorphic minisatellites (SLC6A18-MS3, -MS7, and -MS8). Next, we investigated the relationship between EH and four of the polymorphic minisatellites (SLC6A18-MS1, -MS2, -MS4, and -MS6). We excluded SLC6A18-MS5 from the common/rare allele analysis, because most individuals were heterozygous and hypervariable for this locus. There were no significant differences observed in the overall distribution of these minisatellites, which indicates that these polymorphisms are not responsible for EH susceptibility in the Korean population. A segregation analysis of the minisatellites in SLC6A18 was then conducted by analyzing genomic DNA obtained from two generations of five families and from three generations of two families. The five polymorphic minisatellites were transmitted through meiosis following Mendelian inheritance, which suggests that polymorphic minisatellites could be useful markers for paternity mapping and DNA fingerprinting. In summary, we discovered five novel VNTR polymorphisms in SLC6A18; however, these variations were not associated with EH.

Deletion Polymorphism of UGT2B17 and Its Relation to Lung Cancer

Glucuronidation is a major pathway for NNAL [4-(methylnitrosamno)-1-(3-pyridyl)-1-butanol] and UGT2B17 (UGT, uridine diphospho-glucuronosyltransferase) is from the UGT2B family that glucuronidates carcinogens. UGT2B17 deletion was associated with decreased levels of NNAL and with increased risk of some cancers. The UGT2B17 gene varies in copy number from zero to two per individual in humans. To examine whether UGT2B17 gene deletion is associated with the risk of lung cancer, we investigated copy number variants (CNV) in 271 cancer-free controls and 176 cases of lung cancer in Koreans by a PCR-based method. The frequency of the UGT2B17 deleted alleles was much higher than in other Caucasian and African-American groups which have already been reported. While only up to 10% of Caucasians have zero copies of the gene, up to 74% of Koreans in this study showed that both copies of the gene were deleted. Furthermore, the overall frequency of this dual deletion in female groups was higher than in male groups. However, there was no association between CNV in UGT2B17 and lung cancer. This result suggested that the UGT2B17 deletion allele was not associated with the susceptibility of lung cancers in the Korean group. However, this UGT2B17 CNV polymorphism may be a useful marker for evolutionary analysis among races.

Abstract 1994: Mediators responsible for the invasive progression of superficial bladder cancers

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Bladder cancer is seventh most prevalent type of cancer worldwide and accounts for an estimated 150,000 deaths annually. Urothelial carcinoma of the bladder accounts for more than 90% of bladder cancers. This cancer presents as a heterogeneous disease that consists of two main phenotypic groups with distinct biological behaviors and prognoses: Approximately 80% of patients have tumors that are superficial or non-muscle invasive, and the remaining 20% of tumors presents as a muscle-invasive tumor with dismal prognosis. After early treatment by surgical resection and intravesical immunotherapy, around 20% of these patients have disease progression to invasive tumors and eventually die of the disease. Current methods of predicting the clinical behavior of these tumors prospectively are unreliable. Due to the progress of superficial bladder cancer into invasive bladder cancer, a development of marker that could identify superficial cancers with a high risk of progression is needed. In our microarray analysis from 165 bladder cancer patients, supervised analysis of gene expression data revealed a gene expression signature that is strongly associated with invasive bladder tumors. Gene network analyses of the signature revealed that E2F1 and its downstream effectors EZH2 and SUZ12 could be important mediators for the invasive and metastatic progression of superficial tumors. Furthermore, we investigated how these genes may affect the invasive and metastatic progression of superficial tumors. We investigated the invasive ability by these genes in two groups of bladder cancer cell lines: One group (UC9 and UC14) has a superficial signature of bladder cancer, and the other group (EJ and UC13) has an invasive signature of bladder cancer. We examined the effects of overexpression or siRNA inhibition of these genes on cell growth, wound healing migration and invasion in bladder cancer cell lines. We will report the results estimating the roles of these genes for the invasive and metastatic progression in bladder cancer cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1994.

Minisatellite 5 of SLC6A18 (SLC6A18-MS5): Relationship to Hypertension and Evolutional Level

SLC6A18, one of the neurotransmitters, was reported the possible relationship to hypertension, and it contained eight blocks of minisatellites. In this study, SLC6A18-MS5 sequence which showed the highest heterozygosity among seven minisatellites was analyzed using the Transfac software, the putative binding sites for the transcription factor Pax4 and HNF4 were discovered as a result. The HNF4 is involved in the diabetes pathway and suggested the relationship to hypertension. Thus, we investigated the putative functional significance of allelic variation in this minisatellites with respect to susceptibility for hypertension. To address this possibility, we analyzed genomic DNA from the blood of 301 hypertension-free controls and 184 cases with hypertension. A statistically significant association was not identified between the allelic distribution of SLC6A18-MS5 and occurrence of hypertension. We then examined the meiotic segregation of SLC6A18-MS5 and it was transmitted following Mendelian inheritance. Therefore, this locus could be useful markers for paternity mapping and DNA fingerprinting. Moreover, we undertook a comprehensive analysis of the genomic sequence to address the evolutionary events of these variable repeats. SLC6A18 minisatellites regions are only conserved in human and primates. This result suggestedthat intronic minisatellites analysis is powerful evolution marker for the non-coding regions in primates and can provide a great insight to the molecular evolution of repeated region in primates.