Byung Joon Choi

Genetic analysis of the DBC2 gene in gastric cancer

The DBC2 (Deleted in breast cancer, RhoBTB2) has been identified as a tumor suppressor gene that has growth inhibitory function. To investigate whether genetic alterations of the DBC2 gene are involved in the development of gastric cancer, we analyzed mutations and allelic loss in the DBC2 gene in 95 primary gastric cancers by PCR-SSCP, sequencing and LOH analysis. In the mutational analysis, we found one missense somatic mutation (CGG→TGG, R275W) in the BTB/POZ domain of the gene in a patient with advanced gastric cancer and lymph node metastasis. In addition, we found one known polymorphism and three novel polymorphisms in the coding region of DBC2, which showed an amino acid change, and was detected in both the cancer cells and corresponding normal cells. On LOH analysis, 62 cases were heterozygous for at least one marker and 18 cases (29.0%) showed allelic loss at these markers. In conclusion, the mutations and allelic loss in the DBC2 gene are uncommon in gastric cancers in Korean patients. Further studies to identify the target gene at 8q21 responsible for the development of gastric cancer should be explored.

Gastrokine 1 regulates NF-κB signaling pathway and cytokine expression in gastric cancers.

Gastrokine 1 (GKN1) plays an important role in the gastric mucosal defense mechanism and also acts as a functional gastric tumor suppressor. In this study, we examined the effect of GKN1 on the expression of inflammatory mediators, including NF‐κB, COX‐2, and cytokines in GKN1‐transfected AGS cells and shGKN1‐transfected HFE‐145 cells. Lymphocyte migration and cell viability were also analyzed after treatment with GKN1 and inflammatory cytokines in AGS cells by transwell chemotaxis and an MTT assay, respectively. In GKN1‐transfected AGS cells, we observed inactivation and reduced expression of NF‐κB and COX‐2, whereas shGKN1‐transfected HFE‐145 cells showed activation and increased expression of NF‐κB and COX‐2. GKN1 expression induced production of inflammatory cytokines including IL‐8 and ‐17A, but decreased expression of IL‐6 and ‐10. We also found IL‐17A expression in 9 (13.6%) out of 166 gastric cancer tissues and its expression was closely associated with GKN1 expression. GKN1 also acted as a chemoattractant for the migration of Jurkat T cells and peripheral B lymphocytes in the transwell assay. In addition, GKN1 significantly reduced cell viability in both AGS and HFE‐145 cells. These data suggest that the GKN1 gene may inhibit progression of gastric epithelial cells to cancer cells by regulating NF‐κB signaling pathway and cytokine expression. J. Cell. Biochem. 114: 1800–1809, 2013.

Influence of the hTERT rs2736100 polymorphism on telomere length in gastric cancer.

AIM To investigate the functional consequences of rs2736100 polymorphism in telomere length and examine its link to gastric cancer risk. METHODS Telomere length and human telomerase reverse transcriptase (hTERT) mRNA expression were measured in 35 gastric cancer tissues and 5 cell lines and correlated to rs2736100 polymorphism. The relationship between rs2736100 polymorphism and the risk of gastric cancer were examined in 243 gastric cancer patients and 246 healthy individuals. RESULTS The rs2736100 A allele carrier is closely associated with reduced hTERT mRNA expression and shortened telomere length in gastric cancer tissue and cell lines. When gastric cancers were stratified by histological subtype, telomere length and hTERT mRNA levels were significantly increased in those with the C/C genotype in intestinal-type gastric cancer, but not in diffuse-type gastric cancer. Interestingly, there was no significant difference in the genotype and allele frequencies of the rs2736100 polymorphism between the patients with gastric cancer and healthy controls. CONCLUSION The rs2736100 polymorphism of the hTERT gene is involved in the regulation of hTERT expression and telomere length, but not in the risk of gastric cancer.

GKN1 and miR-185 are associated with CpG island methylator phenotype in gastric cancers

Epigenetic modifications including aberrant DNA methylation play a significant role in cancer development. We investigated mRNA expression levels of GKN1, miR-185, DNMT1 and EZH2, as well as their association with the CpG island methylator phenotype (CIMP) in gastric cancers. Twenty-four incident gastric carcinomas were characterized for methylation status and mRNA expression levels of GKN1, miR-185, DNMT1 and EZH2 were examined. In gastric cancer, methylation frequencies in the Mint1, Mint2, E-CDH, hMLH1 and p16 genes were 41.7%, 41.7%, 29.2%, 25% and 4.2%, respectively. At least one gene was methylated in 19 (79.2%) cases. When the methylation status was classified as high (H) and low (L), 11 (45.8%) cases showed CIMP-H. Twentytwo (91.7%) of 24 gastric cancers showed decreased expression of GKN1 and miR-185, compared to samples from the corresponding non-cancerous gastric mucosa. Increased expression of DNMT1 and EZH2 was found in 21 (87.5%) gastric cancers. Statistically, there was a close association between the methylation status and expression levels of GKN1, miR-185, DNMT1 and EZH2 (P<0.05). These results suggest that GKN1 and miR-185 may be representative and predictive biomarkers for methylation status in gastric carcinogenesis.

Genetic association of KCNA5 and KCNJ3 polymorphisms in Korean children with epilepsy

Shaker-like potassium channel and inward rectifying potassium channel are involved in spontaneity of seizure and pharmacoresistant seizure. Kv1.5 (KCNA5) is a Shaker subfamily channel gene. Mutations of Shaker subfamily channels lead to epilepsy. In addition, Kir3.1 inwardly rectifying channel (KCNJ3) is also one of the independent genes associated with seizure susceptibility. We investigated the allele and genotype frequencies of KCNA5 G182R and E211D polymorphisms and KCNJ3 T1505 polymorphism in 160 Korean pediatric epilepsy patients and 369 healthy Korean children. For the KCNA5 gene, the G182R and E211D polymorphisms showed only the C/C genotype in both healthy and epilepsy groups. For the KCNJ3 gene, the frequency of genotype A/A, A/T, and T/T was 142, 16, and 2 in epilepsy and 327, 42, and 0 in healthy individuals, respectively (P<0.05). Polymorphisms of the KCNA5 G182R and E211D and the KCNJ3 T1505 may not be associated with epilepsy in Koreans.

No association of LCT-13910 single nucleotide polymorphism with gastroenteritis in Korean children

Zinc and lactase deficiency are closely associated with the severity of gastroenteritis in children. Absorption of lactose is dependent on lactase and enhances the absorption of zinc. In the present study, we analyzed the association of the lactase (LCT)-13910 polymorphism and serum zinc levels with the severity of gastroenteritis in Korean children. 133 gastroenteritis patients and 476 healthy controls were examined for their LCT-13910 genotype using a polymerase chain reaction-restriction fragment length polymorphism. We also analyzed serum zinc levels in 111 pediatric patients and compared their severity of gastroenteritis. For the LCT-13910 genotype, all of 133 gastroenteritis patients and 476 healthy children had only the C/C genotype, which is associated with lactase deficiency. In addition, 111 pediatric patients showed no deficit of serum zinc and no association with severity of gastroenteritis. These results suggested that LCT-13910 polymorphism and zinc deficit may not be risk factors and that zinc administration may not be needed in Korean pediatric patients with gastroenteritis.