Intestinal Research

Polymorphisms in PRKCDBP, a Transcriptional Target of TNF-α, Are Associated With Inflammatory Bowel Disease in Korean: Jung-Wook Kim, Chang Kyun Lee, Hyo Jong Kim, Jae-Jun Shim, Jae Young Jang, Seok Ho Dong, Byung-Ho Kim, Young Woon Chang, Sung-Gil Chi; Intest Res 2015;13(3):242-249. Published online June 9, 2015; DOI: https://doi.org/10.5217/ir.2015.13.3.242

<b>Background/Aims</b><br/>

Emerging data indicate that polymorphic sequence variations in the tumor necrosis factor alpha (TNF-α) gene may affect its production, and be associated with the risk of inflammatory bowel disease (IBD). PRKCDBP is a putative tumor suppressor gene and a transcriptional target of TNF-α. The aim of this case-control study is to explore the possible association of single nucleotide polymorphisms (SNPs) in PRKCDBP with the development of IBD in Koreans.

Methods

Genotyping analysis of four SNPs of PRKCDBP [rs35301211 (G210A), rs11544766 (G237C), rs12294600 (C797T), and rs1051992 (T507C)] was performed on 170 ulcerative colitis (UC),131 Crohn's disease (CD) patients, and 100 unrelated healthy controls using polymerase chain reaction and restriction fragment length polymorphism.

Results

Heterozygous configuration of three SNPs (G210A, G237C, and C797T) was very rare in both patients and healthy controls. However, allele frequencies of the T507C SNP showed a significant difference between UC patients and controls (P=0.037). The CC genotype of the T507C SNP was identified in 46.6% (61 of 131) of CD and 49.4% (84 of 170) of UC patients, but only in 33.0% (33 of 100) of healthy controls. Furthermore, CC homozygosity was more prevalent than TC heterozygosity in both CD and UC patients versus controls (P=0.016; gender-adjusted odds ratio [aOR], 2.16; 95% confidence interval [CI], 1.16-4.04 and P=0.009; aOR, 2.09; 95% CI, 1.193.64; respectively)

Conclusions

Our results suggest that the T507C SNP in PRKCDBP, a TNF-α-inducible gene, might be associated with susceptibility to IBD (particularly UC) development in Koreans.

Citations

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Molecular Characterization of hSRBC, a Candidate Tumor Suppressor Gene anda Upstream Regulator of p53 in Human Colon Cancer: Wan Jung Kim, Hyo Jong Kim, Sung-Gil Chi, Jin Oh Kim, Joo Young Cho, Chan Sup Shim; Intest Res 2007;5(2):131-143. Published online December 30, 2007

Abstract PDF: Background/Aims
hSRBC [human Serum deprivation response (sdr)-Related gene product that Binds to c-kinase] was identified using PKCδ or BRCA1 as a probe and located at 11p15.5-p15.4 region. Expression of hSRBC protein was also decreased in a number of breast, lung, and ovarian cancer cell lines, suggesting that hSRBC might be a putative tumor suppressor gene. Methods: The expression status of hSRBC was analyzed in 50 primary colon tumors and their adjacent 50 normal tissues, and 20 colon cancer cell lines. Transcript and protein expression of hSRBC was studied by quantitative RT-PCR and Western blot, respectively. siRNA-mediated knockdown of hSRBC expression was utilized to investigate its association with p53. Results: The mRNA expression of hSRBC was decreased in 60% (12/20) of colon cancer cell lines and 44% (22/50) of patient's colon cancer tissues. Expression of hSRBC mRNA was significantly decreased in tumors compared to non-cancerous cells, while genomic level of hSRBC was not decreased in tumors. hSRBC expression was increased by 5-aza-2’-deoxycytidine treatment and hypermethylation of CpG sites was strongly associated with decreased expression. Ectopic transfection of hSRBC suppressed RKO cell count and hSRBC knockdown by siRNA augmented HCT116 cell numbers. Flow cytometry showed G1 arrest and apoptosis of colon cancer cells by restoration of hSRBC expression in RKO cells. Both basal and etoposide-mediated p53 expression was decreased when hSRBC expression was knockdowned with siRNA. Conclusions: hSRBC expression is frequently decreased by promoter CpG site hypermethylation. hSRBC down-regulates p53 expression in G1 phase and might be a novel upstream regulator of p53. (Intest Res 2007;5:131-143)

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Mutational Analysis of MYH in Patients with Multiple Sporadic Adenomatous Polyps in Korea: Hansoo Kim, Hyo-Jong Kim, Sung-Gil Chi, Gwang-Ro Joo, Seok-Ho Dong, Byung-Ho Kim, Young-Woon Chang, Jung-Il Lee, Rin Chang; Intest Res 2005;3(1):27-32. Published online June 30, 2005

Abstract PDF: Background/Aims
Recently, germ-line mutation in the base-excision-repair gene MYH was identified to cause a novel autosomal recessive form of familial adenomatous polyposis (FAP). Interestingly, a striking evidence for MYH mutations within different ethnic groups has been demonstrated. We have screened 30 patients with multiple adenomatous polyps for MYH mutations to assess its prevalence and ethnic specificity in Korea. Methods: Thirty patients with multiple adenomatous polyps were examined for MYH mutations. Twenty-one men and 9 women presented at a median age of 62.3 years. The mean number of adenomas per patient was 10.0. Sixteen exonic regions and its intronic sequences were amplified by PCR and subjected to SSCP and DNA sequencing analyses. Results: None of the patients was identified to carry any truncating or sequence alterations in MYH. Our screening for the mutational regions, which were recognized from Caucasian patients or affected Indian families, also failed to detect sequence substitutions. Conclusions: Mutation in MYH may be rarely involved in the pathogenesis of multiple sporadic colorectal adenomas in Korea, although large-scale analysis will be required to clarify the presence of specific MYH variants in a subset of patients and its role for the predisposition of multiple colorectal adenomas in Korea. (Intest Res 2005;3:27-32)

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A Roles of Apoptotic Genes in Colon Cancers: Jae Young Jang, Hyo Jong Kim, Sung-Gil Chi, Kil Yeon Lee, Ki Deuk Nam, Nam Hoon Kim, Sang Kil Lee, Kwang Ro Joo, Seok Ho Dong, Byung-Ho Kim, Young Woon Chang, Joung Il Lee, Rin Chang; Intest Res 2004;2(2):71-76. Published online December 22, 2004

Abstract PDF: Badkground/Aims: X-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family that exerts antiapoptotic effects. Recently, XIAP-associated factor 1 (XAF1) and two mitochondrial proteins, Smac/DIABLO and HtrA2, have been identified to negatively regulate the caspase-inhibiting activity of XIAP. We explored the candidacy of XAF1, Smac/DIABLO and HtrA2 as a tumor suppressor in colonic carcinogenesis. Methods: The expression and mutation status of the genes were assessed in 10 colorectal carcinoma cell lines. Results: XAF1 transcript was not expressed or present at extremely low levels in 60% (6/10) of cancer cell lines whereas Smac/DIABLO and HtrA2 are normally expressed in all cell lines examined. XAF1 transcript was reactivated in all low expressor cell lines by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Moreover, bisulfite DNA sequencing analysis for 34 CpG sites in the promoter region revealed a strong association between hypermethylation and gene silencing. Restoration of XAF1 expression resulted in enhanced apoptotic response to etoposide and 5-flurouracil. Conclusions: XAF1 undergoes epigenetic gene silencing in a considerable proportion of human colon cancers by aberrant promoter hypermethylation, suggesting that XAF1 inactivation might be implicated in colonic tumorigenesis. (Intestinal Research 2004;2:71-76)

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A Case of APC, MMR, MYH negative Turcot's Syndrome: Han Soo Kim, Hyo Jong Kim, Sung-Gil Chi, Ki-Duk Nam, Jae-Young Jang, Nam-Hun Kim, Sang-Kil Lee, Kwang-Ro Joo, Seok-Ho Dong, Byung-Ho Kim, Young-Woon Chang, Joung-Il Lee, Rin Chang; Intest Res 2004;2(2):113-119. Published online December 22, 2004

Abstract PDF: Turcot's syndrome, clinically characterized by the coincident occurrence of primary tumors of the colon and the central nervous system (CNS) typically a glioblastoma or a medulloblastoma, can genetically be divided into two syndromes: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon carcinoma (HNPCC). We previously have reported the first case of Turcot's syndrome in Korea associated with cerebral oligodendroglioma. We also have performed genetic analyses of this patient and her family to determine the genetic variants, including mutations in APC gene and mismatch repair gene, in Turcot's syndrome. Recently, germ-line mutation in the base- excision-repair gene MYH was identified to cause a novel autosomal recessive form of FAP. The discovery of MYH polyposis suggests that patients with FAP phenotype, and with a negative APC gene will need genetic testing for MYH mutation. Interestingly, a striking evidence for specific MYH mutations within different ethnic groups has been noted. Therefore, we have analyzed an APC-negative patient with Turcot's syndrome for mutation in MYH gene to assess its possible prevalence and ethnic specificity in Korea. (Intestinal Research 2004;2:113-119)

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Genetic Analysis in a Case of Turcot's Syndrome Associated with Cerebral Oligodendroglioma: Han Soo Kim, Ji Young Park, Hyo Jong Kim, Sung-Gil Chi, Yoon Hwa Kim, Kil Yeon Lee, Yong Hee Joung, Yo Seb Han, Seok Ho Dong, Byung Ho Kim, Young Woon Chang, Joung Il Lee, Rin Chang; Intest Res 2003;1(2):192-196. Published online November 27, 2003

Abstract PDF: Turcot's syndrome (TS) is a genetic disease characterized by primary brain tumor, colon cancer and/or multiple colorectal polyps. The mode of genetic transmission of the syndrome still remains unclear because TS is a rare disorder. The majority of central nervous system (CNS) neoplasms associated with TS are glioma, glioblstoma multiformes and medulloblastoma. Other types of CNS tumors related to TS have been noted in a few case reports, and there are only two reports of oligodendroglioma associated with TS. To the authors' knowledge, this is the first case of a patient with TS who had a cerebral oligodendroglioma and a colorectal adenocarcinoma in Korea. Therefore, the authors performed genetic analysis of this patient and her family to determine the genetic variants, including mutations in APC gene and mismatch repair gene, in Turcot's syndrome. (Intestinal Research 2003;2:192-196)

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