The Korean Society of Gastroenterology & SIDDS 2034 : Slide Session ;K-LG-05 : Lower GI Tract ; Heme Oxygenase-1 Enhances Metastatic Properties of Colon Cancer Through Cancer Cell Escape from Immunological Recognition and Decrease Effector T Cells Recruit

( Geom Seog Seo ),( Suck Chei Choi ),( Wen Yi Jiang ),( Hao Jin ),( Jin Hua Chi ),( Sung Hee Lee ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: A growing body of evidence indicates that HO-1 activation may play a role in carcinogenesis and can potently infi uence the growth and metastasis of tumors.In this study, we investigated the metastatic potential of HO-1 focused on modulation of immunogenicity in colon cancer cells. Methods: By using colon cancer cell lines, HT-29 and Caco-2, the effect of HO-1 on intercellular adhesion molecule-1 (ICAM-1) expression, cell matrix attachment and cancer cell immunogenicity were investigated. In addition, we determined whether the expression of effector T cells (Teff)- and regulatory T cells (Treg)-recruiting chemokines are regulated by HO-1 in HT-29 cells. Results: HO-1 induction by treatment with hemin down-regulated ICAM-1 protein expression in colon cancer cells in dose-dependent way, whereas hemin did not reduce ICAM-1 mRNA expression. HO-1 decreases ICAM-1 expression via tristetraprolin (TTP), an mRNA-binding protein that destabilizes ICAM-1 mRNA. The adhesion of peripheral blood mononuclear lymphocytes (PBMLs) to HT-29 and HT-29 cytotoxicity during co-culture with PBMLs were remarkably decreased by treatment with hemin. In addition, Teff-recruiting chemokines, CCL5 and CXCL10 expressions signifi cantly decreased by hemin in HT-29 cells, whereas hemin did not infi uence CCL22 expression, which is Treg-recruiting chemokine. IFN-γ-induced CXCL10 mRNA expression and protein secretion was also inhibited by hemin in a dose-dependent manner. In contrast, CXCL10 mRNA and protein secretion were up-regulated in HT-29 cells transfected withHO-1-specifi c siRNA, which potentiated IFN-γ-stimulation. Conclusions: The present study suggested that decreased ICAM-1 expression and Teff-recruiting chemokines expression by hemin contributes to cancer cell detach from the primary tumor mass and escape from immunological recognition and cytotoxicity by host effector cells, which may provide a mechanism of HO-1 in the tumor progression and metastasis of colon cancer.

Hirsutenone reduces deterioration of tight junction proteins through EGFR/Akt and ERK1/2 pathway both converging to HO-1 induction

( Geom Seog Seo ),( Wen Yi Jiang ),( Pil Hoon Park ),( Dong Hwan Sohn ),( Jae Hee Cheon ),( Sung Hee Lee ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0

Oxidative stress-induced disruption of epithelial tight junctions (TJ) plays a critical role in the pathogenesis of intestinal disorders, including inflammatory bowel disease (IBD). The current study investigated the protective effect of hirsutenone against disruption of the intestinal barrier in vitro and in a mouse model of colitis. Caco-2 cells were stimulated with tert-butyl hydroperoxide (t-BH). Hirsutenone prevented the t-BH-induced increase in permeability by inhibiting the reduction in zonula occludens-1 (ZO-1) expression, and rapidly stimulated tyrosine phosphorylation of the epidermal growth factor receptor (EGFR). Hirsutenone-mediated protection against the loss of ZO-1 depends on the activation of both ERK1/2 and Akt signaling pathways. Interestingly, hirsutenone-mediated activation of Akt, but not ERK1/2, signaling was EGFR-dependent. Hirsutenone increased heme oxygenase-1 (HO-1) expression through both EGFR/Akt- and ERK1/2-dependent pathways, contributing to the protective effects against TJ dysfunction. Colitis was induced in mice by intrarectal administration of 2,4,6,-trinitrobenzene sulfonic acid (TNBS). Hirsutenone administration improved the clinical parameters and tissue histological appearance, increased HO-1 expression, attenuated reduction of ZO-1 and occludin mRNA, and promoted BrdU incorporation in the colonic epithelium of TNBS-treated mice. Taken together, our results demonstrate that hirsutenone reverse disordered intestinal permeability by activating EGFR/Akt and ERK1/2 pathways, which are involved in the regulation of HO-1 expression. These findings highlight the potential of hirsutenone for clinical applications in the treatment of IBD.ⓒ2014 Elsevier inc All rights reserved.

Original Articvle : The Prevalence of Erosive Esophagitis Is Not Significantly Increased in a Healthy Korean Population -Could It Be Explained?: A Multi-center Prospective Study

( Geom Seog Seo ),( Byung Jun Jeon ),( Jin Soo Chung ),( Young Eun Joo ),( Gwang Ha Kim ),( Gwang Ho Baik ),( Dae Yong Kim ),( Jeong Eun Shin ),( Heung Up Kim ),( Hyun Kyung Park ),( Nayoung Kim ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2013 Journal of Neurogastroenterology and Motility (JNM Vol.19 No.1

Background/Aims Researches on the potential risk factors for the development of erosive esophagitis have been conducted extensively, however, the results are conflicting. The aim of this multicenter study was to identify the prevalence rate and risk factors of erosive esophagitis and their interactions with residency status. Methods A total of 4,023 eligible subjects at 8 tertiary health care centers were evaluated using questionnaires, laboratory tests and endoscopy. Univariate and multivariate analyses were conducted to identify independent risk factors for erosive esophagitis. Results The prevalence rate of reflux esophagitis was 8.8%. Los Angeles grade A was common type of erosive esophagitis. Residence in a large urban areas was negatively associated with the development of erosive esophagitis (OR, 0.60; 95% CI, 0.40-0.90). The high body mass index (≥ 25 kg/m2) was more frequent in residents of small and medium-sized cities than those in big cities (38.8% and 26.9%, respectively; P < 0.001). Seronegativity of Helicobacter pylori was associated with increased erosive esophagitis (OR, 1.91; 95% CI, 1.48-2.46). Triglyceride ≥ 150 mg/dL (OR, 1.65; 95% CI, 1.08-2.07), fasting glucose level ≥ 126 mg/dL (OR, 1.73; 95% CI, 1.06-2.81), and hiatal hernia (OR, 3.11; 95% CI, 1.87-5.16) were also associated with erosive esophagitis. Conclusions The prevalence rate of erosive esophagitis and its risk factors in this study were similar to the result of 8.0% of nationwide study in 2006. Residency and obesity are more important independent risk factors than H. pylori infection status for development of erosive esophagitis in Korea. These results suggest that the prevalence rate of erosive esophagitis in Korea might not increase as in the Western countries. (J Neurogastroenterol Motil 2013; 19:70-77).

Identification of the polymorphisms in IFITM3 gene and their association in a Korean population with ulcerative colitis

Geom Seog Seo,최석채,Jeong Kun Lee,Ji In Yu,윤기중,채수천 생화학분자생물학회 2010 Experimental and molecular medicine Vol.42 No.2

Interferons play critical roles in tumor pathogenesis by controlling apoptosis and through cellular anti-proliferative and differentiation activities. Interferon inducible transmembrane protein (IFITM) family genes have been implicated in several cellular processes such as the homotypic cell adhesion functions of IFN and cellular anti-proliferative activities. Expression levels of IFITM genes have been found to be up-regulated in gastric cancer cells and colorectal tumors. IFITM3 (also known as 1-8U) is a member of the IFITM family, and has been described as a key player in specification of germ cell fate. IFITM3 was first isolated from a genetic screen aimed at identifying genes involved in acquisition of germ cell competence. It has been proposed that epiblast cells have the highest expression of IFITM3 initiated germ cell specification and that homotypic association can discriminate germ cells from their somatic neighbors. In an attempt to better understand the genetic influences of IFITM3 on ulcerative colitis, we have identified possible variation sites and single nucleotide polymorphisms (SNPs) through two exons and their boundary IFITM3 intron sequences including the ∼2.1 kb promoter regions. To determine whether or not these IFITM3 SNPs are associated with susceptibility to ulcerative colitis, frequencies of the genotype and allele of IFITM3 polymorphisms were analyzed on genomic DNAs isolated from patients with ulcerative colitis and from healthy controls. We also investigated the haplotype frequencies constructed by these SNPs in both groups. In this study, we also showed that expression level of IFITM3 mRNA was significantly higher in tissues of the ileum and cecum of the digestive system. We identified a total of seven SNPs and multiple variation regions in the IFITM3 gene. The genotype frequency of the g.-204T>G polymorphism in patients with ulcerative colitis was significantly different from that of the control group. Our results strongly suggest that polymorphisms of the IFITM3 gene may be associated with susceptibility to ulcerative colitis.

Medicinal Chemistry : Heme oxygenase-1 promotes tumor progression and metastasis of colorectal carcinoma cells by inhibiting antitumor immunity

( Geom Seog Seo ),( Wen Yi Jiang ),( Jin Hua Chi ),( Hao Jin ),( Won Chul Park ),( Dong Hwan Sohn ),( Pil Hoon Park ),( Sung Hee Lee ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-

Heme oxygenase-1 (HO-1) is upregulated in colorectal carcinoma (crc) cells.However, the role of HO-1 in the metastatic potential of CRC remains to be elucidated.In this study, we inves tigated the potential of HO-1 to control the antitumor immunity of CRC.Intercellular adhesion molecule-1(ICAM-1)plays an important role in the immune surveillance system. Hemin-induced HO-1 expression suppressed the expression of ICAM-1 in human CRC cells. HO-1 regulated ICAM-1 expression via tristetraprolin, an mRNA-binding protein, at the posttranscriptional level in CRC cells. The upregulated HO-1 espression in CRC cells markedly decreased the adhesion of peripheral blood mononuclear lymphocytes (PBMLs) to CRC cells and PBML-mediated cytotoxicity against CRC cells. Production of CXCL10, an effector T cell-recruiting chemokine, was significantly reduced by the increased HO-1 expression. The expression of the CXCL10 receptor, CKCR3, decreased significantly in PBMLs that adhered to CRC cells. HO-1 expression correlated negatively, although nonsignificantly, with ICAM-1 and CXCL10 expression in xenograft tumors. Taken together, our data suggest that HO-1 expression is functionally linked to the mediation of tumor progression and metastasis of CRC cells by inhibiting antitumor immunity.

The efficacy mechanism of rebamipide in TNBS-induced colitis model of Balb/c mice

( Seo Geom Seog ),( Jay Min Oh ),( Yeon Hwa Kim ),( Sang Wook Kim ),( Yong Sung Kim ),( Joo Jin Yeom ),( Tae Hyeon Kim ),( Suck Chei Choi ),( Chang Duk Jun ),( Yong Ho Nah ) 대한소화기학회 2003 대한소화기학회 추계학술대회 Vol.2003 No.-

<Background & aims> Crohn`s disease is a chronic debilitating disease of unknown etiology that is characterized by severe inflammation of the colon. Rebamipide has recently emerged as a promising candidate for treatment of gastric ulcer. The goal of this

Expression of Proteinase-Activated Receptor 2 in Ulcerative Colitis

( Geom Seog Seo ),( Sang Wook Kim ),( Kyo Sang Yoo ),( Young Woo Sohn ),( Tae Hyeon Kim ),( Suck Chei Choi ),( Yong Ho Nah ),( Ki Jung Yun ),( Jin A Kim ),( Young Mi Lee ) 대한소화기학회 2002 대한소화기학회 추계학술대회 Vol.2002 No.-

REVIEW : Clostridium difficile Infection: What`s New?

( Geom Seog Seo ) 대한장연구학회 2013 Intestinal Research Vol.11 No.1

Since 2000, Clostridium difficile infection has increased substantially in both hospital-acquired and community-acquired diarrhea, not only in North America but also in Europe. There was a steady increase in the incidence and severity of C. difficile infection over the past decade, associated with significantly higher morbidity and mortality. The major risk factors for C. difficile infection appear to be the use of new antimicrobial therapy, long-term hospitalization in old age and emerging hypervirulent strains, such as various ribotypes. Rapid and accurate diagnosis of C. difficile infection is necessary for appropriate treatment as well as reliable epidemiological data. Currently available treatment options are withdrawal of the suspected offending antibiotics and then treating patients with highly effective antibiotics for C. difficile. Multiple recurrence or acute fulminant C. difficile infection could be treated with fecal microbiota transplantation. Promising therapies for treating C. difficile infection should always be equipped with high efficacy and safety in the future. (Intest Res 2013;11:1-13)

아스피린을 장기간 복용하면 대장암 발생 및 사망을 감소시킬 수있는가?: 5개의 무작위 대조연구를 20년간 추적관찰

서검석 ( Geom Seog Seo ) 대한장연구학회 2010 Intestinal Research Vol.8 No.2

1,000명 이상의 사람을 등록하였고, 아스피린을 2.5년 이상 사용한 기준을 만족시키는 5개의 무작위 시험을 선택하였으나, 이 중 하나의 시험(Dutch TIA 아스피린 시험, 283 mg vs 30 mg daily)은 기록의 파기로 인해 제외시켰다. 네 개의 무작위 시험은 Thrombosis prevention trial (TPT), Swedish aspirin low dose trial (SALT), UK-TIA aspirin trail (UK-TIA), British doctor aspirin trial (BDAT)이었다. TPT와 BDAT는 일차 예방효과를, SALT와 UK-TIA는 이차 예방효과를 측정하였다. TPT의 경우 1989-92년에 걸쳐 환자를 등록 (2545/2540)하였고, 아스피린 하루 75 mg/위약으로 구분하였다. SALT의 경우 1984-89년에 걸쳐 환자를 등록(676/684)하였고, 아스피린 하루 75 mg/위약으로 구분하였다. UK-TIA의 경우 1979-85년에 걸쳐 환자를 등록(811/821/817)하였고, 아스피린 하루 300 mg/1,200 mg/위약으로 구분하였다. BDAT의 경우 1978-79년에 걸쳐 환자를 등록(3429/1710)하였고, 아스피린 하루 500 mg/대조군으로 구분하였다. 사망진단서 및 암 등록을 통하여 추적 관찰하였다. 네 개의 무작위 임상시험 등록 인원 14,033명 중391명(2.8%)에서 대장암이 발생하였고 중앙 추적기간은 18.3년이었다. 아스피린 복용 군에서 대장암의 발생 및 사망 위험은 감소(발생 위험도 0.76, 0.60-0.96, P=0.02; 사망 위험도 0.65, 0.48-0.88, P=0.005)하였으나, 직장암 발생 군에서 아스피린 복용은 위험도 감소효과가 없었다(0.90, 0.63-1.30, P=0.58; 0.80, 0.50-1.28, P=0.35). 아스피린 복용 군에서 근위부 대장암 발생의 위험도를 낮추었으나(0.45, 0.28-0.74, P=0.001; 0.34, 0.18-0.66, P=0.001), 원위부 대장암의 위험도는 낮추지 못하였다(1.10, 0.73-1.64, P=0.66; 1.21, 0.66-2.24, P=0.54; 발생률 차이[incidence difference] P=0.04, 사망률 차이[mortality difference] P=0.01). 그러나 아스피린 복용을 5년 이상 유지한 사람(schedule treatment ≥5 years)을 대상으로 다시 정리하면 근위부 대장암 발생은 70% 가량 감소하였고(0.35, 0.20-0.63; 0.24, 0.11-0.52; 양쪽 모두 P<0.0001), 직장암 발생도 감소하였다(0.58, 0.36-0.92, P=0.02; 0.47, 0.26-0.87, P=0.01). 아스피린 복용을 5년간 유지한 후 20년 동안 경과 관찰하였을 때 용량 증량 군(75-300 mg)에서 치명적인 대장암 발생을 줄이지 못하였다(absolute reduction 1.76%, 0.61-2.91; P=0.001). 그러나 Dutch TIA trial 에서는 아스피린 30 mg 군에서 283 mg 군보다 장기 추적 관찰 시 치명적인 대장직장암 발생 위험이 높았다(교차비 2.02, 0.70-6.05, P=0.15). 결론적으로 하루에 적어도 75 mg의 아스피린을 수년간 복용하면 오랜 기간 후에 발생하는 대장암 발생및 사망을 줄일 수 있고 이러한 효과는 근위부 대장의 암 발생 억제에 효과적이다.

림프구양 여포 직장염 치료에서 메살라진 좌제의 유용성

서검석 ( Geom Seog Seo ),최석채 ( Suck Chei Choi ),조은영 ( Eun Young Jo ),최창수 ( Chang Soo Choi ),김지웅 ( Ji Woong Kim ),김태현 ( Tae Hyeon Kim ),윤기중 ( Ki Jung Yun ),나용호 ( Yong Ho Nah ) 대한소화기학회 2006 대한소화기학회지 Vol.47 No.6

목적: 림프구양 여포 직장염은 매우 드문 염증 질환으로 아직 치료 약제가 정립되어 있지 않으나, 메살라진 좌제 사용 후 호전된 증례가 있어 이에 대한 효과를 알아보고자 하였다. 대상 및 방법: 2001년 1월부터 2003년 11월까지 림프구양 여포 직장염으로 진단 받은 8명의 환자들을 후향 분석하였다. 메살라진 좌제 투여 후 증상 호전과 추적 내시경 검사에서 병변 소실이 있을 때 반응군으로 하였다. 결과: 무증상군 3명, 증상군 5명이었다. 증상군의 경우 간헐적인 혈변이 가장 많았다. 평균 추적 기간 14.1개월(2-35), 증상군의 평균 투약 기간은 12개월(3-31)이었다. 증상군 중 4예는 투여 2주 내에 증상 호전을, 투여 3개월 후 추적 대장내시경에서 결절 병변의 개수 감소와 반흔 형성을 보였다. 증상군 1예에서 500 mg을, 4예에서 250 mg의 메살라진 좌제를 사용하였으며 250 mg을 사용한 1예(증상군 2번 환자)에서 반응군의 정의에 포함되지 않았다. 그러나 치료 종결 시점에서는 5예 모두에서 증상 및 조직소견의 호전을 보였다. 반응군의 경우 조직검사에서 림프구양 여포 과증식과 점막 고유판의 과도한 림프구 침윤 소견도 감소하였고, 무증상군 3예는 추적기간 동안 증상 발현이 없었으며 추적 대장내시경을 시행 받은 1예의 경우 육안 소견의 차이는 없었다. 결론: 메살라진 좌제는 증상이 있는 림프구양 여포 직장염 환자에서 증상 및 조직 소견의 호전을 가져오므로 안전하게 사용할 수 있는 약제다. Background/Aims: Lymphoid follicular proctitis (LFP) is an uncommon inflammatory condition confined to the rectum. Patients with LFP constitute a special group with clinical, endoscopic, and histological features unrelated to other types of inflammatory bowel diseases, and have been reported to be refractory to Local steroid and/or oral sulfasalazine therapy. The aim of this study was to clarify whether mesalazine suppositories have a therapeutic effect in LFP. Methods: The histologic slides of 8 cases indexed in our pathology files as "lymphoid follicular proctitis of the rectal mucosa" from January 2001 to November 2003 were reviewed retrospectively. Results: The most common symptom in the patients with LFP was rectal bleeding. The endoscopic mucosal changes were discontinuous, sparing whole circumferential involvement, and were strictly confined to the rectum. Average period of medication was 12 months. All the symptomatic patients with LFP responded to mesalazine suppository therapy. In addition, these patients did not progress to other disease including ulcerative proctitis or Lymphoma. Conclusions: Mesalazine suppository treatment is a useful therapeutic option for symptomatic patients with LFP. (Korean J Gastroenterol 2006;47:420-424)