Soo-Young Na

Oxidative stress causes epigenetic alteration of CDX1 expression in colorectal cancer cells.

The intestine-specific transcription factor, caudal type homeobox-1 (CDX1), is a candidate tumor suppressor gene that plays key roles in regulating intestinal epithelial differentiation and proliferation. It is aberrantly down-regulated in colorectal cancers and colon cancer-derived cell lines by promoter hypermethylation. Since the effects of oxidative stress on the transcription of tumor suppressor genes are largely unknown, this study explored the epigenetic alterations that occur during reactive oxygen species (ROS)-induced silencing of CDX1 in colorectal cancer cells. Oxidative stress by hydrogen peroxide (H2O2) down-regulated CDX1 mRNA levels and protein expression in the human colorectal cancer cell line, T-84. This down-regulation was abolished by pretreatment with the ROS scavenger, N-acetylcysteine. In addition, the DNA methylation inhibitor, 5-aza-2-deoxycytidine (5-Aza-dC) markedly attenuated the decrease in mRNA and protein expression levels induced by H2O2. Moreover, methylation-specific PCR data revealed that H2O2 treatment increased CDX1 promoter methylation, and treatment with 5-Aza-dC reversed this effect, suggesting that an epigenetic regulatory mechanism triggered by ROS-induced methylation may be involved in CDX1 expression. Furthermore, H2O2 treatment resulted in up-regulation of DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) expression and activity, and enhanced the association between DNMT1 and HDAC1. Taken together, these results suggest that ROS-induced oxidative stress silences the tumor suppressor CDX1 through epigenetic regulation, and may therefore be associated with the progression of colorectal cancer.

Who should undergo a colonoscopy among patients with incidental colon uptake on PET-CT?

Abstract Objectives. To investigate the optimal cut-off of the maximum standard uptake value (SUVmax) for the detection of colorectal neoplasms and to suggest those for whom further colonoscopy is recommended among patients with incidental colonic uptake on positron emission tomography-computed tomography (PET-CT). Materials and methods. In 306 patients who underwent colonoscopy within 3 months of receiving PET-CT between January and December 2009, measurements of the per-patient and per-lesion diagnostic performance of PET-CT for the detection of colonic neoplasms were obtained. Receiver operating characteristic (ROC) analysis was used to identify the SUVmax that provided a high probability of diagnosing malignancy and high-grade dysplasia. Results. The per-patient and per-lesion PET-CT detection sensitivities for malignancies were 93.3% (28/30; 95% confidence interval (CI) 76.5% to 98.9%) and 93.5% (29/31, 95% CI 77.2% to 98.9%), respectively; the sensitivities for high-grade dysplasia were both 90.0% (9/10; 95% CI 54.1% to 99.5%). As a criterion to specifically detect both malignancy and high-grade dysplasia on focal uptake, a SUVmax greater than 2.5 yielded a 92.3% per-lesion sensitivity and a 42.9% per-lesion positive predictive value (PPV). In the ROC curve analysis, a cut-off value of SUVmax = 5.8 was established, at which the sensitivity, PPV and positive likelihood ratio for diagnosing malignancy and high-grade dysplasia were 71.8% (28/39; 95% CI 54.9% to 84.5%), 84.8% (28/33; 95% CI 67.3% to 94.3%) and 6.9, respectively. Conclusion. The optimal cut-off value to identify a malignancy or high-grade dysplasia was SUVmax = 5.8. However, to avoid missing a malignancy or high-grade dysplasia, a colonoscopy should be performed above a SUVmax = 2.5.

Reduced Autophagy in 5-Fluorouracil Resistant Colon Cancer Cells

We investigated the role of autophagy in SNUC5/5-FUR, 5-fluorouracil (5-FU) resistant SNUC5 colon cancer cells. SNUC5/5-FUR cells exhibited low level of autophagy, as determined by light microscopy, confocal microscopy, and flow cytometry following acridine orange staining, and the decreased level of GFP-LC3 puncta. In addition, expression of critical autophagic proteins such as Atg5, Beclin-1 and LC3-II and autophagic flux was diminished in SNUC5/5-FUR cells. Whereas production of reactive oxygen species (ROS) was significantly elevated in SNUC5/5-FUR cells, treatment with the ROS inhibitor N-acetyl cysteine further reduced the level of autophagy. Taken together, these results indicate that decreased autophagy is linked to 5-FU resistance in SNUC5 colon cancer cells.

Endoplasmic reticulum stress induces 5-fluorouracil resistance in human colon cancer cells

Colon cancer can be treated with 5-fluorouracil (5-FU), but 5-FU resistance frequently occurs. We determined whether 5-FU resistance arises as a result of endoplasmic reticulum (ER) stress. 5-FU-resistant SNUC5 colon cancer cells (SNUC5/FUR cells) expressed higher levels of ER stress-related proteins than drug-sensitive SNUC5 cells. SNUC5/FUR cells also exhibited more intense ER staining and higher level of mitochondrial Ca(2+) overload. SNUC5/FUR cells transfected with siRNA against GRP78, ATF6, ERK, or AKT were more sensitive to 5-FU than siControl RNA-transfected cells. These results suggested that 5-FU resistance was associated with ER stress in colon cancer.

Dictyopteris undulata Extract Induces Apoptosis via Induction of Endoplasmic Reticulum Stress in Human Colon Cancer Cells.

Background: Induction of endoplasmic reticulum (ER) stress-mediated apoptosis in cancer cells represents an alternative approach for cancer therapy. The objective of this study was to elucidate whether ethanol extract of the marine brown alga Dictyopteris undulata can induce apoptosis, via ER stress, in human colon adenocarcinoma cells. Methods: Anti-proliferative activity was evaluated by the colony forming assay. ER stress response was evaluated using flow cytometry and confocal imaging after Rhod2 and ER tracker staining. The expression of ER stress-related proteins was assessed by Western blotting. Results: D. undulata extract (DUE) inhibited colony forming ability in SW480 cells. Furthermore, DUE induced characteristic signs of ER stress: mitochondrial Ca2+ overloading, ER staining, expression of ER stress-related proteins, phosphorylation of RNA-dependent protein kinase-like ER kinase and inositol requiring enzyme 1, cleavage of activating transcription factor 6, and induction of the pro-apoptotic factors, CCAAT/enhancer-binding protein-homologous protein (CHOP) and caspase-12. Moreover, down-regulation of CHOP by siCHOP RNA attenuated DUE-induced apoptosis. Conclusions: The ER stress response plays an important role in DUE-induced apoptosis in human colon cancer cells.

Impact of inflammatory bowel disease on daily life: an online survey by the Korean Association for the Study of Intestinal Diseases

Background/Aims Inflammatory bowel disease (IBD) is a chronic disabling gastrointestinal disorder that diminishes the quality of life of the affected individuals. Limited data are available regarding the impact of IBD on the daily life of Koreans. Methods Self-administered, computer-aided, internet-based questionnaires were distributed to members of a Korean patient organization for IBD from March to April 2013, by the Korean Association for the Study of Intestinal Diseases. Results A total of 599 patients with IBD (387 with Crohns disease [CD] and 212 with ulcerative colitis [UC]) were enrolled. The majority of patients (81%) expressed feelings of fatigue, weakness, and being worn out in their daily lives during times of flare; this percentage was reduced to 61% during remission. Respondents were absent from work or school for an average period of 18 days because of illness, within the first 6 months; the majority of respondents (64%) felt stressed about their absence. Forty-six percent of the respondents reported having received unfair comments at work, or having suffered discrimination. Forty-seven percent of the respondents felt that IBD had negatively affected their income and earnings. Compared with patients with UC, those with CD reported a more frequent negative impact of IBD on work, or more economic burden. More than half of the respondents (61%) reported that IBD had prevented them from making or keeping friends. Conclusions IBD significantly impacts daily life, including work, education, and social relationships. Treatment that addresses the full spectrum of life of a patient would be more effective.

An adequate level of training for technically competent colonoscopic polypectomy.

Abstract Goals. The purpose of this study is to investigate the learning curve for colonoscopic polypectomy (CP) by trainee endoscopists. Background. The amount of training required to achieve technical competence for CP is uncertain. Study. The CP times and en bloc resection rates of three experienced colonoscopists were obtained from 240 procedures. These data were compared to those of three gastroenterology trainees who performed 750 CP procedures. A trainee procedure was deemed to be a success if en bloc resection was obtained and the CP time was within twice the median CP time of the experienced colonoscopists. Trainees were deemed to be technically competent when they achieved a CP success rate of greater than or equal to 80%. Results. The median CP times and en bloc resection rates for the experienced colonoscopists and trainees were 79 s (range, 20–301 s) and 99.6% (239/240), and 118 s (range, 36–1051 s) and 95.6% (717/750), respectively. The trainee success rate of CP was 72% (540/750). The success rate of the procedure was associated with increased trainee experience (p = 0.003) and reached 80% after 250 procedures. The CP time significantly decreased (p < 0.001) and en bloc resection rate significantly increased (p = 0.011) as trainee experience accumulated. The level of experience was an independent predictor for successful CP. Conclusions. The achievement of technical competence with CP was associated with an accumulation of approximately 250 procedures. These findings suggest that dedicated education and training programs for CP are warranted.

Nationwide Multicenter Study for Overlaps of Common Functional Gastrointestinal Disorders in Korean Patients With Constipation

Background/Aims In spite of increased concerns about the overlaps among the various functional gastrointestinal disorders (FGIDs), studies for the overlap between constipation and other common FGIDs are rare. Therefore, we investigated the patterns of overlaps between constipation and other common FGIDs. Methods This study was designed as a prospective nationwide multi-center questionnaire study using Rome III questionnaires for functional dyspepsia (FD), irritable bowel syndrome (IBS), and functional constipation (FC), as well as various questionnaires about patients’ information, degree of symptoms, and quality of life. For the evaluation of gastroesophageal reflux disease (GERD), GERD-Q was used. Results From 19 centers, 759 patients with constipation were enrolled. The proportions of FC and IBS subtypes of constipation (IBS-C) were 59.4% and 40.6%, respectively. Among them, 492 (64.8%) showed no overlap. One hundred and thirty-six patients (17.9%) presented overlapping GERD, and 80 patients (10.5%) presented overlapping FD. Fifty one (6.7%) of patients were overlapped by both GERD and FD. Coincidental herniated nucleus pulposus (HNP) (P = 0.026) or pulmonary diseases (P = 0.034), reduced fiber intake (P = 0.013), and laxative use (P < 0.001) independently affected the rate of overlaps. These overlapping conditions negatively affected the constipation-associated quality of life, general quality of life, and degree of constipation. Conclusions The overlap of GERD or FD was common in patients with constipation. Coincidental HNP or pulmonary diseases, reduced fiber intake, and laxatives use were found to be independent associated factors for overlapping common FGIDs in Korean patients with constipation.

[Clinical Efficacy of Dynamic Contrast-enhanced Multidetector-row Computed Tomography in Patients with Obscure Gastrointestinal Bleeding].

BACKGROUND/AIMS Obscure gastrointestinal bleeding (OGIB) accounts for 5% of all gastrointestinal (GI) bleeding cases. Dynamic contrast-enhanced multidetector-row CT (DCE-MDCT) is not generally recommended in OGIB patients due to its low sensitivity. However, it can be used to quickly and simply diagnose OGIB according to some guidelines. The aim of this study was to evaluate the clinical efficacy of DCE-MDCT in OGIB patients. METHODS We retrospectively analyzed the medical records of 362 patients who underwent DCE-MDCT between March 2009 and January 2014. A total of 45 patients diagnosed with OGIB were included in this study. Their baseline characteristics and treatment procedure were analyzed retrospectively. The positive rates of DCE-MDCT for the detection of bleeding and associated factors were assessed. RESULTS The mean age of the patients was 59 years, and males represented 51.1%. Melena was the most common symptom (44.4%). Positive rate of DCE-MDCT findings was 20.0% (9/45). Among these patients, intraluminal contrast extravasation was found in 5 patients (55.6%) and intraluminal hematoma or mass lesions were found in 2 patients each (22.2%). Thirty nine patients (86.7%) underwent conservative management, and 6 patients (13.3%) underwent specific treatment, such as endoscopic treatment, embolization, or surgery. Patients who showed positivity in DCE-MDCT more frequently received specific treatment compared with those who were negative (44.4% vs. 5.6%, p=0.010). CONCLUSIONS Although DCE-MDCT showed a low positive rate (20.0%), positive findings of DCE-MDCT could lead to specific treatment. Positive DCE-MDCT findings play a useful role in the management of patients with OGIB.

Seroprevalence of Helicobacter pylori in Korea: A multicenter, nationwide study conducted in 2015 and 2016

The Korean College of Helicobacter and Upper Gastrointestinal Research has studied Helicobacter pylori (H. pylori) prevalence since 1998 and found a dynamic change in its prevalence in Korea. The aim of this study was to determine the recent H. pylori prevalence rate and compare it with that of previous studies according to socioeconomic variables.