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ABSTRACT: BACKGROUND AND AIMS: 15-Hydroxprostaglandin dehydrogenase (15-PGDH) mediates a colon neoplasia suppressor pathway, acting through metabolic antagonism of cyclooxygenase-mediated colon carcinogenesis. To determine whether the colon tumor prevention activity of 15-PGDH acts as a constant or variable effect among individuals, we determined whether 15-PGDH levels remain stable over subsite and time in the human colon, determined the extent of differences in 15-PGDH levels between different individuals, and determined whether 15-PGDH modulation mediates any part of the anti-colon tumor effect of aspirin. METHODS: Using real-time PCR, we measured 15-PGDH mRNA to determine the correlation of 15-PGDH level in replicate colon biopsies, in biopsies from throughout the length of the colon, in repeat biopsies taken 4 months apart, and in paired biopsies of individuals taken before and after aspirin treatment, and by Western-blot for 15-PGDH protein in mice. RESULTS: Colonic 15-PGDH levels varied 4.4-fold across the human population. Within individuals, 15-PGDH levels proved highly reproducible (r = 0.81 in duplicate biopsies) and stable along the length of the colon, with average 15-PGDH levels deviating by only 17 % from rectum to cecum. An individual's 15-PGDH levels are also highly stable over time, with a median coefficient of variation over a 4-month interval of only 12 %. Last, colonic 15-PGDH levels proved resistant to alteration by aspirin, with only a 10 % difference in 15-PGDH levels measured before and after aspirin treatment. CONCLUSIONS: 15-PGDH levels vary across the population in a stable and reproducible manner, and are resistant to alteration by aspirin. 15-PGDH represents an independent target for modulation by candidate colon tumor chemopreventive agents.
Digestive Diseases and Sciences 04/2013; · 2.12 Impact Factor
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Yeon-Mi Ryu,
Seung-Jae Myung,
Young Soo Park,
Dong-Hoon Yang,
Ho June Song,
Jin-Yong Jeong,
Sun Mi Lee,
Miyeoun Song,
Do Hoon Kim,
Hyo-Jeong Lee,
Soo-Kyung Park,
Stephen P Fink,
Sandy D Markowit,
Ki-Wook Jung,
Kyung-Jo Kim,
Byong-Duk Ye,
Jeong-Sik Byeon,
Hwoon-Yong Jung,
Suk-Kyun Yang,
Jin-Ho Kim
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ABSTRACT: Helicobacter pylori (H pylori) infection induces a chronic inflammatory response, which promotes gastric carcinogenesis. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) plays a key role as a tumor suppressor in gastrointestinal cancers. The aim of this study was to elucidate the role of 15-PGDH in gastric carcinogenesis associated with H pylori. 15-PGDH expression in gastric biopsies from H pylori-infected (n=25) and non-infected (n=15) subjects was analyzed by quantitative real-time PCR, western blot analysis, and immunohistochemisty. 15-PGDH DNA methylation was evaluated by methylation specific PCR and pyrosequencing. The expression of 15-PGDH, Snail, ERK1/2, TLR4 and MyD88 in response to H pylori infection was assessed by immunoblot analysis. Compared to negative specimens, H pylori positive specimens had 2-fold lower 15-PGDH mRNA levels and significantly less 15-PGDH protein. In four H pylori infected subjects with longitudinal follow-up, the suppression of 15-PGDH expression was reversed by H pylori eradication therapy. In parallel with suppressing 15-PGDH expression, H pylori infection activated expression of TLR4 and MyD88 expression, increased levels of phospho-ERK1/2, and increased expression of epidermal growth factor receptor (EGFR)-Snail. Inhibition of Snail and MyD88 reversed suppression of 15-PGDH expression and small interfering Myd88 reduced phosphorylated ERK1/2. Similarly, treatment with an ERK1/2 and EGFR inhibitor also restored 15-PGDH expression. Heliocobacter pylori appeared to promote gastric carcinogenesis by suppressing15-PGDH. This process is mediated by the TLR4/MyD88 pathway via ERK1/2 or EGFR - Snail transcriptional regulation. 15-PGDH may be a useful marker and a potential therapeutic target in H pylori-induced gastric carcinogenesis.
Cancer Prevention Research 02/2013; · 4.91 Impact Factor
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Ho June Song,
Seung-Jae Myung,
In-Wha Kim,
Jin-Yong Jeong,
Young Soo Park,
Sun Mi Lee,
Won Hee Nam, Yeon-Mi Ryu,
Stephen P Fink,
Dong-Hoon Yang,
Hwoon-Yong Jung,
Jin-Ho Kim
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ABSTRACT: We investigated the tumor suppressor activity and regulatory mechanism of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in gastric cancer; 15-PGDH expression was lost in 70.1% of malignant human gastric tissues, but was preserved in normal and metaplastic gastritis. KATO III and SNU-719 cells were transfected with pcDNA3.1-empty vector or an expression vector encoding wild-type 15-PGDH. In TUNEL assays apoptotic cell numbers were increased in KATO-PGDH-WT cells compared with control. We found that EGFR and ERK1/2 inhibitors clearly increased the expression of 15-PGDH in KATO III cells. Our findings demonstrate both downregulation and a tumor suppressor activity of 15-PGDH in gastric cancer.
Cancer Investigation 05/2011; 29(4):257-65. · 1.85 Impact Factor
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Soon Man Yoon,
Seung-Jae Myung,
Byong Duk Ye,
In-Wha Kim,
Nam Gon Lee, Yeon Mi Ryu,
Kyeongsoon Park,
Kwangmeyung Kim,
Ick Chan Kwon,
Young Soo Park,
Chan-Sik Park,
Dae Hyuk Moon,
Do Hoon Kim,
Mi Young Do,
Jeong-Sik Byeon,
Suk-Kyun Yang,
Jin-Ho Kim
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ABSTRACT: Early tumor detection is crucial for the prevention of colon cancer. Near-infrared fluorescence (NIRF) imaging using a target-activatable probe may permit earlier disease detection. Matrix metalloproteinases (MMPs) participate in tumorigenesis and tumor growth. The aim of this study was to determine whether NIRF imaging using an MMP-activatable probe can detect colon tumors at early stages.
WE UTILIZED TWO MURINE COLON CANCER MODELS: a sporadic colon cancer model induced by azoxymethane (AOM), and a colitis-associated cancer model induced by a combination of AOM and dextran sodium sulfate (DSS). Colonic lesions were analyzed by histologic examination, Western blotting, immunohistochemical staining, and NIRF imaging using an MMP-activatable probe.
Multiple variable-sized tumors developed in both models and progressed from adenomas to adenocarcinomas over time. At the early stage of the AOM/DSS model, diffuse inflammation was observed within the tumors. MMP expression increased progressively through normal, inflammation, adenoma, and adenocarcionoma stages. NIRF signal intensities were strongly correlated with each tumor stage from adenoma to adenocarcinoma. NIRF imaging also distinguished tumors from inflamed mucosa.
NIRF imaging using a protease-activatable probe may be a useful tool for early tumor detection. This approach could translate to improve the endoscopic detection of colon tumors, especially in patients with inflammatory bowel disease.
Gut and liver 12/2010; 4(4):488-97. · 0.83 Impact Factor
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In-Wha Kim,
Seung-Jae Myung,
Mi Young Do, Yeon-Mi Ryu,
Mi Jung Kim,
Eun-Ju Do,
Sehan Park,
Soon Man Yoon,
Byong Duk Ye,
Jeong-Sik Byeon,
Suk-Kyun Yang,
Jin-Ho Kim
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ABSTRACT: A Western-style diet (WD) is known to play an important role in inflammatory bowel disease and colon carcinogenesis. The purpose of this study was to understand the role of macrophages in WD-induced colitis associated with carcinogenesis.
Male BALB/c mice were fed a WD or a control diet (CD) for 4 weeks and exposed to azoxymethane (AOM) followed by 2% dextran sulfate sodium (DSS) for 7 days.
The WD increased susceptibility to DSS-induced inflammation and accelerated the infiltration of macrophages. The incidence and multiplicity of colon tumors were higher in mice fed the WD than in those fed the CD (P < 0.05). Levels of prostaglandin-endoperoxide synthase (PTGS) 2 and prostaglandin (PG) E(2) in the colon were higher after treatment with AOM and DSS in mice fed the WD than in those fed the CD. In addition, WD consumption increased the DNA binding activity of nuclear factor-kappaB and the serum concentration of tumor necrosis factor (TNF)-α. Mice fed the WD had higher numbers of F4/80-positive cells surrounding cancer cells compared with mice fed the CD. These cells expressed PTGS2, TNF-α and β-catenin, which are up-regulated by the WD. We also found that the WD increased unphosphorylated β-catenin accumulation in the cytoplasm and nucleus of colon cancer cells.
A WD increases the susceptibility to DSS-induced inflammation and accelerates the infiltration of macrophages. In turn, this resulted in the development and progression of colon cancer.
Journal of Gastroenterology and Hepatology 11/2010; 25(11):1785-94. · 2.87 Impact Factor
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ABSTRACT: Osteoporosis associated with estrogen deficiency is defined as an abnormal decrease in bone mass leading to an increased fracture risk. Genistein (GEN), as a phytoestrogen, is a type of soybean-derived isoflavone that possesses structural similarity to estrogen. In this study, we assessed the effect of GEN in ovariectomized (OVX) mice. To determine the effect of GEN on bone metabolism, we investigated gene expression profiles using a radioactive cDNA microarray. Eight-week-old female mice were either sham operated (SHAM) or OVX. From 1 week after the operation, OVX mice were injected daily with intraperitoneal GEN (0.1, 0.5, 1.5 and 3.0 mg/day) or 17beta-estradiol (E2, 0.03 microg/day) for 4 weeks. A cDNA microarray was used to evaluate changes in the expression of 1,152 genes. OVX mice showed bone mineral density (BMD) loss versus SHAM mice (5.8+/-0.4 vs. 6.9+/-0.6 mg/cm2). However, femur BMDs were completely restored by GEN and by E2 administration in OVX mice. Serum osteocalcin in OVX mice treated with 0.5 mg/day of GEN was 1.6-fold (44.30+/-5.73 ng/ml) higher than that in untreated mice. GEN treatment up-regulated 38 genes (e.g., mitogen-activated protein kinase 10) and down-regulated 18 (e.g., matrix metalloproteinase 13). Moreover, GEN was found to have a protective effect on bone loss caused by estrogen deficiency in OVX mice. The present study suggests that GEN modulates bone metabolism-related gene expression, including calciotropic receptor, cytokines, growth factors and bone matrix proteins.
The Journal of Nutritional Biochemistry 04/2006; 17(3):157-64. · 3.89 Impact Factor
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ABSTRACT: In this study, we investigated the effects of PAHs and dioxin on mRNA and plasma protein expression using genomic and proteomic analysis for automobile emission inspectors and waste incineration workers. About 54 workers from automobile emission inspection offices, 31 workers from waste incinerating company and 84 unexposed healthy subjects were enrolled in this study. Urine and air samples were collected and analyzed by HPLC and GC/MS. Comet assays were carried out to evaluate any DNA damage in mononuclear and polynuclear cells. A significant difference in Olive tail moments in mononuclear cells was observed between exposed and control subjects (P < 0.0001). To examine the differences of the gene expression profile in automobile emission inspectors and waste incineration workers, radioactive complementary DNA microarrays were used to evaluate changes in the expression of 1,152 total genes. The gene expression profiles showed that 11 genes were up-regulated and 4 genes were down-regulated in waste incinerating workers as compared with controls. Plasma proteins were analyzed by 2-dimentional electrophoresis with pH 3-10 NL IPG Dry strip. The protein expression profiles showed that 8 proteins were up- regulated and 1 protein, haptoglobin, was down- regulated in automobile emission inspectors and waste incineration workers. Serum paraoxonase/ arylesterase was found only in the plasma of waste incineration workers. The expression of genes and proteins involved in oxidative stress were up-regulated in both automobile emission inspectors and waste incineration workers. Several proteins, such as transthyrethin, sarcolectin and haptoglobin, that were highly up- or down-regulated, could serve as biological monitoring markers for future study.
Experimental and Molecular Medicine 10/2004; 36(5):396-410. · 2.48 Impact Factor
