Altered expression of 15-hydroxyprostaglandin dehydrogenase in chronic rhinosinusitis with nasal polyps / 临床耳鼻咽喉头颈外科杂志

Objective:To investigate the expression level and regulatory mechanism of 15-hydroxyprostaglandin dehydrogenase（HPGD） in chronic rhinosinusitis with nasal polyps（CRSwNP）. Methods:The expression pattern and level of HPGD in CRSwNP and control was observed using immunofluorescence, and western blot was used for analysis of HPGD expression in nasal polyp tissues. The effect of recombinant human high mobility group box-1（HMGB1） on HPGD expression in primary human nasal epithelial cells was observed, and the potential blocking effect of RAGE neutralizing antibody on HMGB1-induced HPGD expression was investigated. Results:The expression of HPGD was elevated in CRSwNP patients compared to the control, while the protein mainly localized at CD68-positive cells and epithelial cells. Recombinant human HMGB1 stimulated an increase in HPGD expression in primary human nasal mucosal epithelial cells at a time-dependent manner. Additionally, increased phosphorylation levels of MEK and elevated RAGE expression were also observed at 12 hours, but decreased at 24 hours after the incubation of HMGB1. The increase in the expression of HPGD induced by HMGB1 in primary human nasal epithelial cells was partly inhibited with RAGE neutralizing antibody. Conclusion:Elevated HPGD expression is observed in CRSwNP, predominantly in macrophages and epithelial cells. HMGB1 regulates HPGD expression through the RAGE-MEK signaling pathway, potentially providing a new target for future regulation of PGE2levels in CRSwNP.

Relationship between expression level of 15-PGDH and clinical prognosis of liver transplantation for hepatocellular carcinoma / 器官移植

Objective To investigate the relationship between the expression level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and clinical prognosis of liver transplantation for hepatocellular carcinoma. Methods The clinical data of 94 recipients undergoing liver transplantation for hepatocellular carcinoma were retrospectively analyzed. The expression of 15-PGDH in the pathological tissues of all recipients was detected by immunohistochemical staining. The relationship between the expression level of 15-PGDH protein and clinical parameters of hepatocellular carcinoma patients was analyzed. The 5-year tumor-free survival and overall survival rates of liver transplant recipients were calculated. The possible independent risk factors of the clinical prognosis of liver transplant recipients were analyzed. Results The expression level of 15-PGDH was significantly correlated with age, Child-Pugh grade and preoperative level of alpha-fetoprotein (AFP) of the recipients (all P < 0.05). The tumor-free survival and overall survival rates of the recipients with low expression of 15-PGDH were significantly lower than those in their counterparts with high expression of 15-PGDH (both P < 0.05). The expression level of 15-PGDH, degree of tumor differentiation and American Joint Committee on Cancer (AJCC) staging were the independent risk factors of clinical prognosis of liver transplantation for hepatocellular carcinoma (all P < 0.05). Conclusions The expression level of 15-PGDH is an independent risk factor of clinical prognosis of liver transplantation for hepatocellular carcinoma.

Reversal Effect and Mechanism of 15-PGHD Induction Drugs on the Multidrug Resistance of Human Breast Cancer Cell Line MCF-7/ADR / 中国药学杂志

OBJECTIVE: To examine the expression of 15-hydroxyprostaglandin dehydrogenase(15-PGDH) in human multidrug-resistant breast cancer line MCF-7/ADR and to explore the reversal effect and mechanism of 15-PGHD induction drugs on MCF-7/ADR cells. METHODS: The RT-PCR and Western blot were used to detect 15-PGDH, COX-2 mRNA and protein expression in MCF-7 and MCF-7/ADR cells. PGE2 levels in supernatant of cells were determined by ELISA assay. Anti-proliferation effect and chemotherapy sensitivity to ADM of 15-PGDH induction drugs (indomethacin, ibuprofen and pioglitazone, dexamethasone) on breast cancer cells were assayed by MTT method. Cell apoptosis was detected by Hochest 33258 stain assay. RESULTS: Compared with MCF-7 cells, the 15-PGDH expression was significantly decreased, COX-2 expression was significantly increased and PGE2 levels in cell supernatant were increased in MCF-7/ADR cells. 15-PGDH induction drugs (indomethacin, ibuprofen and pioglitazone, dexamethasone) increased 15-PGDH expression or both reduced COX-2 expression, and finally reduced PGE2 levels in MCF-7/ADR cells. Effect of chemosensitivity and apoptosis induction of ADM was enhanced and multidrug resistance was partially reversed when co-treated with 15-PGDH induction drugs. CONCLUSION: The expression of 15-PGDH is decreased in human multidrug-resistant breast cancer line MCF-7/ADR. 15-PGDH induction drugs could increase chemosensitivity, promote apoptosis and reverse resistance of MCF-7/ADR cell, the mechanism might related to the influence of PGE2 level by regulated the expression of 15-PGDH and COX-2.

15-Hydroxyprostaglandin dehydrogenase as a marker in colon carcinogenesis: analysis of the prostaglandin pathway in human colonic tissue

BACKGROUND/AIMS: Cyclooxygenase-2 (COX-2), 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and microsomal prostaglandin E synthase-1 (mPGEs-1) regulate prostaglandin E₂ (PGE₂) expression and are involved in colon carcinogenesis. We investigated the expression of PGE₂ and its regulating genes in sporadic human colon tumors and matched normal tissues. METHODS: Twenty colonic adenomas and 27 colonic adenocarcinomas were evaluated. COX-2 and 15-PGDH expression was quantified by real-time polymerase chain reaction. The expression of PGE₂ and mPGEs-1 was measured using enzyme-linked immunosorbent assay and Western blotting, respectively. RESULTS: The expression of COX-2, mPGEs-1, and PGE₂ did not differ between the adenomas and matched distant normal tissues. 15-PGDH expression was lower in adenomas than in the matched normal colonic tissues (P<0.001). In adenocarcinomas, mPGEs-1 and PGE₂ expression was significantly higher (P<0.001 and P=0.020, respectively), and COX-2 expression did not differ from that in normal tissues (P=0.207). 15-PGDH expression was significantly lower in the normal colonic mucosa from adenocarcinoma patients than in the normal mucosa from adenoma patients (P=0.018). CONCLUSIONS: Early inactivation of 15-PGDH, followed by activation of COX-2 and mPGEs-1, contributes to PGE₂ production, leading to colon carcinogenesis. 15-PGDH might be a novel candidate marker for early detection of field defects in colon carcinogenesis.

Relationship between 15-hydroxyprostaglandin dehydrogenase and gastric adenocarcinoma

PURPOSE: Prostaglandin E2 (PGE2) is a contributory carcinogen in gastric adenocarcinoma. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catabolizes PGE2 by oxidizing its 15(s)-hydroxy group. The aim of this study was to investigate the expression of 15-PGDH in gastric adenocarcinoma tissue and the relationship between 15-PGDH expression and clinicopathologic features of gastric adenocarcinoma. METHODS: Ninety-nine patients who underwent surgical resection for gastric adenocarcinoma between January 2007 and December 2007 were enrolled and evaluated retrospectively. RESULTS: In 62 patients (62.6%), 15-PGDH expression was lower in gastric adenocarcinoma tissue than in nonneoplastic tissue. Regarding the relationship between 15-PGDH expression and clinicopathological features, 15-PGDH expression was significantly lower in tissues with poor differentiation (P = 0.002), advanced T stage (P = 0.0319), a higher number of lymph node metastases (P = 0.045), lymphatic invasion (P = 0.031), and vascular invasion (P = 0.036). CONCLUSION: 15-PGDH expression was associated with a subset of clinicopathologic features such as differentiation grade, T stage, lymphatic invasion, and vascular invasion.

Role of 15-hydroxyprostaglandin dehydrogenase down-regulation on the prognosis of hepatocellular carcinoma

BACKGROUND/AIMS: The role of prostaglandin E2 (PGE2) in the modulation of cell growth is well established in colorectal cancer. The aim of this study was to elucidate the significance of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) down-regulation on the prognosis of hepatocellular carcinoma (HCC) patients. METHODS: The expression of 15-PGDH in HCC cell lines and resected HCC tissues was investigated, and the correlation between 15-PGDH expression and HCC cell-line proliferation and patient survival was explored. RESULTS: The interleukin-1-beta-induced suppression of 15-PGDH did not change the proliferation of PLC and Huh-7 cells in the MTS [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The induction of 15-PGDH by transfection in HepG2 cells without baseline 15-PGDH expression was suppressed at day 2 of proliferation compared with empty-vector transfection, but there was no difference at day 3. Among the 153 patients who received curative HCC resection between 2003 and 2004 at our institution, 15-PGDH expression was observed in resected HCC tissues in 56 (36.6%), but the 5-year survival rate did not differ from that of the remaining 97 non-15-PGDH-expressing patients (57.1% vs 59.8%; P=0.93). Among 50 patients who exhibited baseline 15-PGDH expression in adjacent nontumor liver tissues, 28 (56%) exhibited a reduction in 15-PGDH expression score in HCC tissues, and there was a trend toward fewer long-term survivors compared with the remaining 22 with the same or increment in their 15-PGDH expression score in HCC tissues. CONCLUSIONS: The prognostic significance of 15-PGDH down-regulation in HCC was not established in this study. However, maintenance of 15-PGDH expression could be a potential therapeutic target for a subgroup of HCC patients with baseline 15-PGDH expression in adjacent nontumor liver tissue.

15-Hydroxyprostaglandin Dehydrogenase in Colorectal Mucosa as a Potential Biomarker for Predicting Colorectal Neoplasms

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is downregulated during the early stages of colorectal carcinogenesis. The aim of the present study was to investigate the potential role of 15-PGDH in normal-appearing colorectal mucosa as a biomarker for predicting colorectal neoplasms. We obtained paired tumor and normal tissues from the surgical specimens of 32 sporadic colorectal cancer patients. mRNA expression of 15-PGDH was measured using a quantitative real-time PCR assay. We evaluated the association between 15-PGDH mRNA expression in normal-appearing mucosa, the presence of synchronous adenoma, and the cumulative incidence of metachronous adenoma. The relative 15-PGDH expression of normal-appearing mucosa in patients with synchronous adenoma was significantly lower than in patients without synchronous adenoma (0.71 vs 1.00, P = 0.044). The patients in the lowest tertile of 15-PGDH expression in normal-appearing mucosa were most likely to have synchronous adenoma (OR: 10.5, P = 0.024). Patients with low 15-PGDH expression in normal-appearing mucosa also demonstrated more advanced stage colorectal cancer (P = 0.045). However, there was no significant difference in the cumulative incidence of metachronous adenoma according to 15-PGDH mRNA expression in normal-appearing mucosa (P = 0.333). Hence, 15-PGDH in normal-appearing colorectal mucosa can be a useful biomarker of field effect for the prediction of sporadic synchronous neoplasms.

Prognostic Implication of 15-Hydroxyprostaglandin Dehydrogenase Down-Regulation in Patients with Colorectal Cancer

PURPOSE: Prostaglandin (PG) E2 is known to be closely related to cancer progression and is inactivated by 15-hydroxyprostaglandin dehydrogenase (PGDH). 15-PGDH is shown to have tumor suppressor activity and to be down-regulated in various cancers, including colorectal cancer (CRC). Therefore, we evaluated the expression of 15-PGDH and its prognostic effect in patients with CRC. METHODS: 15-PGDH expression was examined by using immunohistochemistry in 77 patients with CRC. Its prognostic significance was statistically evaluated. RESULTS: Negative 15-PGDH expression was noted in 55.8% of the 77 cases of CRC. 15-PGDH expression showed no correlation with any of the various clinicopathologic parameters. The status of lymph node metastasis, tumor-node-metastasis stages, and pre-operative carcinoembryonic antigen levels showed significant prognostic effect. However, univariate analysis revealed down-regulation of 15-PGDH not to be a predictor of poor survival. The 5-year overall survival rate was 71.7% in the group with positive expression of 15-PGDH and 67.1% in the group with negative expression of 15-PGDH, but this difference was not statistically significant (P = 0.751). CONCLUSION: 15-PGDH was down-regulated in 55.8% of the colorectal cancer patients. However, down-regulation of 15-PGDH showed no prognostic value in patients with CRC. Further larger scale or prospective studies are needed to clarify the prognostic effect of 15-PGDH down-regulation in patients with colorectal cancer.

Role of Prostaglandins in Colon Cancer / 대한소화기학회지

Colon cancer is one of the major leading causes of cancer-related deaths in the Western countries. In Korea, the incidence of colon cancer is increasing due to changes in environment and lifestyle such as diet. Chemoprevention strategy using non-steroidal anti-inflammatory drugs (NSAIDs) has been under intensive clinical and epidemiological research as these drugs suppress colorectal cancer. The best known targets of NSAIDs are cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins (PGs) and thromboxane. Among these PGs, prostaglandin E2 (PGE2) can promote tumor growth by binding its receptors and activating signal pathways which control cell proliferation, migration, apoptosis, and angiogenesis. Therefore, COX inhibition is promising approach for chemoprevention of colorectal cancer. However, the prolonged use of COX-2 inhibitors is associated with unacceptable cardiovascular side effects. Thus, new targets involved in PGs metabolism are under investigation. 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key metabolic enzyme of PGE2, was up-regulated in normal colonic epithelium, but decreased in colon cancer. Recent findings suggest that 15-PGDH is involved in the neoplastic progression of initiated colonic epithelial cells. Also, new players related with PGs metabolism including prostaglandin transporter (PGT) and microsomal prostaglandin E synthase (mPGES) were reported to play a role in colorectal cancer development. This review presents current knowledge about the role of prostaglandins and associated proteins in colorectal cancer development and progression.

Decreased Expression of 15-hydroxyprostaglandin Dehydrogenase in Gastric Carcinomas

PURPOSE: Gastric carcinoma tissues release high level of prostaglandin E2 (PGE2) when compared to non-neoplastic mucosa, and cyclooxygenase-2 (COX-2), which is the rate-limiting enzyme in prostaglandin (PG) biosynthesis, is often overexpressed in gastric carcinomas and during gastric carcinogenesis. However, little is known about the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for the biological inactivation of PG, in gastric carcinomas. MATERIALS AND METHODS: We investigated the expression of 15-PGDH in 28 cases of advanced gastric carcinomas by Western blot analysis and also the relation between its expression and the gene promoter methylation. RESULTS: 15-PGDH expression was significantly decreased in gastric carcinomas compared to corresponding non-neoplastic tissues and inversely correlated with the expression of proliferating cell nuclear antigen in gastric carcinomas. However, there was no correlation between 15-PGDH expression and pathological findings such as nodal metastasis and vascular invasion. Promoter hypermethylation of 15-PGDH gene was not detected in carcinomas, with only a negligible expression of the enzyme. CONCLUSION: Our results suggested that 15-PGDH has tumor suppressor activity in gastric carcinomas.