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.

15-Deoxy-Δ(12,14)-prostaglandin J₂ Upregulates the Expression of 15-Hydroxyprostaglandin Dehydrogenase by Inducing AP-1 Activation and Heme Oxygenase-1 Expression in Human Colon Cancer Cells

BACKGROUND: Abnormal upregulation of prostaglandin E₂ (PGE₂) is considered to be a key oncogenic event in the development and progression of inflammation-associated human colon cancer. It has been reported that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme catabolizing PGE₂, is ubiquitously downregulated in human colon cancer. 15-Deoxy-Δ(12,14)-prostaglandin J₂ (15d-PGJ₂), a peroxisome proliferator-activated receptor γ ligand, has been shown to have anticarcinogenic activities. In this study, we investigate the effect of 15d-PGJ₂ on expression of 15-PGDH in human colon cancer HCT116 cells. METHODS: HCT116 cells were treated with 15d-PGJ₂ analysis. The expression of 15-PGDH in the treated cells was measured by Western blot analysis and RT-PCR. In addition, the cells were subjected to a 15-PGDH activity assay. To determine which transcription factor(s) and signaling pathway(s) are involved in 15d-PGJ₂-induced 15-PGDH expression, we performed a cDNA microarray analysis of 15d-PGJ₂-treated cells. The DNA binding activity of AP-1 was measured by an electrophoretic mobility shift assay. To determine whether the AP-1 plays an important role in the 15d-PGJ₂-induced 15-PGDH expression, the cells were transfected with siRNA of c-Jun, a major subunit of AP-1. To elucidate the upstream signaling pathways involved in AP-1 activation by 15d-PGJ₂, we examined its effect on phosphorylation of Akt by Western blot analysis in the presence or absence of kinase inhibitor. RESULTS: 15d-PGJ₂ (10 μM) significantly upregulated 15-PGDH expression at the mRNA and protein levels in HCT-116 cells. 15-PGDH activity was also elevated by 15d-PGJ₂. We observed that genes encoding C/EBP delta, FOS-like antigen 1, c-Jun, and heme oxygenase-1 (HO-1) were most highly induced in the HCT116 cells following 15d-PGJ₂ treatment. 15d-PGJ₂ increased the DNA binding activity of AP-1. Moreover, transfection with specific siRNA against c-Jun significantly reduced 15-PGDH expression induced by 15d-PGJ₂. 15d-PGJ₂ activates Akt and a pharmacological inhibitor of Akt, LY294002, abrogated 15d-PGJ₂-induced 15-PGDH expression. We also observed that an inhibitor of HO-1, zinc protoporphyrin IX, also abrogated upregulation of 15-PGDH and down-regulation of cyclooxygenase-2 expression induced by 15d-PGJ₂. CONCLUSIONS: These finding suggest that 15d-PGJ₂ upregulates the expression of 15-PGDH through AP-1 activation in colon cancer HCT116 cells.

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.

Impacts of Cytosolic Phospholipase A2, 15-Prostaglandin Dehydrogenase, and Cyclooxygenase-2 Expressions on Tumor Progression in Colorectal Cancer

PURPOSE: In addition to cyclooxygenase-2 (COX-2) which is related to prostaglandin E2 synthesis, other enzymes such as cytosolic phospholipase A2 (cPLA2), microsomal prostaglandin E2 synthase-1 (mPGES-1), and 15-prostaglandin dehydrogenase (15-PGDH) have been suggested to be related to carcinogenesis of colorectal cancer (CRC). The aim of this study was to investigate the roles of cPLA2, COX-2, mPGES-1, and 15-PGDH in tumor progression. MATERIALS AND METHODS: cPLA2, COX-2, mPGES-1, 15-PGDH, and vascular endothelial growth factor (VEGF) expressions were immunohistochemically examined in 89 CRC, and their expressions were compared with each other or clinicopathologic parameters as well as VEGF as tumor progression parameters. RESULTS: cPLA2 was expressed in 54.5%, COX-2 in 80.5%, mPGES-1 in 96.4%, 15-PGDH in 46.1%, and VEGF in 65.9%. The expression of cPLA2 correlated with VEGF expression. COX-2 expression was correlated with the depth of invasion, tumor stage, cPLA2, and VEGF expressions. Moreover, VEGF revealed the highest expression in the tissues positive for both cPLA2 and COX-2. Furthermore, 15-PGDH expression was inversely correlated with VEGF expression. CONCLUSION: The present study demonstrates that cPLA2 and mPGES-1, in addition to COX-2, are constitutively overexpressed, and that 15-PGDH might be attenuated in colorectal cancer. Furthermore, cPLA2 and 15-PGDH as well as COX-2 could have an important role in tumor progression.