| Part I Expression of COX-2 and PPAR-y in hepatocellular carcinomaCyclooxygenase (COXs) are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids. Two isoforms of the enzyme have been identified. The isoform designated COX-1 is constitutively expressed in a number of cell types, whereas the isoform designated COX-2 is inducible by a variety of factors, such as cytokines.growth factors, and tumor promoters. Previous studies have suggested that COX-2, but not COX-1, is involved in colon carcinogenesis and may thus be the target for a chetnopreventive effect by the COX inhibitor, nonsteroidal anti-inflammatory drugs.Several studies have demonstrated the up-regulation of COX-2 in transfection experiments of oncogenes such as src and ras, suggesting that up-regulation of COX-2 was a general phenomenon in carcinogenesis. Indeed COX-2 mRNA and protein were recently found to be expressed in human colon carcinoma, gastric carcinoma, and squarmous cell carcinoma. However, COX-2 protein was not found in human breat carcinoma or in human basal cell carcinoma, and COX-2 mRNA was not expressed in mucinous ovarian carcinoma. These observation have suggested that overexpression of COX-2 in carcinoma is not necessarily a universal event in carcinogenesis but may be tumor-specific.Although molecular techniques have shown that COX-2 is involved in the production of cellular adhesion molecules and the inhibition of apoptosis, a precise role of COX-2 in colon carcinogenesis remains unclear. Since Cyclooxygenase are key enzymes in the conversion ofarachidonic acid to prostaglandins and other eicosanoids, and Peroxisome proliferator-activated receptory (PPAR-y) is the endogenic receptor of 15-d-PGJ2, it was postulated that COX-2 may exert its effect via PGs through their endogenic recepror PPAR-y. PPAR-y, a member of the nuclear hormone receptors, can act as ligand-sensitive transcription factor. Activated receptors heterodimerize with retinoid X receptor (RXR) and can alter transcription of target genes after binding to peroxisome proliferators responsive elements (PPRE). PPAR-y was initially reported for its regulatory roles in insulin sensitization and adipocyte differentiation. However , later studies have shown that PPAR-y is also expressed in other cell types and it has been of interest for its role in cell proliferation and cancer.In this study, the expression of COX-2 and PPAR-y in HCC was evaluated. And COX-2 and PPAR-y may be the promising therapeutic gene targets of HCC.Method1.Tissue samples: HCC tissue and adjacent noncancerous liver tissue were obtained from 29 patients. 6 histologically normal liver tissues and 6 cihrrotic liver tissues were used as controls. 2.RT-PCR was used to measure the mRNA levels of COX-2 and PPAR-y in HCC. 3.Western Blotting was performed on representativesamples of HCC tissues and noncancerous liver tissues.Result1. COX-2 mRNA level between HCC and adjascent tissues has no significant difference. And higher expression of COX-2 protein in HCC than adjacent tissue and normal liver tissue was found.2. PPAR-y mRNA level in HCC was higher than adjacent tissue, and PPAR- mRNA was not detected in the controlled normal liver tissue and cihrrotic tissue.conclusionCOX-2 may play a role in the early stages of hepatocarcinogenesis, and PPAR-y may participate in this procedure via PGs.PART IIProapototic and antiproliferative potential of selective COX-2 inhibitor " Etodolac" in human liver tumor cellsHepatocellular carcinoma (HCC) represents more than 4% of all cancer cases worldwide and causes at least 315,000 deaths each year. The prognosis of HCC is generally poor.Even after surgery, 5-year survival rate is limited to 25% to 29%. No effective chemotherapeutic or chemopreventive treatments are available, and currently there is a lack of promising molecular therapeutic target structures.Recent studies have shown that nonsteroidal anti-in-flammatory drugs (NSAIDs) inhibit growth of coloncancerce...
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