l-663536 and Neoplasm-Metastasis

To study the expression of mPGES-1 in hepatocellular carcinoma (HCC), observe the effect of MK886 on down-regulation of mPGES-1 gene expression on the biology of human hepatocarcinoma cell line HepG2 and to investigate its significance in the occurrence, progression, metastasis and invasion.. HCC tissues, para-carcinoma tissues, far-carcinoma tissues and normal liver tissues were collected. The expressions of mPGES-1 were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. The proliferation, adherence, migration and invasion abilities of HepG2 cells interfered by MK886 were assessed by MTT and transwell technique respectively.. The expression of mPGES-1 in HCCs was higher than that in normal liver tissues (P < 0.01), which increased following histological grade. Furthermore, mPGES-1 expression level was higher in the capsule invasion and metastasis tumor than in primary locus. A significant dose-dependent down-regulation of expressions of mPGES-1 gene mRNA and protein were observed in HepG2 cells when MK886 was given for 48 h (F = 140.402, P < 0.01; a'= 0.00714, P < 0.01). Compared with the control group, the growth inhibitory rate of HepG2 cell was observed significantly time and dose-dependent when MK886 was given. The rate of adhesion cells in experimental groups were 85.3% ± 1.3%, 70.5% ± 1.5% and 45.8% ± 2.4%, respectively, less than that in control group 100.0% ± 0 (F = 626.313, P < 0.01). The migration cells was 92.47 ± 1.90, 62.63 ± 1.96 and 37.33 ± 0.83 respectively in the experimental groups after 24 h, lower than that in the control group 128.93 ± 2.60 (F = 1253.805, P < 0.01). The invasion assay revealed that the invading cells were 41.67 ± 1.30, 25.47 ± 1.30 and 13.93 ± 1.66 in the experimental groups, in contrast to 55.67 ± 2.08 in control group after 24 h. The difference between these groups was significant (F = 372.615, P < 0.01). The numbers of adhesion, migration and invasion of HepG2 cells were dose-dependent in MK886 groups.. Over-expression of mPGES-1 was associated with the tumorigenesis and progression of HCC. The down-regulation of mPGES-1 gene expression might indicated the decrease of the invasion and metastasis of HCC.

Topics: Carcinoma, Hepatocellular; Cell Adhesion; Cell Movement; Cell Proliferation; Female; Hep G2 Cells; Humans; Indoles; Intramolecular Oxidoreductases; Liver Neoplasms; Male; Microsomes; Neoplasm Invasiveness; Neoplasm Metastasis; Prostaglandin-E Synthases

Metastasis is a complex process, almost a cascade, involving multiple steps and activities. However, an important factor is that malignant cells are able to penetrate through the multiple basement membrane barriers surrounding tissues, blood vessels, nerves and muscle that would otherwise block their dissemination. Penetration of malignant tumor cells through basement membrane is an active process requiring proteolysis. We report here that inhibitors of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism convert mouse melanoma and human fibrosarcoma cells to a non invasive state by reducing the production of MMP-2, an enzyme required for the degradation of basement membranes. Specific metabolites of each pathway, i.e. PGF2 alpha and 5-HPETE, are able to transcend the block and restore collagenase production, invasiveness in vitro and metastatic activity in vivo. These studies indicate a key role for arachidonic acid metabolites in metastasis and suggest novel therapeutic approaches for inhibiting the spread of cancer.

Topics: Animals; Arachidonic Acid; Caffeine; Collagen; Cyclooxygenase Inhibitors; Dinoprost; Drug Combinations; Extracellular Matrix; Fibrosarcoma; Gelatinases; Humans; Indoles; Indomethacin; Laminin; Leukotrienes; Lipoxygenase Inhibitors; Masoprocol; Matrix Metalloproteinase 2; Melanoma; Metalloendopeptidases; Mice; Neoplasm Metastasis; Proteoglycans; Tumor Cells, Cultured; Umbelliferones