Dioscorea nipponica Attenuates Migration and Invasion by Inhibition of Urokinase-Type Plasminogen Activator through Involving PI3K/Akt and Transcriptional Inhibition of NF-[Formula: see text]B and SP-1 in Hepatocellular Carcinoma.
High mortality and morbidity rates for hepatocellular carcinoma (HCC) in Taiwan primarily result from uncontrolled tumor metastasis. In our previous studies, we have reported that Dioscorea nipponica Makino extract (DNE) has anti-metastasis effects on human oral cancer cells. However, the effect of DNE on hepatoma metastasis have not been thoroughly investigated and remains poorly understood. To determine the effects of DNE on the migration and invasion in HCC cells we used a wound healing model, Boyden chamber assays, gelatin/casein zymography and Western blotting. Transcriptional levels of matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (u-PA) were detected by real-time PCR and promoter assays. In this study, DNE treatment significantly inhibited the migration/invasion capacities of Huh7 cell lines. The results of gelatin/casein zymography and Western blotting revealed that the activities and protein levels of the MMP-9 and u-PA were inhibited by DNE. Tests of the mRNA levels, real-time PCR, and promoter assays evaluated the inhibitory effects of DNE on u-PA expression in human hepatoma cells. A chromatin immunoprecipitation (ChIP) assay showed not only that DNE inhibits u-PA expression, but also the inhibitory effects were associated with the down-regulation of the transcription factors of NF-[Formula: see text]B and SP-1 signaling pathways. Western blot analysis also showed that DNE inhibits PI3K and phosphorylation of Akt. In conclusion, these results show that u-PA expression may be a potent therapeutic target in the DNE-mediated suppression of HCC invasion/migration. DNE may have potential use as a chemo-preventive agent against liver cancer metastasis.
['Hsieh|Ming-Ju|MJ|', 'Yeh|Chao-Bin|CB|', 'Chiou|Hui-Ling|HL|', 'Hsieh|Ming-Chang|MC|', 'Yang|Shun-Fa|SF|']
D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D002465:Cell Movement D027742:Dioscorea D015870:Gene Expression D006801:Humans D008113:Liver Neoplasms D020780:Matrix Metalloproteinase 9 D016328:NF-kappa B D009361:Neoplasm Invasiveness D009362:Neoplasm Metastasis D000081082:Phosphoinositide-3 Kinase Inhibitors D010766:Phosphorylation D008517:Phytotherapy D010936:Plant Extracts D051057:Proto-Oncogene Proteins c-akt D016329:Sp1 Transcription Factor D014158:Transcription, Genetic D014568:Urokinase-Type Plasminogen Activator
Migration Invasion Dioscorea nipponica Makino Hepatoma MMP-9 u-PA