Licochalcone A suppresses migration and invasion of human hepatocellular carcinoma cells through downregulation of MKK4/JNK via NF-κB mediated urokinase plasminogen activator expression.
Hepatocellular cell carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide and in Taiwan. Chemoprevention of cancer with dietary bioactive compounds could potentially reverse, suppress, or prevent cancer progression. Licochalcone A (LicA) is a characteristic chalcone of licorice, which is the root of Glycyrrhiza inflate. It had been reported that LicA has anti-inflammatory, anti-microbial, and anti-tumor properties. However, the effects of LicA on the migration and invasion of human HCC cells have not yet been reported. In the present study, it was found that LicA inhibits the migratory and invasion ability of SK-Hep-1 and HA22T/VGH cells in a dose-dependent manner, as assessed by the cell migration and Matrigel cell invasion assay. Using casein zymography, Western blotting, reverse transcriptase polymerase chain reaction, and an immunofluorescence assay, it was found that LicA induces a dose-dependent inhibition of uPA activity and expression, as well as reduces mRNA levels in SK-Hep-1 and HA22T/VGH cells. LicA was also found to inhibit the expression of phosphor-JNK and phosphor-MKK4 in SK-Hep-1 cells. Furthermore, LicA significantly decreased uPA levels in SP600125-treated or si-MKK4-transfected cells alongside a marked reduction in cell migration and invasion, which supports the notion that an inhibition of MKK4/JNK results in anti-metastatic effects. Moreover, LicA inhibited the expression of nuclear NF-κB, as well as the binding ability of NF-κB to the uPA promoter. These findings further our understanding of the role of LicA in suppressing tumor metastasis and its underlying molecular mechanisms, as well as suggest that LicA may be a promising anti-metastatic agent.
Department of Nephrology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan ; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Jen-Pi
JP
Tsai
School of Medicine, Chung Shan Medical University, Taichung, Taiwan ; Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
Pei-Ching
PC
Hsiao
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Shun-Fa
SF
Yang
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Shu-Ching
SC
Hsieh
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan ; Department of Biotechnology, Asia University, Taichung, Taiwan.
Da-Tian
DT
Bau
Institute of Biochemistry and Biotechnology, College of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Chu-Liang
CL
Ling
Institute of Biochemistry and Biotechnology, College of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Chun-Li
CL
Pai
Institute of Biochemistry and Biotechnology, College of Medicine, Chung Shan Medical University, Taichung, Taiwan ; Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan ; Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan.
Yi-Hsien
YH
Hsieh
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
D047188:Chalcones; D016328:NF-kappa B; D012333:RNA, Messenger; D048670:MAP Kinase Kinase 4; D014568:Urokinase-Type Plasminogen Activator; C070840:licochalcone A