title: Urokinase induces stromal cell-derived factor-1 expression in human hepatocellular carcinoma cells.
abstract: Both the urokinase-type plasminogen activator (uPA) and the uPA receptor (uPAR) play important roles with regard to hepatocellular carcinoma (HCC) progression and metastasis. Notably, the stromal cell-derived factor-1 (SDF-1) is an important chemokine involved in HCC pathology. However, the influence of uPA on SDF-1 expression in human HCC cells remains unknown. We investigated the mechanisms underlying the modulation of SDF-1 expression through uPA stimulation in human HCC SK-Hep-1 cells. SK-Hep-1 cells stimulation with uPA induced increases in the expression and secretion of SDF-1. By using specific inhibitors and small interfering RNA, we have demonstrated that the activation of extracellular signal-related kinase (ERK) and c-Jun-NH(2)-terminal kinase (JNK) pathways are critical for uPA-induced SDF-1 expression. Transcription factor ELISA and chromatin immunoprecipitation assays suggest that uPA increase Sp1- and AP-1-DNA-binding activities in SK-Hep-1 cells. Inhibition of Sp1 and AP-1 activations by specific siRNAs blocked the uPA-induced SDF-1 promoter activity and expression. The effect of uPA on SK-Hep-1 signaling and SDF-1 expression is mediated by uPAR. In summary, our findings serve to elucidate the uPA/uPAR downstream signaling, providing new insight into the function of uPA in HCC cells.
authors.affiliation: Department of Medicine, Armed-Forces Taichung General Hospital, Taichung, Taiwan.
authors.forename: Wen-Hsiu
authors.initials: WH
authors.lastname: Hsu
authors.forename: Cheng-Nan
authors.initials: CN
authors.lastname: Chen
authors.forename: Hai-I
authors.initials: HI
authors.lastname: Huang
authors.forename: Yi-Liang
authors.initials: YL
authors.lastname: Lai
authors.forename: Chun-Yuh
authors.initials: CY
authors.lastname: Teng
authors.forename: Wu-Hsien
authors.initials: WH
authors.lastname: Kuo
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*
chemical_list: D054377:Chemokine CXCL12; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D014568:Urokinase-Type Plasminogen Activator