Restoration of TGF-beta regulation of plasminogen activator inhibitor-1 in Smad3-restituted human choriocarcinoma cells.
Proliferation, migration, and invasiveness of the normal placental extravillous trophoblast (EVT) cells are negatively regulated by transforming growth factor-beta (TGF-beta), whereas malignant EVT (JAR and JEG-3 choriocarcinoma) cells are resistant to TGF-beta. These malignant cells were found to have lost the expression of Smad3. Present study examined whether Smad3 restitution in JAR cells could restore TGF-beta response. We produced a stable Smad3 cDNA-transfected clone (JAR-smad3/c) which exhibited further upregulation of Smad3 in the presence of TGF-beta1. Since anti-invasive effects of TGF-beta in the normal EVT cells were shown to be mediated in part by plasminogen activator inhibitor-1 (PAI-1) and urokinase-type plasminogen activator (uPA), we compared the expression of PAI-1 and uPA in the normal EVT, JAR, and JAR-smad3/c cells in the presence or absence of TGF-beta1. The basal levels of PAI-1 mRNA and secreted PAI-1 and uPA proteins were found to be very low in JAR and JAR-smad3/c cells, as compared to the normal EVT cells. However, TGF-beta1 upregulated PAI-1 and downregulated uPA in JAR-smad3/c cells, but not in JAR cells. Thus, resistance of choriocarcinoma cells to anti-invasive effects of TGF-beta may, at least in part, be due to loss of Smad3 expression.
Xu
Guoxiong
G
Departments of Anatomy and Cell Biology, The University of Western Ontario, London, Ont., Canada N6A 5C1.
Chakraborty
Chandan
C
Lala
Peeyush K
PK
D002460:Cell Line; D002822:Choriocarcinoma / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051900:Smad3 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D014568:Urokinase-Type Plasminogen Activator