title: Activation of mitogen-activated protein kinase is required for migration and invasion of placental site trophoblastic tumor.
abstract: Placental site trophoblastic tumor (PSTT) is a gestational neoplasm derived from the extravillous (intermediate) trophoblast of the implantation site. PSTT is characterized by a highly invasive phenotype, but the molecular mechanisms are poorly understood. In this report, we demonstrate that PSTTs expressed the activated (phosphorylated) form of mitogen-activated protein kinase (MAPK) in 84% of cases, whereas the normal extravillous trophoblastic cells did not. To characterize the role of MAPK activation in PSTT, we established the first PSTT cell culture, IST-2, from a surgically resected PSTT. IST-2 cells expressed HLA-G and Mel-CAM but not E-cadherin, an immunophenotype characteristic of PSTT. IST-2 cells were highly motile and invasive in culture as compared to choriocarcinoma JEG-3 cells and normal extravillous trophoblastic cells. Based on wound assay, time-lapse videomicroscopy for cell tracking, and invasion chamber assays, we found that the motility and invasion of IST-2 cells were significantly reduced (P<0.01) after treatment with the MEK inhibitors CI-1040 and PD 59089, which prevent activation of MAPK. In contrast, neither compound had any effect on normal extravillous trophoblastic cells or JEG-3 cells. In conclusion, our findings demonstrate a functional role of MAPK activation in the motility and invasion of PSTT.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Köbel
authors.forename: Gudrun
authors.initials: G
authors.lastname: Pohl
authors.forename: Wolfgang D
authors.initials: WD
authors.lastname: Schmitt
authors.forename: Steffen
authors.initials: S
authors.lastname: Hauptmann
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D016022:Case-Control Studies; D002465:Cell Movement; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018245:Trophoblastic Tumor, Placental Site / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology*; D014327:Trophoblasts / Q000201:enzymology; D014594:Uterine Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology*
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one