title: Downregulation of ASPP2 in choriocarcinoma contributes to increased migratory potential through Src signaling pathway activation.
abstract: Gestational choriocarcinoma is a malignant tumor derived from placental trophoblast and the most aggressive member of gestational trophoblastic disease (GTD). Apoptosis-stimulating protein of p53-2 (ASPP2) is a member of ASPP family that transactivates p53 and thereby functions as a tumor suppressor. In this study, the expression profile of ASPP2 in choriocarcinoma was examined in comparison with normal placentas and hydatidiform moles, the latter being a type of GTD that carries malignant potential. Downregulation of ASPP2 messenger RNA and protein was demonstrated in choriocarcinoma by quantitative PCR and immunohistochemistry. ASPP2-transfected choriocarcinoma cells (JEG-3 and JAR) showed an increase in apoptosis and a decrease in cell migration as detected by TdT-mediated dUTP nick end labeling and wound healing assays, respectively, illustrating the complex action of ASPP2 on cell functions other than programmed cell death. Activated Src is known to be important in tumor progression. Transfection of ASPP2 but not ASPP1, another tumor-suppressive ASPP, was found to be related to subsequent decreased Src-pY416 phosphorylation, suggesting an inactivating effect of ASPP2 on Src. Moreover, this ASPP2-mediated inactivation of Src could be abolished by RNA interference with C-terminal Src kinase (Csk), a kinase that can inhibit Src activation. Our findings suggested that the ability of ASPP2 to attenuate Src activation was specific to ASPP2 in a Csk-dependent manner. Taken together, we demonstrated a loss of tumor-suppressive ASPP2 in choriocarcinoma with effects on cell migration and apoptosis. We also unveiled a possible mechanistic link between ASPP2 and Csk/Src signaling pathway, implicating the multiple cellular functions of ASPP2.
authors.affiliation: Department of Pathology and.
authors.forename: Victor C Y
authors.initials: VC
authors.lastname: Mak
authors.forename: Lee
authors.initials: L
authors.lastname: Lee
authors.forename: Michelle K Y
authors.initials: MK
authors.lastname: Siu
authors.forename: Oscar G W
authors.initials: OG
authors.lastname: Wong
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Hextan Y S
authors.initials: HY
authors.lastname: Ngan
authors.forename: Esther S Y
authors.initials: ES
authors.lastname: Wong
authors.forename: Annie N Y
authors.initials: AN
authors.lastname: Cheung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D002822:Choriocarcinoma / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D031901:Gestational Trophoblastic Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D011247:Pregnancy; D034622:RNA Interference; D015398:Signal Transduction; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C498406:PPP1R13B protein, human; C090468:TP53BP2 protein, human; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human