title: Dysregulated activation of c-Src in gestational trophoblastic disease contributes to its aggressive progression.
abstract: BACKGROUND
  Gestational trophoblastic disease (GTD) is a heterogeneous group of pregnancy-related disorders. Hydatidiform mole (HM) is the most common type of GTD, whereas gestational choriocarcinoma is the most aggressive. Non-receptor tyrosine kinase c-Src contributes to the transformation to a malignant phenotype in various cancers. However, the role of c-Src in the pathogenesis of GTD remains largely unknown.
  
  
  METHODS
  The expression level of phosphorylated c-Src was determined by immunohistochemistry and Western blotting assay. JAR and JEG-3 cells were treated with hCG, specific c-Src inhibitor saracatinib and PP2, and PKA specific inhibitor, PKI. Cell growth rate and cell migration/invasion ability was determined by cell proliferation and transwell assays respectively.
  
  
  RESULTS
  c-Src was highly activated in HM tissues and choriocarcinoma cells (JAR and JEG-3). c-Src was activated by hCG in a time and concentration-dependent manner, which was abrogated by specific c-Src and PKA inhibitors. Inhibition of c-Src activity in JAR and JEG-3 cells by saracatinib leaded to a decrease in the rate of cell growth and cell migration/invasion ability. Furthermore, inhibition of c-Src phosphorylation induced cell cycle arrest and reduced expressions of cyclin A2, cyclin B1, cyclin E1, FOXD3 and NANOG. Moreover, inhibition of c-Src activity resulted in decreased p-FAK(Tyr397) phosphorylation.
  
  
  CONCLUSIONS
  Our findings indicate an important role of c-Src in the pathogenesis of GTD, and we propose that c-Src inhibitors are potential adjuvant chemotherapeutic drugs for the treatment of GTD.
authors.affiliation: Departments of Pathology and Bio-Bank, The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: W
authors.initials: W
authors.lastname: Wu
authors.affiliation: Departments of Pathology and Bio-Bank, The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Pathology and Bio-Bank, The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Departments of Pathology and Bio-Bank, The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Pathology and Bio-Bank, The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: zhanghj815@126.com.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
mesh_terms: D052117:Benzodioxoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D031901:Gestational Trophoblastic Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D011247:Pregnancy; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C412373:AG 1879; D052117:Benzodioxoles; D006063:Chorionic Gonadotropin; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; C515233:saracatinib; D019061:src-Family Kinases
keywords: Choriocarcinoma; Gestational trophoblastic disease; Human chorionic gonadotrophin; Hydatidiform mole; c-Src