title: Establishment of a choriocarcinoma model from immortalized normal extravillous trophoblast cells transduced with HRASV12.
abstract: Gestational choriocarcinoma is a malignant trophoblastic tumor. The development of novel molecular-targeted therapies is needed to reduce the toxicity of current multiagent chemotherapy and to treat successfully the chemoresistant cases. The molecular mechanisms underlying choriocarcinoma tumorigenesis remain uncharacterized, however, and appropriate choriocarcinoma animal models have not yet been developed. In this study, we established a choriocarcinoma model by inoculating mice with induced-choriocarcinoma cell-1 (iC³-1) cells, generated from HTR8/SVneo human trophoblastic cells retrovirally transduced with activated H-RAS (HRASV12). The iC³-1 cells exhibited constitutive activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and developed into lethal tumors in all inoculated mice. Histopathological analysis revealed that the tumors consisted of two distinct types of cells, reminiscent of syncytiotrophoblasts and cytotrophoblasts, as seen in the human choriocarcinoma. The tumors expressed HLA-G and cytokeratin (trophoblast markers) and hCG (a choriocarcinoma marker). Comparative analysis of gene expression profiles between iC³-1 cells and parental HTR8/SVneo cells revealed that iC³-1 cells expressed matrix metalloproteinases, epithelial-mesenchymal transition-related genes, and SOX3 at higher levels than parental trophoblastic cells. Administration of SOX3-specific short-hairpin RNA decreased SOX3 expression and attenuated the tumorigenic activity of iC³-1 cells, suggesting that SOX3 overexpression might be critically involved in the pathogenesis of choriocarcinoma. Our murine model represents a potent new tool for studying the pathogenesis and treatment of choriocarcinoma.
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University and the Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Takatsune
authors.initials: T
authors.lastname: Shimizu
authors.forename: Hideaki
authors.initials: H
authors.lastname: Naoe
authors.forename: Arisa
authors.initials: A
authors.lastname: Ueki
authors.forename: Joe
authors.initials: J
authors.lastname: Ishizawa
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Chiyoda
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Onishi
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugihara
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.forename: Kouji
authors.initials: K
authors.lastname: Banno
authors.forename: Shinji
authors.initials: S
authors.lastname: Kuninaka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Aoki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002822:Choriocarcinoma / Q000209:etiology* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011247:Pregnancy; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D014594:Uterine Neoplasms / Q000209:etiology* / Q000378:metabolism
chemical_list: D055748:SOXB1 Transcription Factors; C527786:Sox3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)