p21-Activated kinase-1 promotes aggressive phenotype, cell proliferation, and invasion in gestational trophoblastic disease.
Gestational trophoblastic disease (GTD) includes hydatidiform mole (HM), which can develop persistent gestational trophoblastic neoplasia requiring chemotherapy; choriocarcinoma, which is a frankly malignant tumor; placental site trophoblastic tumor; and epithelioid trophoblastic tumor. p21-Activated kinases (PAKs) promote malignant tumor progression. Therefore, this study investigated PAK1, PAK2, and p-PAK2 Ser(20) in the pathogenesis of GTD. By real-time PCR, PAK1 mRNA was significantly higher in HMs, particularly metastatic HMs (P = 0.046) and HMs that developed persistent disease (P = 0.011), when compared with normal placentas. By immunohistochemistry, significantly increased cytoplasmic PAK1 immunoreactivity in cytotrophoblasts was also detected in HMs (P = 0.042) and choriocarcinomas (P = 0.003). In addition, HMs that developed persistent disease displayed higher PAK1 immunoreactivity than those that regressed (P = 0.016), and elevated PAK1 immunoreactivity was observed in placental site trophoblastic tumors. Indeed, there was significant positive correlation between PAK1 expression and the proliferative indices Ki-67 (P = 0.016) and MCM7 (P = 0.026). Moreover, higher PAK1 mRNA and protein expression was confirmed in the choriocarcinoma cell-lines JEG-3 and JAR; however, PAK2 mRNA and p-PAK2 immunoreactivity showed a similar expression pattern in normal first trimester placentas and GTD. Knockdown of PAK1 in JEG-3 and JAR reduced cell proliferation, migration, and invasion ability, up-regulated p16, and down-regulated vascular endothelial growth factor and MT1-MMP expression. This is the first report revealing the involvement of PAK1 in the pathogenesis and clinical progress of GTD.
Siu
Michelle K Y
MK
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.
Yeung
Matthew C W
MC
Zhang
HuiJuan
H
Kong
Daniel S H
DS
Ho
Joanna W K
JW
Ngan
Hextan Y S
HY
Chan
Dominic C W
DC
Cheung
Annie N Y
AN
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D005865:Gestational Age; D031901:Gestational Trophoblastic Disease / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
D007527:Isoenzymes; D054462:p21-Activated Kinases