p-21-Activated kinase-1, -4 and -6 and estrogen receptor expression pattern in normal placenta and gestational trophoblastic diseases.
OBJECTIVE
To delineate the potential role of p21-activated kinases (PAKs) in the pathogenesis of gestational trophoblastic diseases (GTD) by defining the expression pattern of PAK-1, -4 and -6 and their potential implication in estrogen receptor (ER) regulation of normal placental tissue and GTD.


METHODS
We evaluated immunohistochemically 10 normal first-trimester placentas (NP), 10 partial moles (PM), 15 complete moles (CM) and 3 choriocarcinomas (CCA) for PAK-1, PAK-4, PAK-6 and ER expression intensity and localization. Staining outcomes were assessed utilizing non-parametric Kruskal-Wallis one-way analysis of variance test followed by pairwise Wilcoxon Rank Sum tests. Statistical significance was determined by two-sided p-value of <0.05.


RESULTS
In NP, PAK-6 immunoreactivity was predominantly cytoplasmic. Compared to NP, PM and CM demonstrated significant increase of cytoplasmic PAK-6 in cytotrophoblast (p=0.012, p=0.033 respectively), accompanied by significantly increased nuclear immunoreactivity in cytotrophoblast (p=0.008, p=0.045 respectively) and intermediate trophoblast (p=0.003, p=0.015 respectively). PAK-4 was found significantly upregulated in both cytoplasmic and nuclear compartments of cytotrophoblast and syncytiotrophoblast in PM (p=0.004 and p=0.002 for cytotrophoblast; p=0.018 and p=0.002 for syncytiotrophoblast, respectively) and CM (p=0.001 and p=0.001 for cytotrophoblast; p=0.002 and p=0.001 for syncytiotrophoblast, respectively) when compared to NP, whereas PAK-1 expression was significantly reduced in the syncytiotrophoblast of PM (p=0.025 for cytoplasm and p=0.008 for nucleus). Nuclear expression of ER was undetectable in all stained samples.


CONCLUSIONS
Our results reveal PAK-6 upregulation in GTD compared to NP. The absence of nuclear expression of ER might stem in part from the repressive effect of PAK-6 in trophoblastic tissue.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Melina
M
Shoni
Zoltan
Z
Nagymanyoki
Allison F
AF
Vitonis
Cynthia
C
Jimenez
Shu-Wing
SW
Ng
Bradley J
BJ
Quade
Ross S
RS
Berkowitz
D002822:Choriocarcinoma / Q000201:enzymology / Q000378:metabolism; D005260:Female; D031901:Gestational Trophoblastic Disease / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes; D010920:Placenta / Q000201:enzymology / Q000378:metabolism*; D011247:Pregnancy; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D014594:Uterine Neoplasms / Q000201:enzymology / Q000378:metabolism; D054462:p21-Activated Kinases / Q000096:biosynthesis*
D007527:Isoenzymes; D011960:Receptors, Estrogen; D054462:p21-Activated Kinases
Estrogen receptors; Gestational trophoblastic diseases; PAK-6; p-21-Activated Kinases