p-21-Activated kinase-1, -4 and -6 and estrogen receptor expression pattern in normal placenta and gestational trophoblastic diseases

• p-21-Activated Kinase-6 (PAK-6) has increased expression in gestational trophoblastic diseases and might be implicated in its pathophysiology.
• p-21-Activated Kinases (PAKs) may play an important role in regulating and limiting estrogen receptor expression in gestational trophoblastic tissue.

ObjectivesTo 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.MethodsWe 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.ResultsIn 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.ConclusionOur 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.