Overexpressed PAK4 promotes proliferation, migration and invasion of choriocarcinoma.

Gestational trophoblastic disease (GTD) includes frankly malignant choriocarcinoma (CCA) and placental site trophoblastic tumor and potentially malignant hydatidiform mole. p21-Activated kinase (PAK) 4 promotes cell motility. This study investigated the role of PAK4 in the pathogenesis of GTD. PAK4 messenger RNA and protein expressions in clinical samples and cell lines of normal placentas and GTD were determined by quantitative real-time polymerase chain reaction and western blot, respectively. The effects of human chorionic gonadotropin (hCG) and phosphoinositide 3 kinase (PI3K) on the expression and activation of PAK4 were investigated by treating CCA JEG3 and JAR cells with anti-hCG antibody and PI3K inhibitor, respectively. The effects of PAK4 on CCA cell proliferation, migration and invasion were assessed by corresponding functional assays. We demonstrated overexpression of PAK4 in GTD and CCA cell lines at both RNA and protein level. hCG is one of the upstream regulators of PAK4 expression, whereas activation of PAK4 is PI3K/PKB dependent in JEG3 and JAR cells. Significant correlation was found between PAK4 expression and proliferation index minichromosome maintenance complex component 7 (P = 0.007). In JEG3 and JAR cells, stably transfected PAK4 increased proliferation, migration and invasion, whereas small interfering RNA knockdown of PAK4 decreased proliferation, migration and invasion along with downregulated CDK6 and membrane-type 1 matrix metalloproteinase (MT1-MMP) and upregulated p16. We further found PAK4-mediated transcription of MT1-MMP in CCA cells by luciferase reporter assay. Our results demonstrated for the first time that overexpressed PAK4 was involved in the pathogenesis of GTD, promoting proliferation and enhancing cell migration and invasion in CCA cells.

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.

Tranexamic acid-associated necrosis and intralesional thrombosis of uterine leiomyomas: a clinicopathologic study of 147 cases emphasizing the importance of drug-induced necrosis and early infarcts in leiomyomas.

INTRODUCTION: Women with menorrhagia have increased levels of plasminogen activators in the endometrium. Tranexamic acid (cyklokapron), an antifibrinolytic agent, is commonly prescribed worldwide to women with menorrhagia, including those with fibroids. Necrosis in uterine leiomyomas may be associated with pregnancy, and progestogen or oral contraceptive use but its association with tranexamic acid has not been investigated. Four hundred ninety patients with uterine leiomyomas in 2004 and 2005 were reviewed. Their ages ranged from 22 to 86 (mean 47.2). One hundred forty-seven (30%) were treated with tranexamic acid. RESULTS: Infarct-type necrosis was observed in the leiomyomas of 38 patients, 22 of whom had tranexamic acid (15%) whereas the remaining 16 had no drug exposure (4.7%) (odds ratio=3.60; 95% confidence interval: 1.83-6.07; P=0.0003). Two patients who took the drug less than 2 weeks before surgery had early infarcts with appearance resembled coagulative type necrosis. Eleven of the 22 cases of drug-induced necrotic leiomyoma (50%) also showed intralesional thrombus formation, and 4 showed organization of the thrombi. CONCLUSIONS: Infarct-type necrosis and thrombosis of leiomyoma was more commonly observed in patients treated with tranexamic acid. Although the drug is effective for menorrhagia, clinicians should be aware of the possible complications associated with leiomyoma necrosis such as pain and fever. Distinguishing between types of necrosis may not always be straightforward particularly in early infarcts when the reparative connective tissue reaction between the viable and necrotic cells is not well-developed, resulting in an appearance similar to coagulative necrosis. When the overall gross and microscopic features of a leiomyoma with coagulative necrosis favor a benign lesion, the drug history should be reviewed so that this type of early and healing infarct-type necrosis is considered as the underlying cause of the apparent coagulative necrosis. This may otherwise result in a diagnosis of smooth muscle tumor of uncertain malignant potential, leading to prolonged follow-up and unnecessary further surgical intervention.