Abstract
Tumor progression and pregnancy have several features in common. Tumor cells and placental trophoblasts share many signaling pathways involved in migration and invasion. Preeclampsia, associated with impaired differentiation and migration of trophoblastic cells, is an unpredictable and unpreventable disease leading to maternal and perinatal mortality and morbidity. Like in tumor cells, most pathways, in which p21 is involved, are deregulated in trophoblasts of preeclamptic placentas. The aim of the present study was to enlighten p21’s role in tumorigenic choriocarcinoma and trophoblastic cell lines. We show that knockdown of p21 induces defects in chromosome movement during mitosis, though hardly affecting proliferation and cell cycle distribution. Moreover, suppression of p21 compromises the migration and invasion capability of various trophoblastic and cancer cell lines mediated by, at least partially, a reduction of the extracellular signal-regulated kinase 3, identified using transcriptome-wide profiling, real-time PCR, and Western blot. Further analyses show that downregulation of p21 is associated with reduced matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2. This work evinces that p21 is involved in chromosome movement during mitosis as well as in the motility and invasion capacity of trophoblastic and cancer cell lines.
Highlights
The hallmarks of cancer include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis [1,2]
P21 is exceedingly regulated by a myriad of different transcriptional p53-independent controllers and it is induced in differentiated cells [26], which could explain the observed levels in choriocarcinoma cells
With the present work we have studied the roles of p21 in various placental choriocarcinoma and invasive trophoblastic cell lines derived from first trimester placenta
Summary
The hallmarks of cancer include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis [1,2]. Aberrant cell migration and invasion contribute to metastasis responsible for over 90% of cancer-associated deaths [3]. Tumor progression and placenta development have many common features including proliferation and invasion [4]. Invasion of extravillous trophoblasts (EVT) into the maternal decidua is essential for placental embedment and fetal development [4]. Failures in this process have been implicated in a wide spectrum of pregnancy disorders like preeclampsia (PE). The pathophysiology of PE is associated with profound cellular dysfunctions including deregulated proliferation, enhanced apoptosis, defective differentiation with poor invasion of trophoblastic cells, and oxidative stress [6,7,8]
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