Interdependence of JAK-STAT and MAPK signaling pathways during EGF-mediated HTR-8/SVneo cell invasion

PLoS One. 2017 May 25;12(5):e0178269. doi: 10.1371/journal.pone.0178269. eCollection 2017.


Invasion of trophoblast cells is spatio-temporally regulated by various cytokines and growth factors. In pregnancy, complications like preeclampsia, shallow invasion of trophoblast cells and low amounts of epidermal growth factor (EGF) have been reported. In the present study, regulatory mechanisms associated with EGF-mediated invasion in HTR-8/SVneo trophoblastic cells have been delineated. Treatment of HTR-8/SVneo cells with EGF (10 ng/ml) led to eight fold increase (p < 0.05) in invasion. Increased invasion of HTR-8/SVneo cells by EGF was associated with an increase in phosphorylation of ERK½. In addition, significant phosphorylation of STAT1 (ser 727) and STAT3 (both tyr 705 and ser 727 residues) was also observed, accompanied by a decrease in total STAT1. Inhibition of ERK½ phosphorylation by U0126 (10 μM) led to a significant decrease in EGF-mediated invasion with simultaneous decrease in the phosphorylated forms of STAT3 and STAT1. Decrease in total STAT1 was also reversed on inhibition of ERK½. Interestingly, inhibition of STAT3 by siRNA led to a significant decrease in EGF-mediated invasion of HTR-8/SVneo cells and phosphorylation of STAT1, but it did not have any effect on the activation of ERK½. On the other hand, inhibition of STAT1 by siRNA, also led to a significant decrease in the EGF-mediated invasion of HTR-8/SVneo cells, showed concomitant decrease in ERK½ phosphorylation and STAT3 phosphorylation at ser 727 residue. These results suggest cross-communication between ERK½ and JAK-STAT pathways during EGF-mediated increase in invasion of trophoblast cells; phosphorylation at ser 727 residue of both STAT3 and STAT1 appears to be critical.

MeSH terms

  • Blotting, Western
  • Cell Line
  • Embryo Implantation / physiology
  • Epidermal Growth Factor / physiology*
  • Female
  • Humans
  • Janus Kinases / physiology*
  • MAP Kinase Signaling System / physiology*
  • Phosphorylation
  • Placenta / cytology
  • Placenta / physiology*
  • Pregnancy
  • RNA, Small Interfering / metabolism
  • STAT1 Transcription Factor / physiology
  • STAT3 Transcription Factor / physiology*
  • Signal Transduction / physiology*
  • Trophoblasts / physiology*


  • RNA, Small Interfering
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Epidermal Growth Factor
  • Janus Kinases

Grants and funding

This research is funded by J. C. Bose Fellowship (SB/S2/JCB-040/2015) granted to SKG by Science and Engineering Research Board, Department of Science and Technology and Department of Biotechnology project number—BT/PR12312/MED/30/1424/2014, Government of India. SKG would also like to acknowledge National Institute of Immunology, New Delhi, India for financial support. These funding sources have no role in data collection, experimental design and manuscript preparation.