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HGF promotes HTR-8/SVneo cell migration through activation of MAPK/PKA signaling leading to up-regulation of WNT ligands and integrins that target β-catenin

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Abstract

Inadequate migration and invasion of the trophoblast cells during embryo implantation is one of the reasons for pregnancy-related complications such as intrauterine growth restriction and preeclampsia. In the present study, relevance of WNT ligands and integrins associated with hepatocyte growth factor (HGF)-mediated migration of HTR-8/SVneo trophoblastic cells has been investigated. Treatment of HTR-8/SVneo cells with HGF led to a dose-dependent increase in their migration. RT-PCR studies revealed a significant increase in the transcripts of WNT4, WNT11, ITGA2, and ITGAV, which was further confirmed at protein level by Western blotting. HGF treatment also led to increased expression of integrin α2β1 and αVβ5 in HTR-8/SVneo cells. Silencing of WNT4, WNT11, ITGA2, and ITGAV by siRNA led to a significant decrease in HGF-mediated migration of cells. Treatment of cells with HGF led to activation of mitogen-activated protein kinases (MAPK) and protein kinase A (PKA) signaling pathways. Inhibition of MAPK/PKA, by selective inhibitors, led to decrease in the expression of above WNT ligands and integrins. Silencing of WNT4/WNT11 led to concomitant decrease in the expression of ITGA2 and ITGAV and vice versa. HGF treatment also led to significant increase in β-catenin expression, a downstream target of both WNT ligands and integrins. Silencing of β-catenin led to decrease in HGF-mediated migration. β-catenin expression was also down-regulated in WNT4/WNT11/ITGA2/ITGAV silenced cells suggesting a possible cross-communication of WNT ligands and integrins via β-catenin. These studies have established the significance of WNT4/WNT11 as well as ITGA2/ITGAV during HGF-mediated migration of HTR-8/SVneo trophoblastic cells.

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Acknowledgements

This work was supported by the Department of Health Research, Government of India under Grant (GIA/28/2014); Department of Biotechnology, Government of India under Grant (BT/PR12312/MED/30/1424/2014); and J. C. Bose National Fellowship by Science and Engineering Research Board, Department of Science and Technology, Government of India to SKG under Grant (SB/S2/JCB-040/2015). SKG would like to thank the National Institute of Immunology, New Delhi, India for additional financial support. The funding bodies were not involved in the design of the study, data analysis, or writing the manuscript.

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  1. Reproductive Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110 067, India

    Piyush Chaudhary, Sudha Saryu Malhotra & Satish Kumar Gupta

  2. Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Lucknow, 226 025, India

    Piyush Chaudhary & Gosipatala Sunil Babu

  3. Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Lucknow, 226 025, India

    Ranbir Chander Sobti

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  1. Piyush Chaudhary
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PC, SKG, and GSB were involved in project conception and experimental design. PC carried out the experiments. PC, SKG, SSM, GSB, and RCS interpreted the data thus obtained and were involved in writing the manuscript.

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Correspondence to Satish Kumar Gupta.

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Chaudhary, P., Malhotra, S.S., Babu, G.S. et al. HGF promotes HTR-8/SVneo cell migration through activation of MAPK/PKA signaling leading to up-regulation of WNT ligands and integrins that target β-catenin. Mol Cell Biochem 453, 11–32 (2019). https://doi.org/10.1007/s11010-018-3428-3

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