Blood platelets stimulate cancer extravasation through TGFβ-mediated downregulation of PRH/HHEX

Marcolino De Assis, Eudmar; Siddiqui, Yusra Hasan; van den Bosch, Marion; Poole, Alastair W; Jayaraman, Padma-Sheela; Gaston, Kevin

Abstract

Cancer cells go through a process known as epithelial–mesenchymal transition (EMT) during which they acquire the ability to migrate and invade extracellular matrix. Some cells also acquire the ability to move across a layer of endothelial cells to enter and exit the bloodstream; intra- and extravasation, respectively. The transcription factor PRH/HHEX (proline-rich homeodomain/haematopoietically expressed homeobox) controls cell proliferation and cell migration/invasion in a range of cell types. Our previous work showed that PRH activity is downregulated in prostate cancer cells owing to increased inhibitory PRH phosphorylation and that this increases cell proliferation and invasion. PRH inhibits migration and invasion by prostate and breast epithelial cells in part by activating the transcription of Endoglin, a transforming growth factor β (TGFβ) co-receptor. Here we show that depletion of PRH in immortalised prostate epithelial cells results in increased extravasation in vitro. We show that blood platelets stimulate extravasation of cells with depleted PRH and that inhibition of TGFβ signalling blocks the effects of platelets on these cells. Moreover, TGFβ induces changes characteristic of EMT including decreased E-Cadherin expression and increased Snail expression. We show that in prostate cells PRH regulates multiple genes involved in EMT and TGFβ signalling. However, both platelets and TGFβ increase PRH phosphorylation. In addition, TGFβ increases binding of its effector pSMAD3 to the PRH/HHEX promoter and downregulates PRH protein and mRNA levels. Thus, TGFβ signalling downregulates PRH activity by multiple mechanisms and induces an EMT that facilitates extravasation and sensitises cells to TGFβ.

Citation

Marcolino De Assis, E., Siddiqui, Y. H., van den Bosch, M., Poole, A. W., Jayaraman, P.-S., & Gaston, K. (2020). Blood platelets stimulate cancer extravasation through TGFβ-mediated downregulation of PRH/HHEX. Oncogenesis, 9, Article 10. https://doi.org/10.1038/s41389-020-0189-0

• Journal Article Type: Article
• Acceptance Date: Jan 10, 2020
• Online Publication Date: Feb 4, 2020
• Publication Date: Feb 4, 2020
• Deposit Date: Jan 13, 2020
• Publicly Available Date: Feb 10, 2020
• Journal: Oncogenesis
• Electronic ISSN: 2157-9024
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Article Number: 10
• DOI: https://doi.org/10.1038/s41389-020-0189-0
• Keywords: Cancer Research; Molecular Biology
• Public URL: https://nottingham-repository.worktribe.com/output/3719448
• Publisher URL: https://www.nature.com/articles/s41389-020-0189-0
• Additional Information: Received: 4 September 2018; Revised: 7 January 2020; Accepted: 10 January 2020; First Online: 4 February 2020; : The authors declare that they have no conflict of interest.