Research Paper Volume 12, Issue 16 pp 16621—16646
Prolonged treatment with Y-27632 promotes the senescence of primary human dermal fibroblasts by increasing the expression of IGFBP-5 and transforming them into a CAF-like phenotype
- 1 Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
- 2 Key Laboratory of Biotechnology and Biological Resource Utilization in Universities of Shandong and College of Life Science, Dezhou University, Dezhou, China
- 3 Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, China
- 4 Department of Outpatient Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
- 5 Department of Stomatology, Shengli Oilfield Central Hospital, Dongying, Shandong, China
Received: May 22, 2020 Accepted: July 21, 2020 Published: August 25, 2020https://doi.org/10.18632/aging.103910
How to Cite
Copyright © 2020 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The Rho-kinases (ROCK) inhibitor Y-27632 has been shown to promote the growth of epidermal cells, however, its potential effects on human dermal fibroblasts (HDFs) need to be clarified. Here we show that prolonged treatment of HDFs with Y-27632 decreased their growth by inducing senescence, which was associated with induction of the senescence markers p16 and p21, and downmodulation of the ERK pathways. The senescent HDFs induced by Y-27632 acquired a cancer-associated-fibroblast (CAF)-like phenotype to promote squamous cell carcinoma (SCC) cell growth in vitro. Expression of a newly identified target of Y-27632 by RNA-seq, insulin growth factor binding protein 5 (IGFBP-5), was dramatically increased after 24 h of treatment with Y-27632. Adding recombinant IGFBP-5 protein to the culture medium produced similar phenotypes of HDFs as did treatment with Y-27632, and knockdown of IGFBP-5 blocked the Y-27632-induced senescence. Furthermore, Y-27632 induced the expression of an IGFBP-5 upstream gene, GATA4, and knockdown of GATA4 also reduced the Y-27632-induced senescence. In summary, these results demonstrate for the first time that Y-27632 promotes cellular senescence in primary HDFs by inducing the expression of IGFBP-5 and that prolonged treatment with Y-27632 potentially transforms primary HDFs into CAF-like cells.