Abstract
The inactivation of p53 can lead to the formation of pathological scars, including hypertrophic scars and keloids. HOXA5 has been reported to be a critical transcription factor in the p53 pathway in cancers. However, whether HOXA5 also plays a role in pathological scar progression through activating p53 signaling remains unknown. In this study, we first demonstrated that HOXA5 overexpression in hypertrophic scar-or keloids-derived fibroblasts decreased cell proliferation, migration and collagen synthesis, whereas increased cell apoptosis. Furthermore, the results of luciferase activity assays and ChIP PCR assays indicated that HOXA5 transactivated p53 by binding to the ATTA-rich core motif in the p53 promoter. HOXA5 also increased the levels of p21 and Mdm2, which are downstream targets of p53. Interestingly, silencing p53 in these pathological scar-derived fibroblasts partially attenuated HOXA5-mediated growth inhibition effect and HOXA5-induced apoptosis. In addition, 9-cis-retinoic acid augmented the expression of HOXA5 and promoted the effects of HOXA5 on pathological scar-derived fibroblasts, and these effects could be suppressed by HOXA5 knockdown. Thus, our study reveals a role of HOXA5 in mediating the cellular processes of pathological scar-derived fibroblasts by transcriptionally activating the p53 signaling pathway, and 9-cis-retinoic acid may be a potential therapy for pathological scars.
Highlights
Pathological scars, including keloids and hypertrophic scars that are characteristic of excessive dermal fibrosis, are caused by excessive cell proliferation and collagen synthesis during the wound healing process
To investigate the role of homeobox A5 (HOXA5) in the cell biology of fibroblasts derived from keloids (KFb) or from hypertrophic scars (HSFb), we established HOXA5 overexpression in both types of scar-derived fibroblasts (Fig. S1)
We investigated the effects of the HOXA5 overexpression on the apoptosis of KFb and HSFb by flow cytometry
Summary
Pathological scars, including keloids and hypertrophic scars that are characteristic of excessive dermal fibrosis, are caused by excessive cell proliferation and collagen synthesis during the wound healing process. Pathological scars can result in severe organ malformation and dysfunction and are consistently difficult to cure. The underlying molecular mechanism of scar formation and the anti-scarring strategy are the research hotspots. The wound healing process includes three overlapping but distinct stages: inflammation, granulation tissue formation, and remodeling[1]. Each group of stage-specific cells sequentially occur at the wounded site, proliferate, In human breast cancer, the loss of p53 expression may be caused by a lack of homeobox A5 (HOXA5) expression[8]. Homeobox genes are a group of genes that play key roles in both development and postnatal regeneration[9]
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