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.

p53的失活可导致病理性瘢痕的形成，包括增生性瘢痕和瘢痕疙瘩。据报道，HOXA5 是癌症 p53 通路中的关键转录因子。然而，HOXA5 是否也通过激活 p53 信号传导在病理性瘢痕进展中发挥作用仍然未知。在这项研究中，我们首先证明了肥厚性瘢痕或瘢痕疙瘩衍生的成纤维细胞中 HOXA5 的过表达降低了细胞增殖、迁移和胶原蛋白合成，而增加了细胞凋亡。此外，荧光素酶活性测定和 ChIP PCR 测定的结果表明，HOXA5 通过与 p53 启动子中富含 ATTA 的核心基序结合来反式激活 p53。HOXA5 还增加了 p21 和 Mdm2 的水平，它们是 p53 的下游靶标。有趣的是，在这些病理性瘢痕来源的成纤维细胞中沉默 p53 部分减弱了 HOXA5 介导的生长抑制作用和 HOXA5 诱导的细胞凋亡。此外，9-顺式视黄酸增加了 HOXA5 的表达并促进了 HOXA5 对病理性瘢痕来源的成纤维细胞的作用，这些作用可以通过 HOXA5 敲低来抑制。因此，我们的研究揭示了 HOXA5 通过转录激活 p53 信号通路在介导病理性瘢痕来源的成纤维细胞的细胞过程中的作用，并且 9-顺式-视黄酸可能是病理性瘢痕的潜在疗法。并且这些影响可以通过 HOXA5 敲低来抑制。因此，我们的研究揭示了 HOXA5 通过转录激活 p53 信号通路在介导病理性瘢痕来源的成纤维细胞的细胞过程中的作用，并且 9-顺式-视黄酸可能是病理性瘢痕的潜在疗法。并且这些影响可以通过 HOXA5 敲低来抑制。因此，我们的研究揭示了 HOXA5 通过转录激活 p53 信号通路在介导病理性瘢痕来源的成纤维细胞的细胞过程中的作用，并且 9-顺式-视黄酸可能是病理性瘢痕的潜在疗法。