miR‐155 promotes m6A modification of SOX2 mRNA through targeted regulation of HIF‐1α and delays wound healing in diabetic foot ulcer in vitro models

ABSTRACT Objective Diabetic foot ulcers (DFU) are one of the most destructive complications of diabetes mellitus. The aim of this study was to link miR‐155 and SOX2 with DFU to explore the regulation of wound healing by DFU and its potential mechanism. Methods Human keratinocytes (HaCaT) were induced with advanced glycation end products (AGEs) to construct DFU models in vitro. AGE‐induced HaCaT cells were subjected to CCK‐8 assays, flow cytometry, and wound healing assays to evaluate cell proliferation, apoptosis, and migration capacity, respectively. RT–qPCR and Western blotting were used to determine gene and protein expression levels, respectively. N6‐methyladenosine (M6A) levels in total RNA were assessed using an M6A methylation quantification kit. Results Our results suggested that the inhibition of miR‐155 promoted wound healing in an in vitro DFU model, while the knockdown of HIF‐1α reversed this process, and that HIF‐1α was a target protein of miR‐155. In addition, knockdown of HIF‐1α promoted the m6A level of SOX2 mRNA, inhibited the expression of SOX2, and inhibited the activation of the EGFR/MEK/ERK signaling pathway, thus inhibiting the proliferation and migration of HaCaT cells and promoting the apoptosis of HaCaT cells, while overexpression of SOX2 reversed this effect. We also found that METTL3 knockdown had the opposite effect of HIF‐1α knockdown. Conclusions Inhibition of miR‐155 promoted the expression of HIF‐1α and attenuated the m6A modification of SOX2 mRNA, thereby promoting the expression of SOX2 and activating the downstream EGFR/MEK/ERK signaling pathway to promote wound healing in an in vitro DFU model. Diabetic foot ulcers (DFU) are one of the most devastating complications of diabetes. MiR‐155 inhibition and SOX2 have been shown to be associated with wound healing. Our study found that inhibiting miR‐155 can promote the expression of HIF‐1α, reduce the m6A modification of SOX2 mRNA, activate the downstream EGFR/MEK/ERK pathway, and promote wound healing in DFU models.