N7-methylguanosine-related gene decapping scavenger enzymes as a novel biomarker regulating epithelial cell function in diabetic foot ulcers

Abstract

BACKGROUND

Chronic nonhealing wounds, such as diabetic foot ulcer (DFU), suffer from delayed healing. Identifying effective biomarkers or targets is crucial for managing these refractory wounds. While N7-methylguanosine (m7G) methylation is important in RNA modification, its connection to chronic nonhealing wounds is poorly understood.

AIM

To assess the potential m7G biomarkers in DFU and their underlying molecular mechanisms.

METHODS

Differential expression analysis and weighted gene coexpression network analysis identified key genes in DFU. Hub genes were determined through m7G-DFU intersection, and gene set enrichment analysis was conducted. Diagnostic potential of hub genes was assessed using receiver operating characteristic curves. The hub gene’s expression (decapping scavenger enzyme, DCPS) was confirmed using quantitative reverse transcription polymerase chain reaction and immunofluorescence. In vitro, normal human epidermal keratinocyte models were knocked down for DCPS, and the function was assessed through flow cytometry, western blotting, immunofluorescence, Transwell assays, and scratch assays.

RESULTS

Weighted gene coexpression network analysis and differential expression analysis revealed links between DFU datasets and methylation processes, identifying hub gene DCPS as a candidate biomarker. Notably, its diagnostic value was confirmed with a test set and receiver operating characteristic curve, achieving an area under the curve of 0.98 and 0.99. Quantitative reverse transcription polymerase chain reaction and immunofluorescence analyses showed significantly reduced expression of DCPS in the wound skin of DFU patients and streptozotocin-induced diabetic mice, indicating its role as a regulatory factor of m7G in diabetic wounds. Mechanistically, in vitro studies showed that DCPS knockdown significantly reduced cyclin-dependent kinase 6 and cyclin D1 expression, disrupted the epithelial cell cycle, inhibited cell proliferation and migration, and increased apoptosis rates.

CONCLUSION

DCPS was identified as a promising DFU biomarker and therapeutic target, regulating m7G to affect cell cycle, proliferation, and epithelial cell migration during DFU wound healing.

Keywords: Diabetic foot ulcer; N7-methylguanosine; Decapping scavenger enzyme; Biomarker; Normal human epidermal keratinocytes; Cell cycle

Core Tip: This study identified decapping scavenger enzyme (DCPS) as a potential biomarker and therapeutic target for diabetic foot ulcers. It demonstrated that DCPS regulated m7G methylation, which affected cell cycle progression, proliferation, and migration of epithelial cells, which are crucial for wound healing. DCPS expression was significantly reduced in diabetic foot ulcer patients and diabetic mouse models, and its knockdown disrupted cell function, making it a promising target for improving healing in chronic nonhealing wounds.