Long Noncoding RNA CASC2 Facilitated Wound Healing through miRNA‐155/HIF‐1α in Diabetic Foot Ulcers

Abstract

Diabetic foot ulcers (DFU) are among the serious complications which are closely linked to diabetes mellitus. However, there is still a lack of accurate and effective standard prevention and treatment programs for DFU. In this manuscript, we have investigated the function of lncRNA cancer susceptibility candidate 2 (CASC2)/miR-155/hypoxia-inducible factor 1-alpha (HIF-1α) in the wound healing of DFU. We have analyzed lncRNA CASC2`s expression in the marginal tissues of ulcers in patients and mice with DFU. Additionally, the interaction relationship and mechanism between lncRNA CASC2, miR-155, and HIF-1α were determined, which proved the effects of lncRNA CASC2/miR-155/HIF-1α on fibroblasts apoptosis, proliferation, and migration. According to our study, the lncRNA CASC2’s expression was low in the tissues of ulcers of DFU mice and patients. lncRNA CASC2’s overexpression promoted fibroblasts migration, proliferation, and inhibited apoptosis and was beneficial for the healing of wounds, preferably in the DFU mice. In addition, lncRNA CASC2 directly targets miR-155 and HIF-1α functions as miR-155’s target gene. Overexpression of miR-155 abrogated the function of lncRNA CASC2. Similarly, HIF-1α’s inhibition has reversed the effect of miR-155 downregulation on fibroblasts. In general, overexpression of lncRNA CASC2 facilitated wound healing through miR-155/HIF-1α in DFU.

Effect and mechanism of microRNAs on various diabetic wound local cells

“…This dysregulated pathway dampened the migration, proliferation, and collagen production of fibroblasts. 19 Another study reported that in the margin of DFUs miR-29b was downregulated; its upstream lncRNA H19 and downstream FBN1 were upregulated; whereas these changes had positive effects on fibroblast functions, including increased proliferation and migration and decreased apoptosis. 33 It is considered that these changes are attributed to compensatory effects of the body to promote the healing of diabetic chronic wounds.…”

“…32 Similarly, overexpressed miR-155 in the wound not only inhibits the function of fibroblasts but also further inhibits the expression of VEGF by inhibiting the expression of HIF-1α in fibroblasts. 19 Low expression of miR-21-3p in the wound can increase the expression of its target SPRY1, inhibit the function of fibroblasts and inhibit their secretion of VEGF. 30 After the reduction of HIF-1 by miR-210, the Tips: """: increase, "#": decrease, "-": inhibited, "+": enhanced, "/": have no effect or have not been reported in relevant literature.…”

“…Several studies have shown that miR‐155 expression is increased in diabetic wounds, 19,20 which promotes the conversion of macrophages to M1 phenotype by inhibiting negative regulators of inflammation 21 . All of the aforementioned miRs are upregulated in diabetic wounds.…”

Exosomal ncRNAs: The pivotal players in diabetic wound healing

“…Increasing HIF-1α level by lncRNAs is considered as an effective strategy to improve healing process. LncRNA-H19 and lncRNA MIR31HG have been employed to regulate the expression of HIF-1α to enhance the proliferation of fibroblast ( 54 ). In addition, lncRNA FAM83A-AS1 involved several signaling pathways such as glycolysis, hypoxia, and OXPHOS signaling.…”

Non-coding RNAs: Role in diabetic foot and wound healing

“…By contrast, miR-155 overexpression inhibited the function of CASC2[ 75 ]. Another study showed that HIF-1α inhibition reversed the effects of miR-155 downregulation on fibroblasts[ 76 ]. Evidently, lncRNAs have a considerable regulatory role in cellular functions during re-epithelialization and remodeling.…”