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Publication
Dichotomous role of miR193b-3p in diabetic foot ulcers maintains inhibition of
healing and suppression of tumor formation.
Authors Marjanovic J, Ramirez HA, Jozic I, Stone RC, Wikramanayake TC, Head CR, Abdo
Abujamra B, Ojeh N, Kirsner RS, Lev-Tov H, Pastar I, Tomic-Canic M
Submitted By Submitted Externally on 10/5/2022
Status Published
Journal Science translational medicine
Year 2022
Date Published 5/1/2022
Volume : Pages 14 : eabg8397
PubMed Reference 35544594
Abstract Despite the hyperproliferative environment marked by activation of ß-catenin and
overexpression of c-myc, the epidermis surrounding chronic diabetic foot ulcers
(DFUs) is clinically hypertrophic and nonmigratory yet does not undergo
malignant transformation. We identified miR193b-3p as a master regulator that
contributes to this unique cellular phenotype. We determined that induction of
tumor suppressor miR193b-3p is a unique feature of DFUs that is not found in
venous leg ulcers, acute wounds, or cutaneous squamous cell carcinoma (SCC).
Genomic analyses of DFUs identified suppression of the miR193b-3p target gene
network that orchestrates cell motility. Inhibition of migration and wound
closure was further confirmed by overexpression of miR193b-3p in human
organotypic and murine in vivo wound models, whereas miR193b-3p knockdown
accelerated wound reepithelialization in human ex vivo and diabetic murine
wounds in vivo. The dominant negative effect of miR193b-3p on keratinocyte
migration was maintained in the presence of promigratory miR31-5p and miR15b-5p,
which were also overexpressed in DFUs. miR193b-3p mediated antimigratory
activity by disrupting stress fiber formation and by decreasing activity of
GTPase RhoA. Conversely, miR193b-3p targets that typically participate in
malignant transformation were found to be differentially regulated between DFUs
and SCC, including the proto-oncogenes KRAS (Kirsten rat sarcoma viral
proto-oncogene) and KIT (KIT proto-oncogene). Although miR193b-3p acts as a
tumor suppressor contributing to low tumor incidence in DFUs, it also acts as a
master inhibitor of cellular migration and epithelialization in DFUs. Thus,
miR193b-3p may represent a target for wound healing induction, cancer
therapeutics, and diagnostics.




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