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Long noncoding RNA–antisense noncoding RNA in the INK4 locus accelerates wound healing in diabetes by promoting lymphangiogenesis via regulating miR‐181a/Prox1 axis
Author(s) -
He ZhiYou,
Wei TianHong,
Zhang PiHong,
Zhou Jie,
Huang XiaoYuan
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.27260
Subject(s) - lymphangiogenesis , wound healing , cancer research , lymphatic endothelium , biology , long non coding rna , lymphatic vessel , microbiology and biotechnology , rna , lymphatic system , immunology , cancer , metastasis , gene , genetics
Background Slow lymphangiogenesis is one crucial reason for the impaired wound healing process in diabetes. Accumulative evidence showed that long noncoding RNA–antisense noncoding RNA in the INK4 locus (ANRIL) could influence lymphangiogenesis. Besides, miR‐181a has been reported to regulate Prox1 that is essential for lymphangiogenesis. However, the relationship between ANRIL and miR‐181a as well as the definitive function of ANRIL in lymphangiogenesis is not clear. Methods The diabetic mouse model was set up to assess the wound healing rate in vivo. Quantitative real‐time polymerase chain reaction was performed to measure the expressions of ANRIL, miR‐181a, and Prox1. Western blot analysis was used to assess the expressions of vascular endothelial growth factor receptor‐3, lymphatic vessel hyaluronan receptor‐1, Prox1, and epithelial–mesenchymal transition (EMT)‐related proteins. Flow cytometry was used to assess the cell apoptosis. Wound healing assay was used to determine the effect of ANRIL on cell migration. Tube‐formation assay and immunofluorescence staining were performed to determine tube‐formation capacity of human dermal lymphatic endothelial cells (LECs). Results ANRIL and Prox1 were downregulated, whereas miR‐181a was upregulated in the diabetic wound healing mouse model and high glucose (HG)‐induced LECs. The wound healing rate and EMT were inhibited during the diabetic wound healing process. Dual‐luciferase assay proved that miR‐181a could bind Prox1 to repress its expression, whereas ANRIL could sponge miR‐181a to recover Prox1 expression. Overexpression of ANRIL or inhibition of miR‐181a rescued the impairments of survival, migration, EMT formation, and tube formation of LECs caused by HG. Conclusion ANRIL could promote lymphangiogenesis during the diabetic wound healing process via sponging miR‐181a to enhance Prox1 expression, which might help design new therapy to improve the wound healing efficacy for diabetes.