Identification of the MALAT1/miR-106a-5p/ZNF148 Feedback Loop in Regulating HaCaT Cell Proliferation, Migration and Apoptosis

Abstract

Aims: This study aims to investigate the function of positive feedback loops involving noncoding RNA in diabetic wound healing. Methods: We developed a mouse diabetic wound model to confirm that hyperglycemia can impair wound healing. We also used an in vitro keratinocyte model in high-glucose conditions to investigate the mechanism of delayed wound healing. Results:MALAT1 was decreased in diabetic mouse wound tissue and can promote keratinocyte biological functions. MALAT1 could bind to miR-106a-5p to modulate the expression of ZNF148, a target gene of miR-106a-5p. Surprisingly, ZNF148 bound to a region in the MALAT1 promoter to stimulate gene expression. Conclusion: ZNF148-activated MALAT1 increases ZNF148 expression by competitively binding miR-106a-3p, generating a positive feedback loop that enhances keratinocyte function.

Plain language summary

Delayed wound repair is a leading cause of diabetic foot ulcers. However, the molecular mechanism underlying impaired wound healing in diabetes is unclear. In our study we found that a positive feedback loop consisting of MALAT1, miR-106a-5p and ZNF148 could promote chronic wound repair. In diabetic skin tissues, MALAT1 levels were lower, causing impairments in skin cell function. On a molecular level, MALAT1 can bind miR-106a-5p to increase ZNF148 levels. Surprisingly, ZNF148 can bind the promoter of MALAT1 to reverse the decline of MALAT1 levels in diabetic wounds. Our findings advance our understanding of chronic diabetic wounds and, more crucially, open new therapeutic possibilities for this disease.

Graphical abstract

Keywords::

• diabetic wound healing
• feedback loop
• MALAT1
• miR-106a-5p
• ZNF148

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/rme-2022-0189

Author contributions

L-W Kuang: conceptualization, methodology, formal analysis, writing, software, investigation, visualization, original draft, review and editing; C-C Zhang: conceptualization, methodology, formal analysis, writing, software, investigation, visualization, original draft, review and editing; B-H Li: project administration, funding acquisition; H-Z Liu: supervision; H Wang: supervision; G-C Li: project administration, funding acquisition. All authors have read and approved the final version of this manuscript to be published.

Acknowledgments

The authors would like to acknowledge staff at Liyuan Hospital for technical support.

Financial & competing interests disclosure

This study was supported by the young Scientists Fund of the National Science Foundation of China (81801922), Natural Science Foundation of Hubei Province (2020CFB696), and Hubei Province Key R & D Project (2020BCB029). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. All animal experiments confirmed to the Institutional Animal Care and Use Committee Tongji Medical College, Huazhong University of Science and Technology (2020 IACUC no. 2729).

Additional information

Funding

This study was supported by the young Scientists Fund of the National Science Foundation of China (81801922), Natural Science Foundation of Hubei Province (2020CFB696), and Hubei Province Key R & D Project (2020BCB029). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.