The Role of MicroRNAs in Epidermal Barrier

Abstract

MicroRNAs (miRNAs), which mostly cause target gene silencing via transcriptional repression and degradation of target mRNAs, regulate a plethora of cellular activities, such as cell growth, differentiation, development, and apoptosis. In the case of skin keratinocytes, the role of miRNA in epidermal barrier integrity has been identified. Based on the impact of key genetic and environmental factors on the integrity and maintenance of skin barrier, the association of miRNAs within epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids is reviewed. The critical role of miRNAs in the epidermal barrier extends the use of miRNAs for control of relevant skin diseases such as atopic dermatitis, ichthyoses, and psoriasis via miRNA-based technologies. Most of the relevant miRNAs have been associated with keratinocyte differentiation and proliferation. Few studies have investigated the association of miRNAs with structural proteins of corneocytes and cornified envelopes, cell-cell adhesion, and skin lipids. Further studies investigating the association between regulatory and structural components of epidermal barrier and miRNAs are needed to elucidate the role of miRNAs in epidermal barrier integrity and their clinical implications.

Keywords: cell–cell adhesion; epidermal cell differentiation and proliferation; miRNAs; skin barrier integrity; skin lipids.

Figure 1

Role of miR-203 in keratinocyte differentiation and proliferation. As the first and most upregulated miRNA under high calcium concentrations or exposure to unsaturated fatty acids (oleic acid or linoleic acid), miR-203 can control both keratinocyte differentiation and proliferation via downregulation and upregulation of ΔNp63, respectively.

Figure 2

miRNAs involved in both keratinocyte differentiation and proliferation depending on their expression. Upregulation of miR-125b stimulates keratinocyte differentiation via suppression of both p63 and Notch1 expression, whereas its downregulation promotes keratinocyte proliferation by targeting fibroblast growth factor receptor 2 (FGFR2) or AKT serine/threonine kinase 3 (AKT3). Downregulation of miR-146a facilitates keratinocyte proliferation by activating epidermal growth factor receptor (EGFR), whereas its upregulation promotes terminal differentiation of keratinocytes by suppressing EGFR. Downregulation of miR-181a promotes keratinocyte proliferation by targeting Kirsten rat sarcoma 2 viral oncogene homolog (KRAS). However, the increased expression of miR-181a by high calcium or UVA irradiation is associated with keratinocyte differentiation.

Figure 3

Association of miR-21 and miR-31 in skin diseases with distinct keratinocyte proliferation. A distinct proliferation of keratinocytes occurs in psoriasis, the proliferation phase of wound healing, and cutaneous squamous cell carcinoma (cSSC). Upregulation of miR-21 (A) and miR-31 (B) promotes keratinocyte proliferation in several miRNAs identified in these skin diseases associated with keratinocyte proliferation, although the identified targets vary.