Abstract
IKKα plays a mandatory role in keratinocyte differentiation and exerts an important task in non-melanoma skin cancer development. However, it is not fully understood how IKKα exerts these functions. To analyze in detail the role of IKKα in epidermal stratification and differentiation, we have generated tridimensional (3D) cultures of human HaCaT keratinocytes and fibroblasts in fibrin gels, obtaining human skin equivalents that comprise an epidermal and a dermal compartments that resembles both the structure and differentiation of normal human skin. We have found that IKKα expression must be strictly regulated in epidermis, as alterations in its levels lead to histological defects and promote the development of malignant features. Specifically, we have found that the augmented expression of IKKα results in increased proliferation and clonogenicity of human keratinocytes, and leads to an accelerated and altered differentiation, augmented ability of invasive growth, induction of the expression of oncogenic proteins (Podoplanin, Snail, Cyclin D1) and increased extracellular matrix proteolytic activity. All these characteristics make keratinocytes overexpressing IKKα to be at a higher risk of developing skin cancer. Comparison of genetic profile obtained by analysis of microarrays of RNA of skin equivalents from both genotypes supports the above described findings.
Highlights
The epidermis is a stratified squamous epithelium composed mainly of keratinocytes
The histological analysis showed that HaCaT-IKKα keratinocytes stratified faster than HaCaT-Control cells, as higher number of cell layers were observed in their epidermal compartment from 2-days of air-liquid culture onward (Figure 1A, 1D)
While 2-day skin equivalents of HaCat-Control cells showed one basal and one suprabasal layer, in 2-day HaCaT-IKKα equivalents there were 3 to 4 cell layers of keratinocytes, organized into three distinct strata: basal stratum, suprabasal stratum, and an upper stratum formed by cells with flattened nuclei (Figure 1A)
Summary
The epidermis is a stratified squamous epithelium composed mainly of keratinocytes. Basal keratinocytes proliferate and give rise to differentiated cells, which, upon full maturation, generate the squamous cornified cell layer. It has been described that the function of IKKα in epidermis is independent of its kinase activity regulating NF-κB [7], the early death of IKKα null mice after birth precludes the study of many aspects related to mechanisms through which IKKα controls epidermal differentiation. In this regard, it has been recently proposed that the induction of IKKα has an important role in the pathogenesis of skin diseases that course with altered proliferation/differentiation equilibrium, such as psoriasis [8], suggesting an important role of IKKα in the maintenenace of the homeostasis of the epidermis in humans
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