Characterization of Permeability Barrier Dysfunction in a Murine Model of Cutaneous Field Cancerization Following Chronic UV-B Irradiation: Implications for the Pathogenesis of Skin Cancer

Abstract

Chronic ultraviolet B (UV-B) irradiation is known to be one of the most important hazards acting on the skin and poses a risk of developing photoaging, skin with cutaneous field cancerization (CFC), actinic keratosis (AKs), and squamous cell carcinomas (SCCs). Most of the UV-B light is absorbed in the epidermis, affecting the outermost cell layers, the stratum corneum, and the stratum granulosum, which protects against this radiation and tries to maintain the permeability barrier. In the present work, we show an impairment in the transepidermal water loss, stratum corneum hydration, and surface pH after chronic UV-B light exposure in an immunologically intact mouse model (SKH1 aged mice) of skin with CFC. Macroscopic lesions of AKs and SCCs may develop synchronically or over time on the same cutaneous surface due to both the presence of subclinical AKs and in situ SCC, but also the accumulation of different mutations in keratinocytes. Focusing on skin with CFC, yet without the pathological criteria of AKs or SCC, the presence of p53 immunopositive patches (PIPs) within the epidermis is associated with these UV-B-induced mutations. Reactive epidermis to chronic UV-B exposure correlated with a marked hyperkeratotic hyperplasia, hypergranulosis, and induction of keratinocyte hyperproliferation, while expressing an upregulation of filaggrin, loricrin, and involucrin immunostaining. However, incidental AKs and in situ SCC might show neither hypergranulosis nor upregulation of differentiation markers in the upper epidermis. Despite the overexpression of filaggrin, loricrin, involucrin, lipid enzymes, and ATP-binding cassette subfamily A member 12 (ABCA12) after chronic UV-B irradiation, the permeability barrier, stratum corneum hydration, and surface pH were severely compromised in the skin with CFC. We interpret these results as an attempt to restore the permeability barrier homeostasis by the reactive epidermis, which fails due to ultrastructural losses in stratum corneum integrity, higher pH on skin surface, abundant mast cells in the dermis, and the common presence of incidental AKs and in situ SCC. As far as we know, this is the first time that the permeability barrier has been studied in the skin with CFC in a murine model of SCC induced after chronic UV-B irradiation at high doses. The impairment in the permeability barrier and the consequent keratinocyte hyperproliferation in the skin of CFC might play a role in the physiopathology of AKs and SCCs.

A cross-sectional study of Chinese women facial skin status with environmental factors and individual lifestyles

“…As most of the UVB light is absorbed in the epidermis 48 , the outermost cell layers, the stratum corneum, and the stratum granulosum were most affected, resulting in a breakdown of the epidermal physical barrier (protects against radiation and tries to maintain of permeability) 49 . Santiago et al found that skin received chronic UVB radiation had a higher skin surface pH value, with the permeability barrier and stratum corneum hydration severely compromised in a Murine Model of Cutaneous Field Cancerization 50 . This is consistent with our study that female skin exhibits high transcutaneous water dissipation, low hydration and neutral pH in Guangzhou with longer sunshine duration.…”

Introduction to the Special Issue on “Keratinocyte Carcinomas: Biology and Evolving Non-Invasive Management Paradigms”

“…Santiago, J.L. et al [ 7 ] developed a preclinical model of skin with cutaneous field cancerization after chronic ultraviolet (UV) B light exposure in immunocompetent SKH1 aged mice. Compared to non-irradiated controls, UV-B irradiated skin demonstrated impairments in trans-epidermal water loss, stratum corneum hydration, and surface pH in a dose-dependent manner.…”

Plant responses to UV-B radiation: signaling, acclimation and stress tolerance

“…UV-B radiation is potentially harmful to living organisms exposed to sunlight. Excessive UV-B radiation not only causes skin cancers in humans (D’Orazio et al 2013 ; Santiago et al 2021 ), but also leads to cell death in plants physiologically featured with wilting, yellowing or bleaching of leaves (Jenkins 2009 ). UV-B stress can induce damage directly at the DNA level by producing cyclobutene pyrimidine dimers (CPDs), and pyrimidine (6–4) pyrimidinone photoproducts (6–4 PPs) (Britt 1995 ; Molinier et al 2008 ; Quaite et al 1994 ; Sinha and Hader 2002 ; Takahashi et al 2011 ).…”