Arsenic is known to perturb epidermal homeostasis and induce abnormal keratinocyte proliferation, leading to skin carcinogenesis. P63 and its isoforms are essential to regulate epidermal homeostasis. This study aimed to investigate the role of p63 isoforms in abnormal epidermal proliferation induced by arsenic. Using arsenic-induced Bowen's disease (As-BD; an intraepidermal carcinoma) as a disease model, we found that in As-BD, the expression of proliferating basal keratinocytes marker cytokeratin 14 (CK14) and N-terminal truncated p63 isoform (ΔNp63; proliferation regulator) was increased, however, that of the differentiation marker cytokeratin 10 (CK10) and full-length p63 isoform (TAp63; differentiation regulator) was decreased in squamous cells as compared with healthy subjects. These observations were recapitulated in the arsenic-treated skin equivalents (SEs). The SEs showed that arsenic increased epidermal thickness, induced abnormal proliferation, and increased ΔNp63 expression in squamous cells as compared with the control. Treatment of cultured normal human epidermal keratinocytes (HKCs) with arsenic increased CK14 and △Np63 expressions, but decreased TAp63 and CK10 expressions. Furthermore, knockdown of ΔNp63 by RNA interference abrogated arsenic-induced CK14 expression and recovered the reduction of TAp63 and CK10 caused by arsenic. These findings indicated that ΔNp63 is a pivotal regulator in the abnormal cell proliferation in arsenical cancers.
Keywords: Abnormal proliferation; Arsenic; Bowen's disease; Keratinocytes; ΔNp63.
Copyright © 2018. Published by Elsevier Ltd.