ΔNp63α Acts as a Lineage-Survival Oncogene in Squamous Cell Carcinoma

Abstract

CommentaryThe transcription factor p63 is a p53 family member involved in numerous biological processes, including ectodermal development, skin homeostasis, female germline protection and carcinogenesis. Of the multiple isoforms found in higher vertebrates, ΔNp63α is the predominant one expressed in the epidermis. Lacking the N-terminal, but containing the C-terminal transactivation domain, ΔNp63α has both transcriptional repressor and transactivation properties, positively and negatively regulating a plethora of genes, involved in proliferation, stemness, cell death, inflammation and differentiation [1].Two decades following the discovery of TP63, ΔNp63α has been proven to be a crucial player in Squamous Cell Carcinoma (SCC) development and treatment. Particularly because the majority of SCCs overexpress ΔNp63α, often as a result of amplification of the TP63 genomic region [2,3]. In agreement, numerous in vitro studies highlight ΔNp63α as a potential oncogene, due to its ability to bypass oncogene-induced senescence, inhibit apoptosis or induce angiogenesis. On the other hand, observations in patients and genetic mouse models with single-allelic loss of p63 reveal an inverse correlation between ΔNp63α levels and tumor invasiveness and metastasis [2,3]. In addition, tumor ΔNp63α levels were shown to correlate both with better or worse therapeutic responses, adding additional complexity on the diverse regulatory actions of ΔNp63α [3]. However, it is clear that, depending on the stage of the tumor and the type of tissue, ΔNp63α is able to affect tumorigenesis in diverse ways. Over the years, the crucial role of ΔNp63α during development and homeostasis has prompted the generation of transgenic mouse models capable of studying the influence of ΔNp63α during the different stages of carcinogenesis. Previously reported ΔNp63α transgenic mice succumb to spontaneous inflammation early in life, preventing the use of long-term cancer models [4].In a study recently published in the Journal of Investigative Dermatology, we reported a Keratin 5-Cre-recombinase-controlled ROSA26 promoter-based transgenic ΔNp63α mouse model [5]. We demonstrated that these epidermal ΔNp63α-overexpressing mice develop only mild spontaneous phenotypes: epidermal hyperplasia, which gets milder with age, minor hair defects and occasional epidermal cyst development, but no spontaneous inflammation. We explain this difference with the transgenic mice developed by Romano and colleagues by the moderate ΔNp63α overexpression levels in our model due to the relatively weak ROSA26 promoter, avoiding drastic developmental and inflammatory phenotypes. This allowed us to apply the 7,12-dimethylbenz[a]anthracene (DMBA)-based carcinogenesis model and found that ΔNp63α-overexpressing mice developed SCCs much faster and in greater numbers compared to wild-type littermates. No significant differences in DMBA-induced cytotoxicity were observed between transgenic and wild-type epidermis. Instead, isolated keratinocytes from ΔNp63α-overexpressing mice showed a delay ...