title: The downregulation of ΔNp63 in p53-deficient mouse epidermal tumors favors metastatic behavior.
abstract: The TP63 gene codes for two major isoform types, TAp63 and ΔNp63, with probable opposite roles in tumorigenesis. The ΔNp63α protein is frequently amplified and overexpressed in different epithelial tumors. Accordingly, it has been considered a potential oncogene. Nonetheless, a possible metastatic suppressor activity has also been suggested based on the experimental observation that its expression is reduced or even absent in advanced invasive tumors. Such metastatic suppressor activities are often related to tumors bearing point mutated TP53 gene. However, its potential roles in TP53-deficient tumors are poorly characterized. Here we show that in spontaneous tumors, induced by the epidermal-specific Trp53 ablation, the reduction of ΔNp63 expression is an early event, whereas it is re-expressed in the lung metastatic lesions. Using knock down and ectopic expression approaches, we show that ΔNp63 expression opposes the epithelial-mesenchymal transition and reduces the metastatic potential of the cells. This process occurs through the modulation of ΔNp63-dependent downstream targets (including transcription factors and microRNAs) likely to play metastatic roles. Further, ΔNp63 also favors the expression of factors involved in iPS reprogramming, thus suggesting that it can also modulate specific stem cell traits in mouse epidermal tumor cells. Overall, our data assign antimetastatic roles to ΔNp63 in the context of p53 deficiency and epidermis.
authors.affiliation: Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Bornachea
authors.affiliation: Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital, 28041 Madrid, Spain.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: López-Calderón
authors.affiliation: Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital, 28041 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Dueñas
authors.affiliation: Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital, 28041 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Segrelles
authors.affiliation: Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital, 28041 Madrid, Spain.
authors.forename: Corina
authors.initials: C
authors.lastname: Lorz
authors.affiliation: Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital, 28041 Madrid, Spain.
authors.forename: Cristian
authors.initials: C
authors.lastname: Suárez-Cabrera
authors.affiliation: Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Marañón
authors.affiliation: Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Paradela-Dobarro
authors.affiliation: Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital, 28041 Madrid, Spain.
authors.forename: Mirentxu
authors.initials: M
authors.lastname: Santos
authors.affiliation: Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital, 28041 Madrid, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D004817:Epidermis / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D009362:Neoplasm Metastasis; D010750:Phosphoproteins / Q000235:genetics; D017354:Point Mutation; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D010750:Phosphoproteins; C495901:TP53 protein, human; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
keywords: metastasis; miRNA; p53; p63; skin