The downregulation of ΔNp63 in p53-deficient mouse epidermal tumors favors metastatic behavior
| Autor: | Marta Dueñas, María Marañón, Carmen Segrelles, Mirentxu Santos, Jesús M. Paramio, Corina Lorz, Cristian Suárez-Cabrera, Beatriz Paradela-Dobarro, Fernando F. López-Calderón, Olga Bornachea |
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| Přispěvatelé: | Instituto de Salud Carlos III, Fundación Mutua Madrileña, Red Temática de Investigación Cooperativa en Cáncer (España), Comunidad de Madrid, Ministerio de Economía y Competitividad (España) |
| Rok vydání: | 2015 |
| Předmět: |
Keratinocytes
p53 skin Pathology medicine.medical_specialty Epithelial-Mesenchymal Transition Skin Neoplasms Down-Regulation ComputingMilieux_LEGALASPECTSOFCOMPUTING Context (language use) Biology medicine.disease_cause Molecular oncology Cell Line Metastasis Mice medicine Animals Humans Point Mutation metastasis Epithelial–mesenchymal transition Neoplasm Metastasis miRNA p63 Oncogene Stem Cells Tumor Suppressor Proteins Phosphoproteins medicine.disease Immunohistochemistry Gene Expression Regulation Neoplastic Microscopy Fluorescence Oncology Mutation Trans-Activators Cancer research Ectopic expression Epidermis Tumor Suppressor Protein p53 Stem cell Carcinogenesis Transcription Factors Research Paper |
| Zdroj: | Oncotarget Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1949-2553 |
| Popis: | This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al. 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. The study was funded by the following: MINECO grant SAF2012–34378; Comunidad Autónoma de Madrid grant S2010/BMD-2470 (Oncocycle Program); AES grants ISCIII-RETIC RD06/0020/0029 and RD12/0036/0009 to J.M. Paramio. Grants AP99782012 from MMA Foundation to M. Dueñas. AES grant ISCIIIFIS PI12/01959 to M. Santos. |
| Databáze: | OpenAIRE |
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