EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours

• Published in: Scientific reports Vol. 2; no. 1; p. 434
• Main Authors: Bornachea, Olga, Santos, Mirentxu, Martínez-Cruz, Ana Belén, García-Escudero, Ramón, Dueñas, Marta, Costa, Clotilde, Segrelles, Carmen, Lorz, Corina, Buitrago, Agueda, Saiz-Ladera, Cristina, Agirre, Xabier, Grande, Teresa, Paradela, Beatriz, Maraver, Antonio, Ariza, José M., Prosper, Felipe, Serrano, Manuel, Sánchez-Céspedes, Montse, Paramio, Jesús M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.05.2012; Nature Publishing Group
• Subjects: 631/208/212/748; 631/337/384; 631/67/581; 631/67/70; Animals; Blotting, Western; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line; Cells, Cultured; Epidermis; Epidermis - metabolism; Epidermis - pathology; Epithelial-Mesenchymal Transition - genetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomes; Humanities and Social Sciences; Humans; Kaplan-Meier Estimate; Keratinocytes - metabolism; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Metastasis; Mice; MicroRNAs - genetics; multidisciplinary; Mutation; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Science; Signal transduction; STAT3 Transcription Factor - metabolism; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep00434

Missense mutations in TP53 gene promote metastasis in human tumours. However, little is known about the complete loss of function of p53 in tumour metastasis. Here we show that squamous cell carcinomas generated by the specific ablation of Trp53 gene in mouse epidermis are highly metastatic. Biochemical and genome-wide mRNA and miRNA analyses demonstrated that metastases are associated with the early induction of epithelial-mesenchymal transition (EMT) and deregulated miRNA expression in primary tumours. Increased expression of miR-21 was observed in undifferentiated, prometastatic mouse tumours and in human tumours characterized by p53 mutations and distant metastasis. The augmented expression of miR-21, mediated by active mTOR and Stat3 signalling, conferred increased invasive properties to mouse keratinocytes in vitro and in vivo, whereas blockade of miR-21 in a metastatic spindle cell line inhibits metastasis development. Collectively these data identify novel molecular mechanisms leading to metastasis in vivo originated by p53 loss in epithelia.