Publication Date:
2012-07-09
Description:
EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours Scientific Reports 2, 31052012 doi: 10.1038/srep00434 Olga Bornachea Mirentxu Santos Ana Belén Martínez-Cruz Ramón García-Escudero Marta Dueñas Clotilde Costa Carmen Segrelles Corina Lorz Agueda Buitrago Cristina Saiz-Ladera Xabier Agirre Teresa Grande Beatriz Paradela Antonio Maraver José M. Ariza Felipe Prosper Manuel Serrano Montse Sánchez-Céspedes Jesús M. Paramio 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.
Electronic ISSN:
2045-2322
Topics:
Natural Sciences in General
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