EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours.
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.
Molecular Oncology Unit, CIEMAT, Ave. Complutense 40, E-28040 Madrid, Spain.
Olga
O
Bornachea
Mirentxu
M
Santos
Ana Belén
AB
Martínez-Cruz
Ramón
R
García-Escudero
Marta
M
Dueñas
Clotilde
C
Costa
Carmen
C
Segrelles
Corina
C
Lorz
Agueda
A
Buitrago
Cristina
C
Saiz-Ladera
Xabier
X
Agirre
Teresa
T
Grande
Beatriz
B
Paradela
Antonio
A
Maraver
José M
JM
Ariza
Felipe
F
Prosper
Manuel
M
Serrano
Montse
M
Sánchez-Céspedes
Jesús M
JM
Paramio
D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D015603:Keratinocytes / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D058570:TOR Serine-Threonine Kinases