Telomere crisis in kidney epithelial cells promotes the acquisition of a microRNA signature retrieved in aggressive renal cell carcinomas.
Telomere shortening is a major source of chromosome instability (CIN) at early stages during carcinogenesis. However, the mechanisms through which telomere-driven CIN (T-CIN) contributes to the acquisition of tumor phenotypes remain uncharacterized. We discovered that human epithelial kidney cells undergoing T-CIN display massive microRNA (miR) expression changes that are not related to local losses or gains. This widespread miR deregulation encompasses a miR-200-dependent epithelial-to-mesenchymal transition (EMT) that confers to immortalized pre-tumoral cells phenotypic traits of metastatic potential. Remarkably, a miR signature of these cells, comprising a downregulation of miRs with conserved expression in kidney, was retrieved in poorly differentiated aggressive renal cell carcinomas. Our results reveal an unanticipated connection between telomere crisis and the activation of the EMT program that occurs at pre-invasive stages of epithelial cancers, through mechanisms that involve miR deregulation. Thus, this study provides a new rational into how telomere instability contributes to the acquisition of the malignant phenotype.
UMR3244, Telomeres and Cancer Laboratory, Institut Curie, 26 rue d'Ulm, Paris 75248, France.
Luis Jaime
LJ
Castro-Vega
Karina
K
Jouravleva
Win-Yan
WY
Liu
Carolina
C
Martinez
Pierre
P
Gestraud
Philippe
P
Hupé
Nicolas
N
Servant
Benoît
B
Albaud
David
D
Gentien
Sophie
S
Gad
Stéphane
S
Richard
Silvia
S
Bacchetti
Arturo
A
Londoño-Vallejo
D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D016615:Telomere / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
D035683:MicroRNAs