MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells.
Although Akt is known to play a role in human cancer, the relative contribution of its three isoforms to oncogenesis remains to be determined. We expressed each isoform individually in an Akt1(-/-)/Akt2(-/-)/Akt3(-/-) cell line. MicroRNA profiling of growth factor-stimulated cells revealed unique microRNA signatures for cells with each isoform. Among the differentially regulated microRNAs, the abundance of the miR-200 family was decreased in cells bearing Akt2. Knockdown of Akt1 in transforming growth factor-beta (TGFbeta)-treated MCF10A cells also decreased the abundance of miR-200; however, knockdown of Akt2, or of both Akt1 and Akt2, did not. Furthermore, Akt1 knockdown in MCF10A cells promoted TGFbeta-induced epithelial-mesenchymal transition (EMT) and a stem cell-like phenotype. Carcinomas developing in MMTV-cErbB2/Akt1(-/-) mice showed increased invasiveness because of miR-200 down-regulation. Finally, the ratio of Akt1 to Akt2 and the abundance of miR-200 and of the messenger RNA encoding E-cadherin in a set of primary and metastatic human breast cancers were consistent with the hypothesis that in many cases breast cancer metastasis may be under the control of the Akt-miR-200-E-cadherin axis. We conclude that induction of EMT is controlled by microRNAs whose abundance depends on the balance between Akt1 and Akt2 rather than on the overall activity of Akt.
Iliopoulos
Dimitrios
D
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Polytarchou
Christos
C
Hatziapostolou
Maria
M
Kottakis
Filippos
F
Maroulakou
Ioanna G
IG
Struhl
Kevin
K
Tsichlis
Philip N
PN
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D004848:Epithelium / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009362:Neoplasm Metastasis; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015820:Cadherins; D035683:MicroRNAs; D020033:Protein Isoforms; D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt