miR-564 acts as a dual inhibitor of PI3K and MAPK signaling networks and inhibits proliferation and invasion in breast cancer.
Dysregulation of PI3K and MAPK pathways promotes uncontrolled cell proliferation, apoptotic inhibition and metastasis. Individual targeting of these pathways using kinase inhibitors has largely been insufficient due to the existence of cross-talks between these parallel cascades. MicroRNAs are small non-coding RNAs targeting several genes simultaneously and controlling cancer-related processes. To identify miRNAs repressing both PI3K and MAPK pathways in breast cancer, we re-analyzed our previous miRNA mimic screen data with reverse phase protein array (RPPA) output, and identified miR-564 inhibiting both PI3K and MAPK pathways causing markedly decreased cell proliferation through G1 arrest. Moreover, ectopic expression of miR-564 blocks epithelial-mesenchymal transition (EMT) and reduces migration and invasion of aggressive breast cancer cells. Mechanistically, miR-564 directly targets a network of genes comprising AKT2, GNA12, GYS1 and SRF, thereby facilitating simultaneous repression of PI3K and MAPK pathways. Notably, combinatorial knockdown of these target genes using a cocktail of siRNAs mimics the phenotypes exerted upon miR-564 expression. Importantly, high miR-564 expression or low expression of target genes in combination is significantly correlated with better distant relapse-free survival of patients. Overall, miR-564 is a potential dual inhibitor of PI3K and MAPK pathways, and may be an attractive target and prognostic marker for breast cancer.
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
Merve
M
Mutlu
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
Özge
Ö
Saatci
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
Suhail A
SA
Ansari
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
Emre
E
Yurdusev
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
Huma
H
Shehwana
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
Özlen
Ö
Konu
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
Umar
U
Raza
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
Özgür
Ö
Şahin
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
C577008:MIRN564 microRNA, human; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases