Regulation of Let-7a-5p and miR-199a-5p Expression by Akt1 Modulates Prostate Cancer Epithelial-to-Mesenchymal Transition via the Transforming Growth Factor-beta Pathway

Akt1 suppression in advanced cancers has been indicated to promote metastasis. Our understanding of how Akt1 orchestrates this is incomplete. Using the NanoString (R)-based miRNA and mRNA profiling of PC3 and DU145 cells, and subsequent data analysis using the DIANA-mirPath, dbEMT, nCounter, and Ingenuity (R) databases, we identified the miRNAs and associated genes responsible for Akt1-mediated prostate cancer (PCa) epithelial-to-mesenchymal transition (EMT). Akt1 loss in PC3 and DU145 cells primarily induced changes in the miRNAs and mRNAs regulating EMT genes. These include increased miR-199a-5p and decreased let-7a-5p expression associated with increased TGF beta-R1 expression. Treatment with locked nucleic acid (LNA) miR-199a-5p inhibitor and/or let-7a-5p mimic induced expression changes in EMT genes correlating to their anticipated effects on PC3 and DU145 cell motility, invasion, and TGF beta-R1 expression. A correlation between increased miR-199a-5p and TGF beta-R1 expression with reduced let-7a-5p was also observed in high Gleason score PCa patients in the cBioportal database analysis. Collectively, our studies show the effect of Akt1 suppression in advanced PCa on EMT modulating miRNA and mRNA expression changes and highlight the potential benefits of miR-199a-5p and let-7a-5p in therapy and/or early screening of mPCa.

Automated summary

Akt1 suppression in advanced prostate cancer promotes metastasis, but our understanding of its specific regulatory mechanisms is incomplete. By analyzing the miRNA and mRNA profiles of PC3 and DU145 cells, we identified the role of miRNAs and associated genes in Akt1-mediated epithelial-to-mesenchymal transition (EMT) in prostate cancer. We found that miR-199a-5p and let-7a-5p are involved in regulating TGF beta-R1 expression, and their expression changes correlate with EMT gene expression and cell motility in PC3 and DU145 cells. These findings highlight the potential therapeutic and early screening benefits of targeting miR-199a-5p and let-7a-5p in metastatic prostate cancer.