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Akt1 suppression in advanced cancers has been indicated to promote metastasis. Our understanding of how Akt1 orchestrates this is incomplete. Using the NanoString®-based miRNA and mRNA profiling of PC3 and DU145 cells, and subsequent data analysis using the DIANA-mirPath, dbEMT, nCounter, and Ingenuity® 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 TGFβ-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 TGFβ-R1 expression. A correlation between increased miR-199a-5p and TGFβ-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.

The Multi-gene claudin (CLDN) family of tight junction proteins have isoform-specific roles in blood-tissue barrier regulation. Although CLDN17, a putative anion pore-forming CLDN, is assumed to regulate anion balance across the blood-tissue barriers, our knowledge about CLDN17 is limited. The current study investigated how Cldn17 deficiency in mice affects blood-tissue barrier integrity and vascular permeability. Cldn17−/− mice revealed no breeding abnormalities, but the newborn pups exhibited delayed growth until they turned 8-weeks. Adult Cldn17−/− mice displayed electrolyte imbalance, oxidative stress, increased vascular leakage, increased bone density, and organ injury. In addition, these mice demonstrated increased leukocytosis. A xenograft model to study pathological neovascularization showed higher vascular density in tumors developed in Cldn17−/− mice compared to wild-type controls. RNA-sequencing revealed hyperactivation of signaling pathways associated with inflammation and reactive oxygen species generation, demonstrating the importance of Cldn17 in blood-tissue barrier maintenance.