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Previous reports, including our experimental results, showed that macrophages migrate to prostate cancer (PCa) cells. We tested whether the migrated macrophages affect the susceptibility of castration-resistant PCa (CRPC) cells to cytotoxic actions of natural killer (NK) cells. We found treatment of tumor cells with the conditioned media (CM) of the PMA/IL-4 treated THP-1 cells (M2 type macrophages) (THP-1 CM) decreased the susceptibility of tumor cells to NK cell cytotoxicity, as a result of increased programmed death receptor ligand 1 (PD-L1) and decreased NK group 2D (NKG2D) ligands in CRPC cells. Meanwhile, the decreased susceptibility of tumor cells was also detected when NK cells were treated with THP-1 CM and used in NK cell cytotoxicity tests. Therefore, we observed higher resistance of CRPC cells when both tumor and NK cells were treated with THP-1 CM than when tumor cells or NK cells were individually treated. We further discovered that the PMA/IL-4 treated THP-1 cells secrete a high level of IL-6, so blocking the IL-6 action significantly decreased the PD-L1 level while recovering the NKG2D ligands, thus increasing the susceptibility of CRPC cells to NK cell action. Moreover, we discovered that JAK-Stat3 is the most critical IL-6 downstream signaling in triggering the THP-1 CM effect. Consequently, we found the susceptibility of CRPC cells to NK cells was increased when either JAK or Stat 3 inhibitor was added when tumor cells were treated with THP-1 CM, and that the best effect was observed when the JAK inhibitor and PD-L1 Ab were added together. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) are endogenous small noncoding RNA molecules that suppress gene expression via degradation or translational inhibition of their target genes. Many miRNAs are associated with cardiac hypertrophy and heart failure. In this study, we pursued to identify miRNAs that negatively regulate cardiac hypertrophy by utilizing a surgical model for regression of cardiac hypertrophy. Microarray analysis revealed that 15 miRNAs out of the 696 miRNAs tested were specifically up-regulated during the regression period. Among these regression-specific miRNAs, nine microRNAs, which have not been previously reported, were further tested for their effects on phenylephrine (PE)-treated neonatal cardiomyocytes. Consequently, five miRNAs (miR-101b, 142-3p, 181d, 24-2∗, and 450a) completely abrogated PE-induced hypertrophy as determined by measurements of cell size and fetal gene expression. Conversely, antagomers of these miRNAs exacerbated the PE-induced hypertrophy. Collectively, these findings suggest that the five miRNAs newly identified by using our cardiac hypertrophy-regression surgical model negatively regulate cardiac hypertrophy and could be used as potential therapeutic targets for the treatment of heart diseases. [Copyright &y& Elsevier]