Macrophages are polarized into functional classically activated and alternatively activated (M2) phenotypes depending on their microenvironment, and these cells play an important role in the immune system. M2-like polarization of tumor-associated macrophages (TAMs) is activated by various secretions from cancer cells; however, the interaction between cancer cells and TAMs is not well understood. Recent studies showed that cancer cell-derived extracellular vesicles (EVs) contribute to tumor development and modulation of the tumor microenvironment. In the current study, we investigated colorectal cancer-derived EVs containing miR-145 with respect to the polarization of TAMs. Colorectal cancer cells positively secreted miR-145 via EVs, which were taken up by macrophage-like cells. Interestingly, colorectal cancer-derived EVs polarized macrophage-like cells into the M2-like phenotype through the downregulation of An in vivo study showed that EV-treated macrophages caused significant enlargement of the tumor volumes. These findings suggest that colorectal cancer cells use miR-145 within EVs to efficiently modulate M2-like macrophage polarization and tumor progression.

The Warburg effect is a well-known feature in cancer-specific metabolism. We previously reported on the role of microRNA (miR)-145 as a tumor-suppressor in human bladder cancer (BC) cells. In this study, we reveal that miR-145 decreases the Warburg effect by silencing KLF4 in BC cells. The expression levels of miR-145 were significantly lower in clinical BC samples and BC cell lines compared to those in normal tissues and HUC cells. Luciferase assay results showed that miR-145 directly bound to 3′UTR of KLF4, which was shown to be overexpressed in the clinical BC samples using Western blot analysis and immunohistochemistry. Remarkable growth inhibition and apoptosis were induced by the ectopic expression of miR-145 or by the gene silencing of KLF4 (siR-KLF4). Also, Warburg effect-related genes such as PTBP1/PKMs were regulated by the transfection of BC cells with miR-145 or siR-KLF4. These results thus indicate that the miR-145/KLF4/PTBP1/PKMs axis is one of the critical pathways that maintain the Warburg effect in BC carcinogenesis. MiR-145 perturbed the Warburg effect by suppressing the KLF4/PTBP1/PKMs pathway in BC cells, resulting in significant cell growth inhibition.

Androgen receptor (AR) is a ligand-activated transcription factor and a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated gene expression provides new opportunities for therapeutic intervention. Poly(ADP-ribose) Polymerase (PARP) is a family of enzymes, which posttranslationally modify a range of proteins and regulate many different cellular processes. PARP-1 and PARP-2 are two well-characterized PARP members, whose catalytic activity is induced by DNA-strand breaks and responsible for multiple DNA damage repair pathways. PARP inhibitors are promising therapeutic agents that show synthetic lethality against many types of cancer (including PCa) with homologous recombination (HR) DNA-repair deficiency. Here, we show that, beyond DNA damage repair function, PARP-2, but not PARP-1, is a critical component in AR transcriptional machinery through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to genome-wide prostate-specific enhancer regions. Analyses of PARP-2 expression at both mRNA and protein levels show significantly higher expression of PARP-2 in primary PCa tumors than in benign prostate tissues, and even more so in castration-resistant prostate cancer (CRPC) tumors. Selective targeting of PARP-2 by genetic or pharmacological means blocks interaction between PARP-2 and FOXA1, which in turn attenuates AR-mediated gene expression and inhibits AR-positive PCa growth. Next-generation antiandrogens act through inhibiting androgen synthesis (abiraterone) or blocking ligand binding (enzalutamide). Selective targeting of PARP-2, however, may provide an alternative therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA-repair deficiency status.

The metabolism in tumor cells shifts from oxidative phosphorylation to glycolysis even in an aerobic environment. This phenomenon is known as the Warburg effect. This effect is regulated mainly by polypyrimidine tract‐binding protein 1 (PTBP1), which is a splicer of the mRNA for the rate‐limiting enzymes of glycolysis, pyruvate kinase muscle 1 and 2 (PKM1 and PKM2). In the present study, we demonstrated that miR‐133b reduced PTBP1 expression at translational level and that the expression levels of miR‐133b were significantly downregulated in gastric cancer clinical samples and human cell lines, whereas the protein expression level of PTBP1 was upregulated in 80% of the 20 clinical samples of gastric cancer examined. Ectopic expression of miR‐133b and knockdown of PTBP1 in gastric cancer cells inhibited cell proliferation through the induction of autophagy by the switching of PKM isoform expression from PKM2‐dominant to PKM1‐dominant. The growth inhibition was partially canceled by an autophagy inhibitor 3‐MA or a reactive oxygen species scavenger N‐acetylcysteine. These findings indicated that miR‐133b acted as a tumor‐suppressor through negative regulation of the Warburg effect in gastric cancer cells.