miR-21a negatively modulates tumor suppressor genes PTEN and miR-200c and further promotes the transformation of M2 macrophages.

miR-21a is well-known to inhibit PTEN expression. We have previously shown that PTEN suppressed the transformation of M2 macrophages in the tumor microenvironment. Therefore, we hypothesized that miR-21a could influence M2 macrophage transformation by regulating PTEN expression. In this study, we identified how miR-21a reduced the expression of both PTEN mRNA and protein in murine macrophage cell lines and primary macrophages. Moreover, opposite effects were identified upon the use of a miR-21a inhibitor. Using a cytokine array, we identified the cytokines closely associated with miR-21a-mediated macrophage transformation to the M2 phenotype. miR-21a mimics could also enhance the migratory ability of murine breast cancer 4T1 cells, the growth of breast cancer in vivo and CD206 intratumor expression. In addition, quantitative PCR (qPCR) and methylation-specific PCR analysis showed that miR-21a enhanced miR-200c methylation and then decreased miR-200c and PTEN expression. These effects could be reversed by treatment with 5'-Aza, a DNA-demethylating agent. MiR-200c was predicted to target the PTEN 3'UTR, but qPCR illustrated the miR-200c mimic that increased PTEN expression, and 5'-Aza could enhance its effect. The above results indicate that miR-21a negatively modulates two tumor suppressor genes, miR-200c and PTEN, thereby promoting M2 macrophage transformation. This demonstrates that miR-21a represents a novel target for improving the overall tumor microenvironment.

Adrenergic receptor ß2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment.

Stress and its related hormones epinephrine (E) and norepinephrine (NE) play a crucial role in tumor progression. Macrophages in the tumor microenvironment (TME) polarized to M2 is also a vital pathway for tumor deterioration. Here, we explore the underlying role of macrophages in the effect of stress and E promoting breast cancer growth. It was found that the weight and volume of tumor in tumor bearing mice were increased, and dramatically accompanied with the rising E level after chronic stress using social isolation. What is most noteworthy, the number of M2 macrophages inside tumor was up-regulated with it. The effects of E treatment appear to be directly related to the change of M2 phenotype is reproduced in vitro. Moreover, E receptor ADRß2 involved in E promoting M2 polarization was comprehended simultaneously. Our results imply psychological stress is influential on specific immune system, more essential for the comprehensive treatment against tumors.