Abstract
microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications.
Highlights
MiRNAs are small endogenous non–protein-coding RNAs that posttranscriptionally regulate the expression of multiple target genes in different cell types
Tumors of miR-21–/– mice exhibited an increased number of TUNEL-positive cells (Figure 1C) and reduced tumor-associated vasculature, as shown by the diminished CD31+ vessel-like structures (Figure 1D). These results indicate that loss of miR-21 increases tumor cell death, diminishes tumor angiogenesis, and provides evidence that miR-21 expression in cells other than cancer cells has an important role in promoting tumor growth
We have used a variety of different mouse models to assess how miR-21 in noncancerous cells of the tumor microenvironment (TME) contributes to tumor progression
Summary
MiRNAs are small endogenous non–protein-coding RNAs that posttranscriptionally regulate the expression of multiple target genes in different cell types. In this manner, miRNAs control many physiological cellular processes, as well as several pathologies. Widespread dysregulation of miRNA expression has been reported in tumor cells, with either an oncogenic or a tumor suppressive role [1]. MiRNAs have been reported to be dysregulated in cells from the tumor microenvironment (TME) [3]. Their role in cancer progression is not just limited to regulating cancer cell behavior.
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