Abstract 205: The three-throng role of miR-21 in cancer

MicroRNAs (miRNAs) are short (20-25 nucleotide) RNA molecules, representing one of the largest class of regulatory RNAs. miR-21 is overexpressed in virtually all types of tumor tissues compared to normal noncancerous tissues. Despite the appreciation of miRNA dysregulation, mouse models of cancer have focused on genetic changes in the epithelial tumor cells. Results from several miR-21 transgenic and knockout mouse models show that miR-21-deficiency reduces tumorigenesis and broad miR-21 overexpression leads to pre-B cell lymphoma, yet the underline mechanisms of miR-21 promoting tumorigenesis remain elusive. We used knockout mice to dissect the role of miR-21 in cancer and found three distinct functions for this oncogene. (1) miR-21 is anti-apoptotic; its genetic ablation results in increased apoptotic cell death in a chemical induced skin carcinogenesis model. (2) miR-21 is pro-necrosis; using two pathological necrosis mouse models (acute pancreatitis and cardiac ischemia) and one cell line model, we found loss of miR-21 inhibits necrosis when apoptosis is attenuated naturally or artificially; this suggests that tumor cells with high miR-21 levels would choose necrosis over apoptosis to provoke inflammation, which can provide a fertile environment for tumor growth. (3) We also found a direct role of miR-21 in tumor stroma. During the past decade, epithelial cell-derived solid tumors have increasingly been recognized as organs consisting of parenchyma (tumor cells) and stroma (the surrounding connective, supporting, and inflammatory cells). One such stromal cell is the macrophage and there is a growing body of evidence suggesting that tumor-associated macrophages (TAMs) promote tumor cell proliferation, migration, invasion, angiogenesis, and progression. Plasticity and diversity are hallmarks of macrophages. Two distinct states of polarized activation for macrophages are well-characterized: the classically activated (M1) and the alternatively activated (M2). Differential cytokine production is a key feature of polarized macrophages. The M1 phenotype is typically IL-12high/IL-10low, whereas M2 macrophage is IL-12low/IL-10high. TAMs observed in most human cancers are M2-like. miR-21 upregulates IL-10 through repressing the expression of programmed cell death 4 (PDCD4) that is a negative regulator of IL-10 and down-regulates IL-12 through repressing its α-subunit (IL12A), indicating that its overexpression drives macrophages toward the tumor-promoting M2 phenotype (IL-12low/IL-10high). Our in vitro data suggest that miR-21 deficiency primes macrophages towards the M1 phenotype. Using a syngeneic tumor model, we show that miR-21-null mice bear smaller tumors compared to the wild-type control. Taken together, these data suggest that miR-219s oncogenic role comes from both tumor cells (pro-necrosis and anti-apoptosis) and the stroma, including TAMs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 205. doi:1538-7445.AM2012-205