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c-Myc dysregulation is one of the most common abnormalities found in human cancer. MicroRNAs (miRNAs) are functionally intertwined with the c-Myc network as multiple miRNAs are regulated by c-Myc, while others directly suppress c-Myc expression. In this work, we identified miR-33b as a primate-specific negative regulator of c-Myc. The human miR-33b gene is located at 17p11.2, a genomic locus frequently lost in medulloblastomas, of which a subset displays c-Myc overproduction. Through a small-scale screening with drugs approved by the US Food and Drug Administration (FDA), we found that lovastatin upregulated miR-33b expression, reduced cell proliferation and impaired c-Myc expression and function in miR-33b-positive medulloblastoma cells. In addition, a low dose of lovastatin treatment at a level comparable to approved human oral use reduced tumour growth in mice orthotopically xenografted with cells carrying miR-33b, but not with cells lacking miR-33b. This work presents a highly promising therapeutic option, using drug repurposing and a miRNA as a biomarker, against cancers that overexpress c-Myc.

MicroRNA-21 (miR-21) is frequently up-regulated in cancer and the majority of its reported targets are tumor suppressors. Through functional suppression, miR-21 is implicated in practically every walk of oncogenic life: the promotion of cell proliferation, invasion and metastasis, genome instability and mutation, inflammation, replicative immortalization, abnormal metabolism, angiogenesis, and evading apoptosis, immune destruction, and growth suppressors. In particular, miR-21 is strongly involved in apoptosis. In this article, we reviewed the experimentally validated targets of miR-21 and found that two thirds are linked to intrinsic and/or extrinsic pathways of cellular apoptosis. This suggests that miR-21 is an oncogene which plays a key role in resisting programmed cell death in cancer cells and that targeting apoptosis is a viable therapeutic option against cancers expressing miR-21.

MicroRNA 21 (miR-21) is overexpressed in virtually all types of carcinomas and various types of hematological malignancies. To determine whether miR-21 promotes tumor development in vivo, we knocked out the miR-21 allele in mice. In response to the 7,12-dimethylbenz[ a ]anthracene (DMBA)/12- O -tetradecanoylphorbol-13-acetate mouse skin carcinogenesis protocol, miR-21 -null mice showed a significant reduction in papilloma formation compared with wild-type mice. We revealed that cellular apoptosis was elevated and cell proliferation was decreased in mice deficient of miR-21 compared to wild-type animals. In addition, we found that a large number of validated or predicted miR-21 target genes were up-regulated in miR-21 -null keratinocytes, which are precursor cells to skin papillomas. Specifically, up-regulation of Spry1 , Pten , and Pdcd4 when miR-21 was ablated coincided with reduced phosphorylation of ERK, AKT, and JNK, three major downstream effectors of Ras activation that plays a predominant role in DMBA-initiated skin carcinogenesis. These results provide in vivo evidence that miR-21 exerts its oncogenic function through negatively regulating its target genes.

Nuclear factor kB (NF-kB) is a transcriptional factor that regulates a battery of genes that are critical to innate and adaptive immunity, cell proliferation, inflammation, and tumor development. MicroRNAs (miRNAs) are short RNA molecules of 20‐25 nucleotides in length that negatively regulate gene expression in animals and plants primarily by targeting 3 ′ untranslated regions of mRNAs. In this work, we review the convergence of miRNAs and NF-kB signaling and dysregulation of miRNAs and NF-kB activation in human diseases, particularly in cancer. The function of miR-146, miR-155, miR-181b, miR-21, and miR-301a in NF-kB activation and their impact on tumorigenesis are discussed. Given that over 1000 human miRNAs have been identified, rendering miRNAs one of the most abundant classes of regulatory molecules, deciphering their biological function and pathological contribution in NF-kB dysregulation is essential to appreciate the complexity of immune systems and to develop therapeutics against 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-21's 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