MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic. In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.

MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

Over the past several years it has become clear that alterations in the expression of microRNA (miRNA) genes contribute to the pathogenesis of most — if not all — human malignancies. These alterations can be caused by various mechanisms, including deletions, amplifications or mutations involving miRNA loci, epigenetic silencing or the dysregulation of transcription factors that target specific miRNAs. Because malignant cells show dependence on the dysregulated expression of miRNA genes, which in turn control or are controlled by the dysregulation of multiple protein-coding oncogenes or tumour suppressor genes, these small RNAs provide important opportunities for the development of future miRNA-based therapies.

/pdf/causes-and-consequences-of-microrna-dysregulation-in-cancer-1oe9jwwj8l.pdf

Causes and consequences of microRNA dysregulation in cancer

Gene-based therapy is the intentional modulation of gene expression in specific cells to treat pathological conditions This modulation is accomplished by introducing exogenous nucleic acids such as DNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA) or antisense oligonucleotides Given the large size and the negative charge of these macromolecules, their delivery is typically mediated by carriers or vectors In this Review, we introduce the biological barriers to gene delivery in vivo and discuss recent advances in material sciences, nanotechnology and nucleic acid chemistry that have yielded promising non-viral delivery systems, some of which are currently undergoing testing in clinical trials The diversity of these systems highlights the recent progress of gene-based therapy using non-viral approaches

Non-viral vectors for gene-based therapy

MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs), controlling genes involved in cellular processes such as inflammation, cell-cycle regulation, stress response, differentiation, apoptosis, and migration. Thus, miRNAs have been implicated in the regulation of virtually all signaling circuits within a cell, and their dysregulation has been shown to play an essential role in the development and progression of cancer. Here, after a brief description of miRNA genomics, biogenesis, and function, we discuss the effects of miRNA dysregulation in the cellular pathways that lead to the progressive conversion of normal cells into cancer cells and the potential to develop new molecular miRNA-targeted therapies.

MicroRNAs in cancer.

https://www.cell.com/cell/pdf/S0092-8674(09)00446-2.pdf

Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

Systemic Delivery of Tumor Suppressor microRNA Mimics Using a Neutral Lipid Emulsion Inhibits Lung Tumors in Mice

MicroRNAs have been increasingly implicated in human cancer and interest has grown about the potential to use microRNAs to combat cancer. Lung cancer is the most prevalent form of cancer worldwide and lacks effective therapies. Here we have used both in vitro and in vivo approaches to show that the let-7 microRNA directly represses cancer growth in the lung. We find that let-7 inhibits the growth of multiple human lung cancer cell lines in culture, as well as the growth of lung cancer cell xenografts in immunodeficient mice. Using an established orthotopic mouse lung cancer model, we show that intranasal let-7 administration reduces tumor formation in vivo in the lungs of animals expressing a G12D activating mutation for the K-ras oncogene. These findings provide direct evidence that let-7 acts as a tumor suppressor gene in the lung and indicate that this miRNA may be useful as a novel therapeutic agent in lung cancer.

The let-7 microRNA reduces tumor growth in mouse models of lung cancer.

LB-194 Lung cancer is the most prevalent form of cancer worldwide and accounts for the most cancer deaths. MicroRNAs (miRNAs) are small, non-protein coding RNAs that have recently emerged as important regulators of gene expression and direct proper cellular growth, differentiation and cell death - all mechanisms that go awry in cancer. The let-7 miRNA is postulated to function as a tumor suppressor gene in a variety of human tissues, particularly in the lung, by negatively regulating the post-transcriptional expression of multiple oncogenes including RAS, MYC, and HMGA2, as well as other cell cycle progression genes. Here we have used both in vitro and in vivo approaches to show that let-7 directly represses cancer growth in  the lung. We show that let-7 inhibits the growth of multiple human lung cancer cell lines in culture, as well as the growth of lung cancer cell xenografts in immunodeficient mice. Using the established Lox-Stop-Lox K-ras mouse lung cancer model, we find that intranasal let-7 administration can reduce tumor formation in vivo in the lungs of animals expressing a G12D activating mutation for the K-ras oncogene. These findings support the notion that let-7 functions as a tumor suppressor in the lung and indicates that this miRNA could be used as a therapeutic agent to treat lung cancer.

The let-7 microrna reduces tumor growth in mouse models of lung cancer

MicroRNAs (miRNAs) have recently emerged as an important new class of cellular regulators that control various cellular processes and are implicated in human diseases, including cancer. Here, we show that loss of let-7 function enhances lung tumor formation in vivo, strongly supporting the hypothesis that let-7 is a tumor suppressor. Moreover, we report that exogenous delivery of let-7 to established tumors in mouse models of non-small-cell lung cancer (NSCLC) significantly reduces the tumor burden. These results demonstrate the therapeutic potential of let-7 in NSCLC and point to miRNA replacement therapy as a promising approach in cancer treatment.

/pdf/regression-of-murine-lung-tumors-by-the-let-7-microrna-187823r6b1.pdf

Regression of murine lung tumors by the let-7 microRNA.

Tumor cells use preexisting prosurvival signaling pathways to evade the damaging and cytotoxic effects of anticancer agents. Radiation therapy is a primary form of cytotoxic anticancer treatment, but agents that successfully modify the radiation response in vivo are lacking. MicroRNAs (miRNA) are global gene regulators that play critical roles in oncogenesis and have been found to regulate prosurvival pathways. However, there is little understanding of how cellular miRNA expression affects the response of a cancer to cytotoxic therapy and ultimately outcome. The let-7 family of miRNAs regulates expression of oncogenes, such as RAS, and is specifically down-regulated in many cancer subtypes. In fact, low levels of let-7 predict a poor outcome in lung cancer. Here, we report that the let-7 family of miRNAs is overrepresented in a class of miRNAs exhibiting altered expression in response to radiation. More strikingly, we also can create a radiosensitive state when the select let-7 family of miRNAs is overexpressed in vitro in lung cancer cells and in vivo in a Caenorhabditis elegans model of radiation-induced cell death, whereas decreasing their levels causes radioresistance. In C. elegans, we show that this is partly through control of the proto-oncogene homologue let-60/RAS and genes in the DNA damage response pathway. These findings are the first direct evidence that miRNAs can suppress resistance to anticancer cytotoxic therapy, a common feature of cancer cells, and suggest that miRNAs may be a viable tool to augment current cancer therapies.

https://cancerres.aacrjournals.org/content/canres/67/23/11111.full.pdf

Phong Trang

Papers

Systemic Delivery of Tumor Suppressor microRNA Mimics Using a Neutral Lipid Emulsion Inhibits Lung Tumors in Mice

The let-7 microRNA reduces tumor growth in mouse models of lung cancer.

The let-7 microrna reduces tumor growth in mouse models of lung cancer

Regression of murine lung tumors by the let-7 microRNA.

MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy.