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.

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Causes and consequences of microRNA dysregulation in cancer

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

Early studies have shown how aberrantly expressed microRNAs are a hallmark of several diseases like cancer. MicroRNA expression profiling was shown to be associated with tumour development, progression and response to therapy, suggesting their possible use as diagnostic, prognostic and predictive biomarkers. Moreover, based on the increasing number of studies demonstrating that microRNAs can function as potential oncogenes or oncosuppressor genes, with the goal to improve disease response and increase cure rates, miRNA-based anticancer therapies have recently been exploited, either alone or in combination with current targeted therapies. The advantage of using microRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Here, we review our current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools.

https://www.embopress.org/doi/pdf/10.1002/emmm.201100209

MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review

'miR2Disease', a manually curated database, aims at providing a comprehensive resource of microRNA deregulation in various human diseases. The current version of miR2Disease documents 1939 curated relationships between 299 human microRNAs and 94 human diseases by reviewing more than 600 published papers. Around one-seventh of the microRNA-disease relationships represent the pathogenic roles of deregulated microRNA in human disease. Each entry in the miR2Disease contains detailed information on a microRNA-disease relationship, including a microRNA ID, the disease name, a brief description of the microRNA-disease relationship, an expression pattern of the microRNA, the detection method for microRNA expression, experimentally verified target gene(s) of the microRNA and a literature reference. miR2Disease provides a user-friendly interface for a convenient retrieval of each entry by microRNA ID, disease name, or target gene. In addition, miR2Disease offers a submission page that allows researchers to submit established microRNA-disease relationships that are not documented. Once approved by the submission review committee, the submitted records will be included in the database. miR2Disease is freely available at http://www.miR2Disease.org.

/pdf/mir2disease-a-manually-curated-database-for-microrna-4njeg3ns8f.pdf

miR2Disease: a manually curated database for microRNA deregulation in human disease

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

The present invention concerns methods and compositions involving RNase III and polypeptides containing RNase III domains to generate RNA capable of triggering RNA-mediated interference (RNAi) in a cell. In some embodiments, the RNase III is from a prokaryote. RNase III activity will cleave a double-stranded RNA molecule into short RNA molecules that may trigger or mediate RNAi (siRNA). Compositions of the invention include kits that include an RNase III domain-containing polypeptide. The present invention further concerns methods using polypeptides with RNase III activity for generating RNA molecules that effect RNAi, including the generation of a number of RNA molecules to the same target.

Methods and compositions relating to polypeptides with rnase iii domains that mediate rna interference

Described herein is the use of antibody-based delivery agents to target and deliver nucleic acid agents into specific cell types. Herein, we describe methods used that improve the ability of conjugates that load over 3 siRNA per conjugate and target siRNA to cells expressing the appropriate cell surface antigens. We also contemplate the use of antibody, targeting peptides, small molecules, aptamers and all other factors known in the art that can specifically target tissues. In each case, these targeting moieties can be conjugated using chemical crosslinking agents to carriers enabling directed delivery of nucleic acids.

Lance Ford

Papers

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

Methods and compositions relating to polypeptides with rnase iii domains that mediate rna interference

Increasing efficiency of nucleic acid delivery in vivo using targeting conjugates

RNA Interference Technology: Six methods of inducing RNAi in mammalian cells

Verfahren und Zusammensetzungen, die miRNA und miRNA-Inhibitorischen Molekülen verbunden sind