Exploiting the therapeutic potential of microRNAs in human cancer

Cho, William C.

doi:10.1517/14728222.2012.663354

Cited by 22 publications

(12 citation statements)

References 28 publications

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“…As the critical roles of miRNAs in cancers are gradually explored, their applications as potential therapeutic targets have generated great interest in developing novel strategy for treating cancer [21]–[22]. Either individually or as a cluster, the expression levels of miR-96, miR-182, and miR-183 have been shown to be up-regulated in several cancers, including prostate cancer, breast cancer, lung cancer, medulloblastoma, bladder cancer and etc.…”

Section: Discussionmentioning

confidence: 99%

Synthetic miRNA-Mowers Targeting miR-183-96-182 Cluster or miR-210 Inhibit Growth and Migration and Induce Apoptosis in Bladder Cancer Cells

et al. 2012

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BackgroundMicroRNAs (miRNAs) function as endogenous regulators of biological behaviors of human cancers. Several natural non-coding RNAs are reported to inhibit miRNAs by base-pairing interactions. These phenomena raise questions about the ability of artificial device to regulate miRNAs. The purpose of this study is to create synthetic devices that target a single miRNA or a miRNA cluster and to ascertain their therapeutic effects on the phenotypes of bladder cancer cells.Methodology/Principal FindingsTandem bulged miRNA binding sites were inserted into the 3′ untranslated region (UTR) of the SV-40 promoter-driven Renilla luciferase gene to construct two “miRNA-mowers” for suppression of miR-183-96-182 cluster or miR-210. A third device with tandem repeat sequences not complementary to any known miRNA was generated as an untargeted-control. In functional analyses, bladder cancer T24 and UM-UC-3 cells were transfected with each of the three devices, followed by assays for detection of their impacts. Luciferase assays indicated that the activities of the luciferase reporters in the miRNA-mowers were decreased to 30–50% of the untargeted-control. Using Real-Time qPCR, the expression levels of the target miRNAs were shown to be reduced 2-3-fold by the corresponding miRNA-mower. Cell growth, apoptosis, and migration were tested by MTT assay, flow cytometry assay, and in vitro scratch assay, respectively. Cell growth inhibition, increased apoptosis, and decreased motility were observed in miRNA-mowers-transfected bladder cancer cells.Conclusions/SignificanceNot only a single target miRNA but also the whole members of a target miRNA cluster can be blocked using this modular design strategy. Anti-cancer effects are induced by the synthetic miRNA-mowers in the bladder cancer cell lines. miR-183/96/182 cluster and miR-210 are shown to play oncogenic roles in bladder cancer. A potentially useful synthetic biology platform for miRNA loss-of-function study and cancer treatment has been established in this work.

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Section: Discussionmentioning

confidence: 99%

Synthetic miRNA-Mowers Targeting miR-183-96-182 Cluster or miR-210 Inhibit Growth and Migration and Induce Apoptosis in Bladder Cancer Cells

et al. 2012

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“…As seen in the previous chapter, deregulation of miRNAs is associated with the development and progression of several cancer types [61,96,576,[580][581][582][583]. The bioactivity of miRNA is generally linked to Argonaute (Ago)-family proteins that serve as a direct interaction partner of the miRNA within the RNA-induced silencing complex (RISC).…”

Section: Mirnas Regulating Proteinsmentioning

confidence: 99%

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

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Abstract:Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.Keywords: Epigenetics, anticancer therapy, DNA methyltransferases, protein methyltransferases, demethylases, deacetylases, acetyltransferases, histone post-translational modifications, drug design, crystallography, small-molecule inhibitors. INTRODUCTIONThe term epigenetics currently refers to the mechanisms of temporal and spatial control of gene activity that do not depend on the DNA sequence, influencing the physiological and pathological development of an organism. The molecular mechanisms by which epigenetic changes occur are complex and cover a wide range of processes including paramutation, bookmarking, imprinting, gene silencing, carcinogenesis progression, and, most importantly, regulation of heterochromatin and histone modifications [1]. At a biochemical level, epigenetic alterations in chromatin involve methylation of DNA patterns, several forms of histone modifications and microRNA (miRNA) expression. All these processes modulate the structure of chromatin leading to the activation or silencing of gene expression [2][3][4][5][6]. More specifically, the chromatin remodeling is accomplished by two main mechanisms that concern the methylation of cytosine residues in DNA and a variety of post-translational modifications (PTMs) occurring at the N-terminal tails of histone proteins. These PTMs include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, ADPribosylation, carbonylation, citrullination and biotinylation [7,8]. Among all PTMs for example, histone tails can have its lysine residues acetylated, methylated or ubiquitilated; arginine can be methylated; serine and threonine residues can be phosphorylated [9][10][11][12][13][14][15][16][17]. These covalent modifications are able to cause other PTMs and the ensemble of this cross-talk is known as the his...

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“…Thus, miRNA based therapeutics may have superior advantages by targeting multiple pain-associated genes and miRNA-based drugs may be the most appropriate therapy for the prevention or treatment of neuropathic and neurogenic pain. At least, recent developments provide an optimistic perspective on the evolution of therapeutic ncRNAs despite the drawback of unresolved obstacles for successful delivery and unknown, however unlikely, off-target effects (Cho, 2012). …”

Section: Translation Of Pre-clinical and Clinical Results Into Solutimentioning

confidence: 99%

microRNAs in nociceptive circuits as predictors of future clinical applications

Kress

Hüttenhofer

Landry

et al. 2013

Front. Mol. Neurosci.

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Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs – and microRNAs (miRNAs) in particular – regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals.

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Exploiting the therapeutic potential of microRNAs in human cancer

Cited by 22 publications

References 28 publications

Synthetic miRNA-Mowers Targeting miR-183-96-182 Cluster or miR-210 Inhibit Growth and Migration and Induce Apoptosis in Bladder Cancer Cells

Synthetic miRNA-Mowers Targeting miR-183-96-182 Cluster or miR-210 Inhibit Growth and Migration and Induce Apoptosis in Bladder Cancer Cells

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

microRNAs in nociceptive circuits as predictors of future clinical applications

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