Development of Novel Therapeutic Agents by Inhibition of Oncogenic MicroRNAs

Nguyen, Dan J.M.; Chang, Suhwan

doi:10.3390/ijms19010065

Cited by 67 publications

(66 citation statements)

References 118 publications

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“…Recent developments on miRNAs have accelerated the evolution of methods and chemical modifications that make it possible to inhibit miRNAs in a stable manner, and to optimize their delivery. These are locked nucleic acids (LNA), peptide nucleic acids (PNA), phosphorothioate groups, miRNA sponges and nanoparticles ( McKiernan et al, 2013 ; Nguyen and Chang, 2017 ). Phosphorothioate oligonucleotides increase the resistance to 3′-exonuclease hydrolysis and bind more promiscuously and with higher affinity to proteins than antisense oligonucleotides with phosphodiester linkages, which are present in natural DNA and RNA ( Gilar et al, 1998 ; Crooke et al, 2017 ).…”

Section: Mirnas: Therapeutic Strategiesmentioning

confidence: 99%

Emerging microRNA Therapeutic Approaches for Cystic Fibrosis

et al. 2018

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Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains the most common life-shortening diseases affecting the exocrine organs. The absence of this channel results in an imbalance of ion concentrations across the cell membrane and results in more abnormal secretion and mucus plugging in the gastrointestinal tract and in the lungs of CF patients. The direct introduction of fully functional CFTR by gene therapy has long been pursued as a therapeutical option to restore CFTR function independent of the specific CFTR mutation, but the different clinical trials failed to propose persuasive evidence of this strategy. The last ten years has led to the development of new pharmacotherapies which can activate CFTR function in a mutation-specific manner. Although approximately 2,000 different disease-associated mutations have been identified, a single codon deletion, F508del, is by far the most common and is present on at least one allele in approximately 70% of the patients in CF populations. This strategy is limited by chemistry, the knowledge on CFTR and the heterogenicity of the patients. New research efforts in CF aim to develop other therapeutical approaches to combine different strategies. Targeting RNA appears as a new and an important opportunity to modulate dysregulated biological processes. Abnormal miRNA activity has been linked to numerous diseases, and over the last decade, the critical role of miRNA in regulating biological processes has fostered interest in how miRNA binds to and interacts explicitly with the target protein. Herein, this review describes the different strategies to identify dysregulated miRNA opens up a new concept and new opportunities to correct CFTR deficiency. This review describes therapeutic applications of antisense techniques currently under investigation in CF.

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Section: Mirnas: Therapeutic Strategiesmentioning

confidence: 99%

Emerging microRNA Therapeutic Approaches for Cystic Fibrosis

et al. 2018

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“…By affecting mRNA levels in cells, a single miRNA can concurrently regulate several dozen genes, and notably, more than half the genes in the human genome have thus far been shown to be regulated by miRNAs [ 31 ]. Furthermore, aberrant miRNA expression has been shown to result in various diseases, including cancer [ 32 , 33 , 34 , 35 , 36 ]; accordingly, several miRNAs are regarded as key targets for disease treatment, and antineoplastic agents such as Taxol and curcumin have been found to regulate miRNAs when used in cancer therapy [ 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Inhibits the Progression of Hepatocellular Carcinoma through MicroRNA Let7i-3p Mediated RAF1 Reduction

Wang

Yeh

et al. 2018

IJMS

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Melatonin is the main pineal hormone that relays light/dark-cycle information to the circadian system. Recent studies have examined the intrinsic antitumor activity of melatonin in various cancers, including hepatocellular carcinoma (HCC), the primary life-threatening malignancy in both sexes in Taiwan. However, the detailed regulatory mechanisms underlying melatonin’s anti-HCC activity remain incompletely understood. Here, we investigated the mechanisms by which the anti-HCC activity of melatonin is regulated. Human hepatoma cell lines were treated with 1 and 2 mM melatonin, and functional assays were used to dissect melatonin’s antitumor effect in HCC; small-RNA sequencing was performed to identify the microRNAs (miRNAs) involved in the anti-HCC activity of melatonin; and quantitative RT-PCR and Western blotting were used to elucidate how miRNAs regulate melatonin-mediated HCC suppression. Melatonin treatment at both doses strongly inhibited the proliferation, migration and invasion capacities of Huh7 and HepG2 cell lines, and melatonin treatment markedly induced the expression of the miRNA let7i-3p in cells. Notably, transfection of cells with a let7i-3p mimic drastically reduced RAF1 expression and activation of mitogen-activated protein kinase signaling downstream from RAF1, and rescue-assay results demonstrated that melatonin inhibited HCC progression by modulating let7i-3p-mediated RAF1 suppression. Our findings support the view that melatonin treatment holds considerable promise as a therapy for HCC.

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“…Inhibition of KRAS by reconstitution of miRs-96 and -143 is critical, because these miRs do not discriminate between wild-type and mutated KRAS due to targeting of the conserved 3'-UTRs of their corresponding mRNAs. miR inhibitors are referred to as antagomirs and are single-stranded RNA molecules in the range of 22-25 nts complementary to a site of the mRNA which is the target of the miR under consideration, preventing binding of the corresponding miR to its target mRNA (21,22,123,124). Usually, chemical modifications such as 2'-methoxy groups and phosphothioates are incorporated into antagomirs to make them resistant to degradation (21,22).…”

Section: Therapeutic Aspectsmentioning

confidence: 99%