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      Is Open Access

      Mir-34: A New Weapon Against Cancer?

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The microRNA(miRNA)-34a is a key regulator of tumor suppression. It controls the expression of a plethora of target proteins involved in cell cycle, differentiation and apoptosis, and antagonizes processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. In this review, we focus on the molecular mechanisms of miR-34a-mediated tumor suppression, giving emphasis on the main miR-34a targets, as well as on the principal regulators involved in the modulation of this miRNA. Moreover, we shed light on the miR-34a role in modulating responsiveness to chemotherapy and on the phytonutrients-mediated regulation of miR-34a expression and activity in cancer cells. Given the broad anti-oncogenic activity of miR-34a, we also discuss the substantial benefits of a new therapeutic concept based on nanotechnology delivery of miRNA mimics. In fact, the replacement of oncosuppressor miRNAs provides an effective strategy against tumor heterogeneity and the selective RNA-based delivery systems seems to be an excellent platform for a safe and effective targeting of the tumor.

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          Targeting microRNAs in cancer: rationale, strategies and challenges.

          Ramiro Garzon, Guido Marcucci, Carlo Croce (2010)
          MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that regulate gene expression. Early studies have shown that miRNA expression is deregulated in cancer and experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression. Based on these observations, miRNA-based anticancer therapies are being developed, either alone or in combination with current targeted therapies, with the goal to improve disease response and increase cure rates. The advantage of using miRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. In this Review, we describe the role of miRNAs in tumorigenesis and critically discuss the rationale, the strategies and the challenges for the therapeutic targeting of miRNAs in cancer.
          Article 0 comments Cited 508 times – based on 0 reviews     Review now
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            SMAD proteins control DROSHA-mediated microRNA maturation.

            Brandi Davis, Aaron C Hilyard, Giorgio Lagna … (2008)
            MicroRNAs (miRNAs) are small non-coding RNAs that participate in the spatiotemporal regulation of messenger RNA and protein synthesis. Aberrant miRNA expression leads to developmental abnormalities and diseases, such as cardiovascular disorders and cancer; however, the stimuli and processes regulating miRNA biogenesis are largely unknown. The transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) family of growth factors orchestrates fundamental biological processes in development and in the homeostasis of adult tissues, including the vasculature. Here we show that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is mediated by miR-21. miR-21 downregulates PDCD4 (programmed cell death 4), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signalling promotes a rapid increase in expression of mature miR-21 through a post-transcriptional step, promoting the processing of primary transcripts of miR-21 (pri-miR-21) into precursor miR-21 (pre-miR-21) by the DROSHA (also known as RNASEN) complex. TGF-beta- and BMP-specific SMAD signal transducers are recruited to pri-miR-21 in a complex with the RNA helicase p68 (also known as DDX5), a component of the DROSHA microprocessor complex. The shared cofactor SMAD4 is not required for this process. Thus, regulation of miRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signalling pathways.
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              miR-221 overexpression contributes to liver tumorigenesis.

              Pascal Pineau, Stefano Volinia, Katherine McJunkin … (2010)
              MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most up-regulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of miR-221. Taken together, these data reveal an important contribution for miR-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of miR-221 may prove to be a promising approach to liver cancer treatment.
              Article 0 comments Cited 245 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Ther Nucleic Acids
                Journal ID (iso-abbrev): Mol Ther Nucleic Acids
                Title: Molecular Therapy. Nucleic Acids
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2162-2531
                Publication date (Print): September 2014
                Publication date (Electronic): 23 September 2014
                Publication date PMC-release: 1 September 2014
                Volume: 3
                Issue: 9
                Page: e195
                Affiliations
                [1 ]Department of Biochemistry, Biophysics and General Pathology, Second University of Naples , Naples, Italy
                [2 ]Department of Experimental and Clinical Medicine, Magna Graecia University and Medical OncologyUnit, T. Campanella Cancer Center, Salvatore Venuta University Campus , Catanzaro, Italy
                [3 ]Department of Pharmacy, University “Federico II” of Naples , Naples, Italy
                [4 ]Laboratory for Translational Oncology and Personalized Medicine, Rashid Latif Medical College , Lahore, Pakistan
                [5 ]Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University , Philadelphia, Pennsylvania, USA
                Author notes
                [* ]Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy. E-mail: Michele.caraglia@ 123456unina2.it or Michele.caraglia@ 123456alice.it
                Article
                Publisher Item ID: mtna201447
                DOI: 10.1038/mtna.2014.47
                PMC ID: 4222652
                PubMed ID: 25247240
                SO-VID: a1ca8300-1e97-4c8f-a632-e0bf236d535a
                Copyright © Copyright © 2014 American Society of Gene & Cell Therapy
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                Date received : 03 August 2014
                Date accepted : 11 August 2014
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: apoptosis,cancer,cell cycle,delivery,dna damage,microrna,mir-34a,multiple myeloma,nanotechnology,p53
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: apoptosis, cancer, cell cycle, delivery, dna damage, microrna, mir-34a, multiple myeloma, nanotechnology, p53

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