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      The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases

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          Abstract

          Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial–mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

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          Most cited references102

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          Epithelial-mesenchymal transitions in development and disease.

          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Reduced accumulation of specific microRNAs in colorectal neoplasia.

            Short non-coding RNAs are known to regulate cellular processes including development, heterochromatin formation, and genomic stability in eukaryotes. Given the impact of these processes on cellular identity, a study was undertaken to investigate possible changes in microRNA (miRNA) levels during tumorigenesis. A total of 28 different miRNA sequences was identified in a colonic adenocarcinoma and normal mucosa, including 3 novel sequences and a further 7 that had previously been cloned only from mice. Human homologues of murine miRNA sequences, miR-143 and miR-145, consistently display reduced steady-state levels of the mature miRNA at the adenomatous and cancer stages of colorectal neoplasia.
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              Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells.

              MicroRNA (miRNA) transfer via exosomes may mediate cell-to-cell communication. Interestingly, specific miRNAs are enriched in exosomes in a cell-type-dependent fashion. However, the mechanisms whereby miRNAs are sorted to exosomes and the significance of miRNA transfer to acceptor cells are unclear. We used macrophages and endothelial cells (ECs) as a model of heterotypic cell communication in order to investigate both processes. RNA profiling of macrophages and their exosomes shows that miRNA sorting to exosomes is modulated by cell-activation-dependent changes of miRNA target levels in the producer cells. Genetically perturbing the expression of individual miRNAs or their targeted transcripts promotes bidirectional miRNA relocation from the cell cytoplasm/P bodies (sites of miRNA activity) to multivesicular bodies (sites of exosome biogenesis) and controls miRNA sorting to exosomes. Furthermore, the use of Dicer-deficient cells and reporter lentiviral vectors (LVs) for miRNA activity shows that exosomal miRNAs are transferred from macrophages to ECs to detectably repress targeted sequences. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                22 November 2018
                December 2018
                : 19
                : 12
                : 3711
                Affiliations
                [1 ]Department of Functional Genomics, Proteomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca 400015, Romania; simona.visan19@ 123456gmail.com (S.V.); dani_cruceriu@ 123456yahoo.com (D.C.); loredana_balacescu@ 123456yahoo.com (L.B.)
                [2 ]11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400015, Romania; dr.geni@ 123456yahoo.co.uk (D.S.); calincainap2015@ 123456gmail.com (C.C.)
                [3 ]Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca 400015, Romania
                [4 ]Department of Molecular Biology and Biotechnology, “Babes-Bolyai” University, Cluj-Napoca 400006, Romania
                [5 ]5th Department of Internal Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400006, Romania; roberta786@ 123456yahoo.com
                [6 ]Department of Gastroenterology, Wilhelmina Hospital Assen, Europaweg-Zuid 1, 9401 RK Assen, The Netherlands
                [7 ]Department of Surgery, Municipal Hospital, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400139, Romania; mihai.stefan.muresan@ 123456gmail.com
                [8 ]11th Department of Oncological Surgery and Gynecological Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400015, Romania; cosminlisencu@ 123456yahoo.com (C.L.); airimie@ 123456umfcluj.ro (A.I.)
                [9 ]Department of Surgery, The Oncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca 400015, Romania
                Author notes
                [* ]Correspondence: obalacescu@ 123456yahoo.com
                [†]

                All authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-1689-9148
                Article
                ijms-19-03711
                10.3390/ijms19123711
                6321452
                30469518
                0f598038-6566-4f3f-8e7f-a96d3256b822
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 October 2018
                : 20 November 2018
                Categories
                Review

                Molecular biology
                mirnas,colorectal cancer,exosomes,liver,metastases
                Molecular biology
                mirnas, colorectal cancer, exosomes, liver, metastases

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