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      MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9

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          Abstract

          Growing evidence suggests that microRNAs are involved in the development and progression of colorectal cancer (CRC). In the present study, deregulation and functioning of tumor-suppressive miR-215-5p was evaluated in CRC. In total, 448 tumor tissues and 325 paired adjacent healthy tissues collected from Czech and Spain cohorts of CRC patients have been used for miR-215-5p expression analyses. A series of in vitro experiments have been performed using transient transfection of miR-215-5p mimics into four CRC cell lines to identify specific cellular processes affected by miR-215-5p. Further, the effects of miR-215-5p on tumor growth were evaluated in vivo using NSG mice and stable cell line overexpressing miR-215-5p. Target mRNAs of miR-215-5p were tested using luciferase assay and western blot analyses. We found that miR-215-5p is significantly downregulated in tumor tissues compared with non-tumor adjacent tissues and its decreased levels correlate with the presence of lymph node metastases, tumor stage, and shorter overall survival in CRC patients. Overexpression of miR-215-5p significantly reduced proliferation, clonogenicity, and migration of CRC cells, lead to cell cycle arrest in G2/M phase and p53-dependent induction of apoptosis. The ability of miR-215-5p to inhibit tumor growth was confirmed in vivo. Finally, we confirmed epiregulin and HOXB9 to be the direct targets of miR-215-5p. As epiregulin is EGFR ligand and HOXB9 is its transcriptional inducer, we suggest that the main molecular link between miR-215-5p and CRC cells phenotypes presents the EGFR signaling pathway, which is one of the canonical pathogenic pathways in CRC.

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          Requirement for p53 and p21 to sustain G2 arrest after DNA damage.

          After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle. It is shown here that this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21. After disruption of either the p53 or the p21 gene, gamma radiated cells progressed into mitosis and exhibited a G2 DNA content only because of a failure of cytokinesis. Thus, p53 and p21 appear to be essential for maintaining the G2 checkpoint in human cells.
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            Establishment of human tumor xenografts in immunodeficient mice.

            Heterotransplantation of human cancer cells or tumor biopsies into immunodeficient rodents (xenograft models) has, for the past two decades, constituted the major preclinical screen for the development of novel cancer therapeutics. Despite limitations, these models have identified clinically efficacious agents, and remain the 'workhorse' of the pharmaceutical industry. However, if therapeutic approaches to treating tumors according to their molecular characteristics are to be achieved, additional new models of human cancer will be required to represent the genetic diversity that exists within tumor histologies. This protocol details a method for establishing xenografts from primary solid-tumor isolates or cells grown in culture. The procedure relies on immunodeficient mice to provide a host for the establishment of human xenografts. The procedure can be completed in 1-2 h with results being obtained in 1-4 months.
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              p53-Responsive micrornas 192 and 215 are capable of inducing cell cycle arrest.

              microRNAs provide a novel layer of regulation for gene expression by interfering with the stability and/or translation of specific target mRNAs. Overall levels of microRNAs are frequently down-regulated in cancer cells, and reducing general microRNA processing increases cancerogenesis in transgenic models, suggesting that at least some microRNAs might act as effectors in tumor suppression. Accordingly, the tumor suppressor p53 up-regulates miR-34a, a microRNA that contributes to apoptosis and acute senescence. Here, we used array hybridization to find that p53 induces two additional, mutually related clusters of microRNAs, leading to the up-regulation of miR-192, miR-194, and miR-215. The same microRNAs were detected at high levels in normal colon tissue but were severely reduced in many colon cancer samples. On the other hand, miR-192 and its cousin miR-215 can each contribute to enhanced CDKN1A/p21 levels, colony suppression, cell cycle arrest, and cell detachment from a solid support. These effects were partially dependent on the presence of wild-type p53. Antagonizing endogenous miR-192 attenuated 5-fluorouracil-induced accumulation of p21. Hence, miR-192 and miR-215 can act as effectors as well as regulators of p53; they seem to suppress cancerogenesis through p21 accumulation and cell cycle arrest.
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                Author and article information

                Contributors
                +420 549 496 876 , on.slaby@gmail.com
                Journal
                Oncogenesis
                Oncogenesis
                Oncogenesis
                Nature Publishing Group UK (London )
                2157-9024
                4 December 2017
                4 December 2017
                November 2017
                : 6
                : 11
                : 399
                Affiliations
                [1 ]ISNI 0000 0001 2194 0956, GRID grid.10267.32, Central European Institute of Technology, Masaryk University, ; Brno, Czech Republic
                [2 ]Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic
                [3 ]ISNI 0000 0001 2194 0956, GRID grid.10267.32, Department of Pharmacology, , Faculty of Medicine, Masaryk University, ; Brno, Czech Republic
                [4 ]ISNI 0000 0001 0534 3000, GRID grid.411372.2, Department of Clinical Analysis, , Santa Lucia University Hospital, ; Cartagena, Spain
                [5 ]ISNI 0000 0001 0534 3000, GRID grid.411372.2, Department of Pathology, , Santa Lucia University Hospital, ; Cartagena, Spain
                Author information
                http://orcid.org/0000-0002-8450-0584
                Article
                6
                10.1038/s41389-017-0006-6
                5868056
                29199273
                5217fea5-f17f-4d32-ae55-4faca8d7dce2
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 8 May 2017
                : 16 September 2017
                : 18 September 2017
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                © The Author(s) 2017

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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