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      miR-125a-5p Functions as Tumor Suppressor microRNA And Is a Marker of Locoregional Recurrence And Poor prognosis in Head And Neck Cancer 1

      research-article
      * , 2 , * , 2 , * , * , * , , , * , *
      Neoplasia (New York, N.Y.)
      Neoplasia Press
      MTT, 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide, DAPI, 4′,6-diamidino-2-phenylindole, 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1, BrdU, 5-bromo-2′-deoxyuridine, CO2, carbon dioxide, cDNA, complementary DNA, DMSO, dimethylsulfoxide, DNA, deoxyribonucleic acid, ECL, electrochemiluminescence, EDTA, ethylenediaminetetraacetic acid, EGFR, epidermal growth factor receptor, ERBB2, erythroblastic oncogene B 2, FBS, fetal bovine serum, HNSCC, head and neck squamous cell carcinoma, HPV, human papillomavirus, LNA, locked nucleic acid, mRNA, messenger RNA, miRNA, microRNA, PARP, poly(ADP-ribose) polymerase, mTORC1, mTOR complex 1, PBS, phosphate-buffered saline, PCR, polymerase chain reaction, qRT-PCR, quantitative real-time polymerase chain reaction, redox, reduction–oxidation, S6K1, S6 kinase 1, snRNA, small nuclear RNA, SDS, sodium dodecyl sulfate, TCGA, The Cancer Genome Atlas, TXNRD1, thioredoxin reductase 1

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          Abstract

          MicroRNAs (miRNAs) are short single-stranded RNAs, measuring 21 to 23 nucleotides in length and regulate gene expression at the post-transcriptional level through mRNA destabilization or repressing protein synthesis. Dysregulation of miRNAs can lead to tumorigenesis through changes in regulation of key cellular processes such as cell proliferation, cell survival, and apoptosis. miR-125a-5p has been implicated as a tumor suppressor miRNA in malignancies such as non-small cell lung cancer and colon cancer. However, the role of miR-125a-5p has not been fully investigated in head and neck squamous cell carcinoma (HNSCC). We performed microRNA microarray profiling of HNSCC tumor samples obtained from a prospective clinical trial evaluating the role of postoperative radiotherapy in head and neck cancer. We also mined through The Cancer Genome Atlas to evaluate expression and survival data. Biological experiments, including cell proliferation, flow cytometry, cell migration and invasion, clonogenic survival, and fluorescent microscopy, were conducted using HN5 and UM-SCC-22B cell lines. miR-125a-5p downregulation was associated with recurrent disease in a panel of high-risk HNSCC and then confirmed poor survival associated with low expression in HNSCC via the Cancer Genome Atlas, suggesting that miR-125a-5p acts as a tumor suppressor miRNA. We then demonstrated that miR-125a-5p regulates cell proliferation through cell cycle regulation at the G 1/S transition. We also show that miR-125a-5p can alter cell migration and modulate sensitivity to ionizing radiation. Finally, we identified putative mRNA targets of miR-125a-5p, including ERBB2, EIF4EBP1, and TXNRD1, which support the tumor suppressive mechanism of miR-125a-5p. Functional validation of ERBB2 suggests that miR-125a-5p affects cell proliferation and sensitivity to ionizing radiation, in part, through ERBB2. Our data suggests that miR-125a-5p acts as a tumor suppressor miRNA, has potential as a diagnostic tool and may be a potential therapeutic target for the management and treatment of squamous cell carcinoma of the head and neck.

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          Most cited references31

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          miRDB: an online resource for microRNA target prediction and functional annotations

          MicroRNAs (miRNAs) are small non-coding RNAs that are extensively involved in many physiological and disease processes. One major challenge in miRNA studies is the identification of genes regulated by miRNAs. To this end, we have developed an online resource, miRDB (http://mirdb.org), for miRNA target prediction and functional annotations. Here, we describe recently updated features of miRDB, including 2.1 million predicted gene targets regulated by 6709 miRNAs. In addition to presenting precompiled prediction data, a new feature is the web server interface that allows submission of user-provided sequences for miRNA target prediction. In this way, users have the flexibility to study any custom miRNAs or target genes of interest. Another major update of miRDB is related to functional miRNA annotations. Although thousands of miRNAs have been identified, many of the reported miRNAs are not likely to play active functional roles or may even have been falsely identified as miRNAs from high-throughput studies. To address this issue, we have performed combined computational analyses and literature mining, and identified 568 and 452 functional miRNAs in humans and mice, respectively. These miRNAs, as well as associated functional annotations, are presented in the FuncMir Collection in miRDB.
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            OncoLnc: linking TCGA survival data to mRNAs, miRNAs, and lncRNAs

            OncoLnc is a tool for interactively exploring survival correlations, and for downloading clinical data coupled to expression data for mRNAs, miRNAs, or long noncoding RNAs (lncRNAs). OncoLnc contains survival data for 8,647 patients from 21 cancer studies performed by The Cancer Genome Atlas (TCGA), along with RNA-SEQ expression for mRNAs and miRNAs from TCGA, and lncRNA expression from MiTranscriptome beta. Storing this data gives users the ability to separate patients by gene expression, and then create publication-quality Kaplan-Meier plots or download the data for further analyses. OncoLnc also stores precomputed survival analyses, allowing users to quickly explore survival correlations for up to 21 cancers in a single click. This resource allows researchers studying a specific gene to quickly investigate if it may have a role in cancer, and the supporting data allows researchers studying a specific cancer to identify the mRNAs, miRNAs, and lncRNAs most correlated with survival, and researchers looking for a novel lncRNA involved with cancer lists of potential candidates. OncoLnc is available at http://www.oncolnc.org.
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              Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline.

              To provide recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer.
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                Author and article information

                Contributors
                Journal
                Neoplasia
                Neoplasia
                Neoplasia (New York, N.Y.)
                Neoplasia Press
                1522-8002
                1476-5586
                18 July 2019
                September 2019
                18 July 2019
                : 21
                : 9
                : 849-862
                Affiliations
                [* ]Department of Radiation Oncology, Division of Molecular Radiation Biology, UT Southwestern Medical Center, Dallas, TX 75390
                []Department of Thoracic Head and Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030
                Author notes
                [* ]Address all correspondence to: Michael D. Story, PhD, Department of Radiation Oncology, Division of Molecular Radiation Biology, UT Southwestern Medical Center, Dallas, Texas 75390. Michael.Story@ 123456UTSouthwestern.edu
                [2]

                D.T.V. and N.K.K. contributed equally to this article.

                Article
                S1476-5586(19)30060-0
                10.1016/j.neo.2019.06.004
                6642270
                31325708
                4cf7cb82-71cc-4049-bf6f-f45756902767

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 29 January 2019
                : 3 June 2019
                : 12 June 2019
                Categories
                Original article

                mtt, 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide,dapi, 4′,6-diamidino-2-phenylindole,4e-bp1, eukaryotic translation initiation factor 4e-binding protein 1,brdu, 5-bromo-2′-deoxyuridine,co2, carbon dioxide,cdna, complementary dna,dmso, dimethylsulfoxide,dna, deoxyribonucleic acid,ecl, electrochemiluminescence,edta, ethylenediaminetetraacetic acid,egfr, epidermal growth factor receptor,erbb2, erythroblastic oncogene b 2,fbs, fetal bovine serum,hnscc, head and neck squamous cell carcinoma,hpv, human papillomavirus,lna, locked nucleic acid,mrna, messenger rna,mirna, microrna,parp, poly(adp-ribose) polymerase,mtorc1, mtor complex 1,pbs, phosphate-buffered saline,pcr, polymerase chain reaction,qrt-pcr, quantitative real-time polymerase chain reaction,redox, reduction–oxidation,s6k1, s6 kinase 1,snrna, small nuclear rna,sds, sodium dodecyl sulfate,tcga, the cancer genome atlas,txnrd1, thioredoxin reductase 1

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