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      Transcriptome Analysis Identifies LINC00152 as a Biomarker of Early Relapse and Mortality in Acute Lymphoblastic Leukemia

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 2 , 8 , 9 , 10 , 11 , 6 , 12 , 13 , 14 , 15 , 16 , 12 , 13 , 2 , 2 , 17 , 15 , 16 , 14 , 18 , 18 , 19 , 19 , 19 , 2 , 20 , * , 3 , *
      Genes
      MDPI
      acute lymphoblastic leukemia, long noncoding RNA, LINC00152, LINC001013, early relapse, microarray expression analysis

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          Abstract

          Evidence showing the role of long non-coding RNAs (lncRNAs) in leukemogenesis have emerged in the last decade. It has been proposed that these genes can be used as diagnosis and/or prognosis biomarkers in childhood acute lymphoblastic leukemia (ALL). To know if lncRNAs are associated with early relapse and early mortality, a microarray-based gene expression analysis in children with B-lineage ALL (B-ALL) was conducted. Cox regression analyses were performed. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated. LINC00152 and LINC01013 were among the most differentially expressed genes in patients with early relapse and early mortality. For LINC00152 high expression, the risks of relapse and death were HR: 4.16 (95% CI: 1.46–11.86) and HR: 1.99 (95% CI: 0.66–6.02), respectively; for LINC01013 low expression, the risks of relapse and death were HR: 3.03 (95% CI: 1.14–8.05) and HR: 6.87 (95% CI: 1.50–31.48), respectively. These results were adjusted by NCI risk criteria and chemotherapy regimen. The lncRNA–mRNA co-expression analysis showed that LINC00152 potentially regulates genes involved in cell substrate adhesion and peptidyl–tyrosine autophosphorylation biological processes. The results of the present study point out that LINC00152 could be a potential biomarker of relapse in children with B-ALL.

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          Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer

          Background Previous studies identified microRNAs (miRNAs) and messenger RNAs with significantly different expression between normal pancreas and pancreatic cancer (PDAC) tissues. Due to technological limitations of microarrays and real-time PCR systems these studies focused on a fixed set of targets. Expression of other RNA classes such as long intergenic non-coding RNAs or sno-derived RNAs has rarely been examined in pancreatic cancer. Here, we analysed the coding and non-coding transcriptome of six PDAC and five control tissues using next-generation sequencing. Results Besides the confirmation of several deregulated mRNAs and miRNAs, miRNAs without previous implication in PDAC were detected: miR-802, miR-2114 or miR-561. SnoRNA-derived RNAs (e.g. sno-HBII-296B) and piR-017061, a piwi-interacting RNA, were found to be differentially expressed between PDAC and control tissues. In silico target analysis of miR-802 revealed potential binding sites in the 3′ UTR of TCF4, encoding a transcription factor that controls Wnt signalling genes. Overexpression of miR-802 in MiaPaCa pancreatic cancer cells reduced TCF4 protein levels. Using Massive Analysis of cDNA Ends (MACE) we identified differential expression of 43 lincRNAs, long intergenic non-coding RNAs, e.g. LINC00261 and LINC00152 as well as several natural antisense transcripts like HNF1A-AS1 and AFAP1-AS1. Differential expression was confirmed by qPCR on the mRNA/miRNA/lincRNA level and by immunohistochemistry on the protein level. Conclusions Here, we report a novel lncRNA, sncRNA and mRNA signature of PDAC. In silico prediction of ncRNA targets allowed for assigning potential functions to differentially regulated RNAs. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0358-5) contains supplementary material, which is available to authorized users.
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            Analysis of long non-coding RNA expression profiles in gastric cancer.

            To investigate the expression patterns of long non-coding RNAs (lncRNAs) in gastric cancer. Two publicly available human exon arrays for gastric cancer and data for the corresponding normal tissue were downloaded from the Gene Expression Omnibus (GEO). We re-annotated the probes of the human exon arrays and retained the probes uniquely mapping to lncRNAs at the gene level. LncRNA expression profiles were generated by using robust multi-array average method in affymetrix power tools. The normalized data were then analyzed with a Bioconductor package linear models for microarray data and genes with adjusted P-values below 0.01 were considered differentially expressed. An independent data set was used to validate the results. With the computational pipeline established to re-annotate over 6.5 million probes of the Affymetrix Human Exon 1.0 ST array, we identified 136053 probes uniquely mapping to lncRNAs at the gene level. These probes correspond to 9294 lncRNAs, covering nearly 76% of the GENCODE lncRNA data set. By analyzing GSE27342 consisting of 80 paired gastric cancer and normal adjacent tissue samples, we identified 88 lncRNAs that were differentially expressed in gastric cancer, some of which have been reported to play a role in cancer, such as LINC00152, taurine upregulated 1, urothelial cancer associated 1, Pvt1 oncogene, small nucleolar RNA host gene 1 and LINC00261. In the validation data set GSE33335, 59% of these differentially expressed lncRNAs showed significant expression changes (adjusted P-value < 0.01) with the same direction. We identified a set of lncRNAs differentially expressed in gastric cancer, providing useful information for discovery of new biomarkers and therapeutic targets in gastric cancer.
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              Emerging mechanisms of long noncoding RNA function during normal and malignant hematopoiesis.

              Long noncoding RNAs (lncRNAs) are increasingly recognized as vital components of gene programs controlling cell differentiation and function. Central to their functions is an ability to act as scaffolds or as decoys that recruit or sequester effector proteins from their DNA, RNA, or protein targets. lncRNA-modulated effectors include regulators of transcription, chromatin organization, RNA processing, and translation, such that lncRNAs can influence gene expression at multiple levels. Here we review the current understanding of how lncRNAs help coordinate gene expression to modulate cell fate in the hematopoietic system. We focus on a growing number of mechanistic studies to synthesize emerging principles of lncRNA function, emphasizing how they facilitate diversification of gene programming during development. We also survey how disrupted lncRNA function can contribute to malignant transformation, highlighting opportunities for therapeutic intervention in specific myeloid and lymphoid cancers. Finally, we discuss challenges and prospects for further elucidation of lncRNA mechanisms.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                13 March 2020
                March 2020
                : 11
                : 3
                : 302
                Affiliations
                [1 ]Programa de Doctorado, Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; d.a.barcenas@ 123456outlook.com
                [2 ]Unidad de Investigación Médica en Epidemiologia Clínica, UMAE Hospital de Pediatría “Dr. Silvestre Frenk Freund”, Centro Médico Nacional “Siglo XXI”, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; jcarlos_nu@ 123456hotmail.com (J.C.N.-E.); janetflores22@ 123456yahoo.com.mx (J.F.-L.); maria_luisa_2000_mx@ 123456yahoo.com (M.L.P.-S.); turunci@ 123456gmail.com (D.A.D.-R.)
                [3 ]Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; ahidalgo@ 123456inmegen.gob.mx
                [4 ]Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; frebeltran@ 123456hotmail.com
                [5 ]Programa de Maestría en Investigación Clínica Experimental en Salud, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; didier_may@ 123456outlook.com
                [6 ]Servicio de Hematología Pediátrica, Hospital General “Gaudencio González Garza”, Centro Médico Nacional “La Raza”, IMSS, Mexico City 02990, Mexico; elvajimenez@ 123456yahoo.com (E.J.-H.); nanuvi_2401@ 123456yahoo.com.mx (N.N.N.-V.)
                [7 ]Unidad de Investigación Médica en Inmunología e Infectología, Hospital de Infectología “Dr. Daniel Méndez Hernández”, Centro Médico Nacional “La Raza”, IMSS, Mexico City 02990, Mexico; bekkermendez@ 123456yahoo.com
                [8 ]Servicio de Hemato-Oncologia, Hospital Infantil de México Federico Gómez, Secretaria de Salud (SS), Mexico City 06720, Mexico; auroramedina@ 123456aol.com.mx
                [9 ]Servicio de Hemato-Oncología Hospital Infantil de Tamaulipas, Secretaría de Salud (SS), Cd. Victoria Tamaulipas 87070, Mexico; lilianatamez@ 123456hotmail.com
                [10 ]Servicio de Ortopedia Pediátrica, Hospital Infantil de Tamaulipas, Secretaría de Salud (SS), Cd. Victoria Tamaulipas 87070, Mexico; ortopediatra81@ 123456gmail.com
                [11 ]Departamento de Genética, Hospital Infantil de Tamaulipas, Secretaría de Salud (SS), Cd. Victoria Tamaulipas 87070, Mexico; lara_mayor@ 123456hotmail.com
                [12 ]Servicio de Onco-Pediatría, Hospital Juárez de México, Secretaría de Salud (SS), Mexico City 07760, Mexico; penaloza_6@ 123456yahoo.es (J.G.P.-G.); m_mvelazquez@ 123456yahoo.com.mx (M.M.V.-A.)
                [13 ]Servicio de Hematología Pediátrica, Centro Médico Nacional “20 de Noviembre”, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Mexico City 03100, Mexico; victoriabanco@ 123456yahoo.com.mx (L.V.F.-V.); sketch0712@ 123456gmail.com (L.E.M.-P.)
                [14 ]Hospital General Regional 1 “Dr. Carlos McGregor Sánchez Navarro”, IMSS, Mexico City 03103, Mexico; dibs_amador@ 123456hotmail.com (R.A.-S.); itamarga@ 123456hotmail.com (A.I.G.-Á.)
                [15 ]Servicio de Hematología Pediátrica, Hospital General de México “Dr. Eduardo Liceaga”, Secretaría de Salud (SS), Mexico City 06720, Mexico; rmespinosa1605@ 123456hotmail.com (R.M.E.-E.); beatrizcortes101087@ 123456gmail.com (B.C.-H.)
                [16 ]Servicio de Hematología Pediátrica UMAE Hospital de Pediatría “Dr. Silvestre Frenk Freund”, Centro Médico Nacional “Siglo XXI”, IMSS, Mexico City 06720, Mexico; jorge.martintr@ 123456imss.gob.mx (J.A.M.-T.); kas_anastacia@ 123456yahoo.com (K.A.S.-L.)
                [17 ]Servicio de Oncología, Hospital Pediátrico de Moctezuma, Secretaria de Salud del D.F., Mexico City 15530, Mexico; torresoncoped@ 123456live.com.mx
                [18 ]Servicio de Hemato-Oncología Pediátrica, Hospital Regional No. 1 de Octubre, ISSSTE, Mexico City 07300, Mexico; jessydenise22@ 123456hotmail.com (J.D.S.-J.); ale.garciavelazquez@ 123456gmail.com (A.J.G.-V.)
                [19 ]Unidad de Investigación en Genética Humana, UMAE Hospital de Pediatría “Dr. Silvestre Frenk Freund”, Centro Médico Nacional “Siglo XXI”, IMSS, Mexico City 06720, Mexico; hayrov@ 123456gmail.com (H.R.-V.); mine_mr@ 123456hotmail.com (M.M.-R.); sero__82@ 123456hotmail.com (O.A.S.-R.)
                [20 ]Coordinación de Investigación en Salud, IMSS, Mexico City 06720, Mexico
                Author notes
                [* ]Correspondence: juan.mejiaa@ 123456imss.gob.mx or arangurejm@ 123456gmail.com (J.M.M.-A.); sjimenez@ 123456inmegen.gob.mx (S.J.-M.); Tel.: +52–55–5350–1900 (ext. 1155) (S.J.-M.)
                Author information
                https://orcid.org/0000-0002-8070-9727
                https://orcid.org/0000-0003-2315-3977
                https://orcid.org/0000-0001-6862-7879
                https://orcid.org/0000-0002-4118-0269
                https://orcid.org/0000-0003-2152-3954
                https://orcid.org/0000-0002-6590-9712
                Article
                genes-11-00302
                10.3390/genes11030302
                7140896
                32183133
                8c94ca1a-6e21-4d37-afc1-c458a632751e
                © 2020 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
                : 30 January 2020
                : 12 March 2020
                Categories
                Article

                acute lymphoblastic leukemia,long noncoding rna,linc00152,linc001013,early relapse,microarray expression analysis

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