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Tytuł:
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Upregulation of human endogenous retrovirus-K (HML-2) mRNAs in hepatoblastoma: Identification of potential new immunotherapeutic targets and biomarkers.
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Autorzy:
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Grabski DF; Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia; Myles H. Thaler Center for AIDS and Human Retrovirus Research, University of Virginia, Charlottesville, Virginia.
Ratan A; Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia.
Gray LR; Myles H. Thaler Center for AIDS and Human Retrovirus Research, University of Virginia, Charlottesville, Virginia; Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia.
Bekiranov S; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
Rekosh D; Myles H. Thaler Center for AIDS and Human Retrovirus Research, University of Virginia, Charlottesville, Virginia; Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia.
Hammarskjold ML; Myles H. Thaler Center for AIDS and Human Retrovirus Research, University of Virginia, Charlottesville, Virginia; Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia.
Rasmussen SK; Myles H. Thaler Center for AIDS and Human Retrovirus Research, University of Virginia, Charlottesville, Virginia; Seattle Children's Hospital, Division of Transplantation, University of Washington Department of Surgery, 4800 Sand Point Way, Seattle, WA 98105. Electronic address: .
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Źródło:
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Journal of pediatric surgery [J Pediatr Surg] 2021 Feb; Vol. 56 (2), pp. 286-292. Date of Electronic Publication: 2020 May 27.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: Philadelphia, PA : Saunders
Original Publication: New York.
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MeSH Terms:
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Endogenous Retroviruses*/genetics
Hepatoblastoma*/genetics
Liver Neoplasms*/genetics
Biomarkers ; Child ; Humans ; Immunotherapy ; RNA, Messenger/genetics ; Up-Regulation
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Grant Information:
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R01 CA206275 United States CA NCI NIH HHS
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Contributed Indexing:
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Keywords: Fetal tumor; Hepatoblastoma; Human endogenous retrovirus-K; Immunotherapy; Tumor biomarker
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Substance Nomenclature:
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0 (Biomarkers)
0 (RNA, Messenger)
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Entry Date(s):
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Date Created: 20200720 Date Completed: 20210624 Latest Revision: 20210624
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Update Code:
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20240105
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DOI:
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10.1016/j.jpedsurg.2020.05.022
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PMID:
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32682541
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Purpose: Hepatoblastoma is the most common liver malignancy in children. In order to advance therapy against hepatoblastoma, novel immunologic targets and biomarkers are needed. Our purpose in this investigation is to examine hepatoblastoma transcriptomes for the expression of a class of genomic elements known as Human Endogenous Retrovirus (HERVs). HERVs are abundant in the human genome and are biologically active elements that have been associated with multiple malignancies and proposed as immunologic targets in a subset of tumors. A sub-family of HERVs, HERV-K(HML-2) (HERV-K), have been shown to be tightly regulated in fetal development, making investigation of these elements in pediatric tumors paramount.
Methods: We first created a HERVK-FASTA file utilizing 91 previously described HML-2 proviruses. We then concatenated the file onto the GRCh38.95 cDNA library from Ensembl. We used this reference database to evaluate existing RNA-seq data from 10 hepatoblastoma tumors and 3 normal liver controls (GEO accession ID: GSE8977575). Quantification and differential proviral expression analysis between hepatoblastoma and normal liver controls was performed using the pseudo-alignment program Salmon and DESeq2, respectively.
Results: HERV-K mRNA was expressed in hepatoblastoma from multiple proviral loci. All expressed HERV-K proviral loci were upregulated in hepatoblastoma compared to normal liver controls. Five HERV-K proviruses (1q21.3, 3q27.2, 7q22.2, 12q24.33 and 17p13.1) were significantly differentially expressed (p-adjusted value <0.05, |log2 fold change| > 1.5) across conditions. The provirus at 17p13.1 had an approximately 300-fold increased expression in hepatoblastoma as compared to normal liver. This was in part due to the near absence of HERV-K mRNA at the 17p13.1 locus in fully differentiated liver samples.
Conclusions: Our investigation demonstrates that HERV-K is expressed from multiple loci in hepatoblastoma and that the expression is increased for several proviruses compared to normal liver controls. Our results suggest that HERV-K mRNA expression may be useful as a biomarker in hepatoblastoma, given the large differential expression profiles in hepatoblastoma, with very low mRNA levels in liver control samples.
(Copyright © 2020. Published by Elsevier Inc.)
