Deregulation of miRNAs-cMYC circuits is a key event in refractory celiac disease type-2 lymphomagenesis: Clinical Science

V. Vaira, G. Gaudioso, M.A. Laginestra, A. Terrasi, C. Agostinelli, S. Bosari, A. Di Sabatino, A. Vanoli, M. Paulli, S. Ferrero, L. Roncoroni, V. Lombardo, L.P. Perera, S. Fabris, Maurizio Vecchi, S. Pileri, L. Elli

Research output: Contribution to journalArticlepeer-review

Abstract

A percentage of celiac disease (CD) patients develop refractory type-2 disease (RCD2), a condition associated with increased risk of enteropathy-associated T-cell-lymphoma (EATL) and without therapeutic option. Therefore, we profiled the miRNome in series of peripheral T-cell lymphomas (PTCLs), CD, RCD1 or 2 and in the murine interleukin-15 (IL15)-transgenic (TG) model of RCD. The transcriptome was analyzed in 18 intestinal T-cell lymphomas (ITLs). Bioinformatics pipelines provided significant microRNA (miRNA) lists and predicted targets that were confirmed in a second set of patients. Our data show that ITLs have a unique miRNA profile with respect to other PTCLs. The c-MYC regulated miR-17/92 cluster distinguishes monomorphic epitheliotropic ITL (MEITL) from EATL and prognosticates EATL outcome. These miRNAs are decreased in IL15-TG mice upon Janus kinase (JAK) inhibition. The random forest algorithm identified a signature of 38 classifier miRNAs, among which, themiR-200 and miR-192/215 families were progressively lost in RCD2 and ITL-CD, whereas miR-17/92 and C19MCmiRNAs were up-regulated. Accordingly, SMAD3,MDM2, c-Myc and activated-STAT3 were increased in RCD2 and EATL tissues while JAK inhibition in IL15-TG mice restored their levels to baseline. Our data suggest that miRNAs circuit supports activation of STAT3 and c-Myc oncogenic signaling in RCD2, thus contributing to lymphomagenesis. This novel understanding might pave the way to personalized medicine approaches for RCD and EATL. ©2020 The Author(s).
Original languageEnglish
Pages (from-to)1151-1166
Number of pages16
JournalClin. Sci.
Volume134
Issue number10
DOIs
Publication statusPublished - 2020

Keywords

  • CD2 antigen
  • CD20 antigen
  • CD3 antigen
  • CD4 antigen
  • CD5 antigen
  • CD56 antigen
  • CD7 antigen
  • CD8 antigen
  • granzyme B
  • interleukin 15
  • Janus kinase
  • Ki 67 antigen
  • microRNA
  • microRNA 106a 5p
  • microRNA 17
  • microRNA 17 5p
  • microRNA 195
  • microRNA 19b 3p
  • microRNA 200
  • microRNA 20b 5p
  • microRNA 215
  • microRNA 92
  • microRNA 92a 3p
  • Myc protein
  • perforin
  • protein MDM2
  • Smad3 protein
  • STAT3 protein
  • T lymphocyte receptor gamma chain
  • transcriptome
  • unclassified drug
  • CD103 antigen
  • microRNA 17 p
  • microRNA 192
  • microRNA 19b 1 5p
  • tumor necrosis factor receptor superfamily member 8
  • tumor marker
  • anaplastic large cell lymphoma
  • angioimmunoblastic t cell lymphoma
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • bioinformatics
  • cancer survival
  • celiac disease
  • classifier
  • clinical article
  • cohort analysis
  • controlled study
  • duodenum biopsy
  • enzyme inhibition
  • female
  • gene expression profiling
  • gene targeting
  • human
  • human cell
  • intestine lymphoma
  • intestine villus atrophy
  • mouse
  • NK T cell lymphoma
  • nonhuman
  • peripheral T cell lymphoma
  • priority journal
  • prognosis
  • protein RNA binding
  • random forest
  • refractory celiac disease type 2 lymphomagenesis
  • regulatory mechanism
  • upregulation
  • aged
  • cancer prognosis
  • celiac disease type 2
  • down regulation
  • gene amplification
  • human tissue
  • immunohistochemistry
  • immunophenotyping
  • intestine cell
  • male
  • personalized medicine
  • protein expression
  • retrospective study
  • RNA purification
  • T lymphocyte
  • algorithm
  • animal
  • biological model
  • carcinogenesis
  • gene expression regulation
  • genetics
  • intestine
  • lymphoma
  • metabolism
  • pathology
  • transgenic mouse
  • Algorithms
  • Animals
  • Biomarkers, Tumor
  • Carcinogenesis
  • Celiac Disease
  • Female
  • Gene Expression Regulation, Neoplastic
  • Intestines
  • Lymphoma
  • Male
  • Mice, Transgenic
  • MicroRNAs
  • Models, Biological
  • Prognosis
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins c-myc
  • Smad3 Protein
  • Up-Regulation

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