title: MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1.
abstract: OBJECTIVE
  Recent microarray and RNA-sequencing studies have uncovered aberrantly expressed microRNAs (miRNA) in Barrett's esophagus-associated esophageal adenocarcinoma. The functional significance of these miRNAs in esophageal adenocarcinoma initiation and progression is largely unknown.
  
  
  METHODS
  Expression levels of miR-199a/b-3p, -199a-5p, -199b-5p, -200b, -200c, -223, and -375 were determined in microdissected tissues from cardiac mucosa, Barrett's esophagus, dysplastic Barrett's esophagus, and esophageal adenocarcinoma using quantitative real-time PCR. miR-223 expression was validated in precursors and esophageal adenocarcinomas from 95 patients with esophageal adenocarcinoma by in situ hybridization (ISH). miR-223 was transfected into two esophageal adenocarcinoma cell lines, and in vitro assays were conducted. Target genes were identified using Illumina microarray, and results were validated in cell lines and human specimens.
  
  
  RESULTS
  miR-199 family members and miR-223 were significantly overexpressed in esophageal adenocarcinoma, however, only miR-223 showed a stepwise increase during esophageal adenocarcinoma carcinogenesis. A similar trend was observed by ISH, which additionally showed that miR-223 is exclusively expressed by the epithelial compartment. miR-223-overexpressing cells had statistically significantly more migratory and invasive potential than scramble sequence-transfected cells. PARP1 was identified as a direct target gene of miR-223 in esophageal adenocarcinoma cells. Increased sensitivity to chemotherapy was observed in cells with enforced miR-223 expression and reduced PARP1.
  
  
  CONCLUSIONS
  miR-223 is significantly upregulated during the Barrett's esophagus-dysplasia-esophageal adenocarcinoma sequence. Although high miR-223 levels might contribute to an aggressive phenotype, our results also suggest that patients with esophageal adenocarcinoma with high miR-223 levels might benefit from treatment with DNA-damaging agents.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mirte Mayke
authors.initials: MM
authors.lastname: Streppel
authors.forename: Shweta
authors.initials: S
authors.lastname: Pai
authors.forename: Nathaniel R
authors.initials: NR
authors.lastname: Campbell
authors.forename: Chaoxin
authors.initials: C
authors.lastname: Hu
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yabuuchi
authors.forename: Marcia Irene
authors.initials: MI
authors.lastname: Canto
authors.forename: Jean S
authors.initials: JS
authors.lastname: Wang
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Montgomery
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001471:Barrett Esophagus / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000096:biosynthesis*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C525067:MIR223, human; C531408:mirn199 microRNA, human; C499320:PARP1 protein, human