title: A novel signaling role for miR-451 in esophageal tumor microenvironment and its contribution to tumor progression.
abstract: OBJECTIVE
  We evaluated miR-451 expression in serum and tissue samples of esophageal squamous cell carcinoma (ESCC) patients. Then, we examined a secretory role of miR-451 in esophageal tumor microenvironment.
  
  
  METHODS
  miR-451 expression was evaluated in 39 serum samples from esophageal SCC patients compared to 39 normal individuals as well as 26 pairs of fresh-frozen tumor and adjacent normal tissues from patients with ESCC, using qRT-PCR. In a co-culture system of human normal fibroblasts (HFSF-PI3) and esophageal cancer cell line (KYSE-30), we evaluated exosomal miR-451 secretion into the conditioned medium (CM) of both cell lines. Then, we analyzed the effect of primiR-451-transfected fibroblasts on the migration potency of their neighboring KYSE-30 cells.
  
  
  RESULTS
  We detected miR-451 over-expression in serum samples of esophageal cancer patients compared to the normal group (P = 0.005). Interestingly, fresh-frozen tumor tissues from the same patients showed miR-451 down-regulation compared to their adjacent normal counterparts (P = 0.043). Co-culturing the KYSE-30 cell line with normal fibroblasts significantly induced miR-451 exosomal secretion into the CM. Moreover, co-culture of KYSE-30 cell line with miR-451-over-expressing fibroblasts significantly induced migration tendency in KYSE-30 cell line compared to the mock-transfected fibroblasts (P < 0.0001). In this system, MIF expression (a validated target of miR-451) in the KYSE-30 cell line was increased although this alteration was not statistically significant (fold change = 4.44).
  
  
  CONCLUSIONS
  Our data suggest that cancer-associated fibroblasts use exosomal miR-451 as a signaling molecule to provide a favorable niche for tumor cell migration and cancer progression. Our findings provide new insights into the stromal role of miR-451 in the esophageal tumor microenvironment as a communicatory molecule and suggest a signaling role for miR-451 in extracellular matrix cross-talks.
authors.affiliation: Division of Genetics, Department of Biology, Faculty of Science, University of Isfahan, Isfahan, Iran.
authors.forename: S
authors.initials: S
authors.lastname: Khazaei
authors.affiliation: Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: N
authors.initials: N
authors.lastname: Nouraee
authors.affiliation: Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran.
authors.forename: A
authors.initials: A
authors.lastname: Moradi
authors.affiliation: Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran. sjmowla@modares.ac.ir.
authors.forename: S J
authors.initials: SJ
authors.lastname: Mowla
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018920:Coculture Techniques; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: C531201:MIRN451 microRNA, human; D035683:MicroRNAs
keywords: Esophageal cancer; Exosome; Migration; Secretory miRNA; Serum; Tumor microenvironment; miR-451