MicroRNA modulated networks of adaptive and innate immune response in pancreatic ductal adenocarcinoma

PLoS One. 2019 May 31;14(5):e0217421. doi: 10.1371/journal.pone.0217421. eCollection 2019.

Abstract

Despite progress in treatment strategies, only ~24% of pancreatic ductal adenocarcinoma (PDAC) patients survive >1 year. Our goal was to elucidate deregulated pathways modulated by microRNAs (miRNAs) in PDAC and Vater ampulla (AMP) cancers. Global miRNA expression was identified in 19 PDAC, 6 AMP and 25 paired, histologically normal pancreatic tissues using the GeneChip 4.0 miRNA arrays. Computational approaches were used for miRNA target prediction/identification of miRNA-regulated pathways. Target gene expression was validated in 178 pancreatic cancer and 4 pancreatic normal tissues from The Cancer Genome Atlas (TCGA). 20 miRNAs were significantly deregulated (FC≥2 and p<0.05) (15 down- and 5 up-regulated) in PDAC. miR-216 family (miR-216a-3p, miR-216a-5p, miR-216b-3p and miR-216b-5p) was consistently down-regulated in PDAC. miRNA-modulated pathways are associated with innate and adaptive immune system responses in PDAC. AMP cancers showed 8 down- and 1 up-regulated miRNAs (FDR p<0.05). Most enriched pathways (p<0.01) were RAS and Nerve Growth Factor signaling. PDAC and AMP display different global miRNA expression profiles and miRNA regulated networks/tumorigenesis pathways. The immune response was enriched in PDAC, suggesting the existence of immune checkpoint pathways more relevant to PDAC than AMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / genetics*
  • Adult
  • Aged
  • Ampulla of Vater / pathology
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / pathology
  • Computational Biology
  • Down-Regulation
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / immunology
  • Gene Regulatory Networks / immunology
  • Humans
  • Immunity, Innate / genetics*
  • Male
  • MicroRNAs / metabolism*
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Retrospective Studies
  • Up-Regulation

Substances

  • MicroRNAs

Grants and funding

Research funds were obtained from São Paulo Research Foundation (FAPESP) (grant #2016/03905-2 to P. P. Reis). T.F.F. was funded, in separate time periods, through the Coordination for the Improvement of Higher Level Education (CAPES) and FAPESP - fellowship #2014/00367-4. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.