Cisplatin and phenanthriplatin modulate long-noncoding RNA expression in A549 and IMR90 cells revealing regulation of microRNAs, Wnt/β-catenin and TGF-β signaling

Sci Rep. 2021 May 17;11(1):10408. doi: 10.1038/s41598-021-89911-z.

Abstract

The monofunctional platinum(II) complex, phenanthriplatin, acts by blocking transcription, but its regulatory effects on long-noncoding RNAs (lncRNAs) have not been elucidated relative to traditional platinum-based chemotherapeutics, e.g., cisplatin. Here, we treated A549 non-small cell lung cancer and IMR90 lung fibroblast cells for 24 h with either cisplatin, phenanthriplatin or a solvent control, and then performed microarray analysis to identify regulated lncRNAs. RNA22 v2 microRNA software was subsequently used to identify microRNAs (miRNAs) that might be suppressed by the most regulated lncRNAs. We found that miR-25-5p, -30a-3p, -138-5p, -149-3p, -185-5p, -378j, -608, -650, -708-5p, -1253, -1254, -4458, and -4516, were predicted to target the cisplatin upregulated lncRNAs, IMMP2L-1, CBR3-1 and ATAD2B-5, and the phenanthriplatin downregulated lncRNAs, AGO2-1, COX7A1-2 and SLC26A3-1. Then, we used qRT-PCR to measure the expression of miR-25-5p, -378j, -4516 (A549) and miR-149-3p, -608, and -4458 (IMR90) to identify distinct signaling effects associated with cisplatin and phenanthriplatin. The signaling pathways associated with these miRNAs suggests that phenanthriplatin may modulate Wnt/β-catenin and TGF-β signaling through the MAPK/ERK and PTEN/AKT pathways differently than cisplatin. Further, as some of these miRNAs may be subject to dissimilar lncRNA targeting in A549 and IMR90 cells, the monofunctional complex may not cause toxicity in normal lung compared to cancer cells by acting through distinct lncRNA and miRNA networks.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Cisplatin / therapeutic use
  • Down-Regulation / drug effects
  • Fibroblasts
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Regulatory Networks / drug effects
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • MicroRNAs / metabolism
  • Organoplatinum Compounds / pharmacology*
  • Organoplatinum Compounds / therapeutic use
  • Phenanthridines / pharmacology*
  • Phenanthridines / therapeutic use
  • RNA, Long Noncoding / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation / drug effects
  • Wnt Signaling Pathway / drug effects
  • Wnt Signaling Pathway / genetics
  • beta Catenin / metabolism

Substances

  • CTNNB1 protein, human
  • MicroRNAs
  • Organoplatinum Compounds
  • Phenanthridines
  • RNA, Long Noncoding
  • Transforming Growth Factor beta
  • beta Catenin
  • phenanthriplatin
  • Cisplatin