microRNA-381 suppresses the growth and increases cisplatin sensitivity in non-small cell lung cancer cells through inhibition of nuclear factor-κB signaling

Biomed Pharmacother. 2018 Feb;98:538-544. doi: 10.1016/j.biopha.2017.12.092. Epub 2017 Dec 27.

Abstract

microRNA (miR)-381 is downregulated and exhibits anti-invasive activity in non-small cell lung cancer (NSCLC). In this study, we investigated the role of miR-381 in proliferation, tumorigenesis, and cisplatin resistance of NSCLC cells. The effects of miR-381 overexpression on proliferation, tumorigenesis, cell cycle progression, and cisplatin sensitivity were examined. Overexpression of miR-381 significantly inhibited cell proliferation and colony formation in vitro and tumorigenesis in vivo. Ectopic expression of miR-381 arrested NSCLC cells at G0/G1 phase, which was accompanied by increased expression of p21 and p27 and decreased expression of cyclin D1 and CDK4. Compared to A549 parental cells, cisplatin-resistant equivalents (A549/CDDP) had reduced levels of miR-381. miR-381 re-sensitized A549/CDDP cells to cisplatin and potentiated cisplatin-induced apoptosis. Mechanistically, miR-381 interfered with the activation of nuclear factor (NF)-κB through repression of inhibitor of differentiation 1 (ID1). Co-expression of ID1 reversed the suppression of proliferation and enhancement of cisplatin cytotoxicity by miR-381. Taken together, miR-381 can induce growth suppression and chemosensitization in NSCLC, largely through inactivation of NF-κB via downregulation of ID1. Restoration of miR-381 represents a potential therapeutic strategy for NSCLC.

Keywords: Apoptosis; Cell cycle arrest; Key words; Lung cancer; Tumor suppressor; miR-381.

MeSH terms

  • A549 Cells
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / genetics
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / genetics*
  • Cisplatin / pharmacology*
  • Down-Regulation / genetics
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics*
  • NF-kappa B / genetics*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*

Substances

  • Antineoplastic Agents
  • MIRN381 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • Cisplatin