Synaptic acetylcholinesterase targeted by microRNA-212 functions as a tumor suppressor in non-small cell lung cancer

Int J Biochem Cell Biol. 2013 Nov;45(11):2530-40. doi: 10.1016/j.biocel.2013.08.007. Epub 2013 Aug 22.

Abstract

Acetylcholinesterase expression is modulated in various types of tumor, which suggests it is associated with tumor development; however, the mechanism of acetylcholinesterase gene regulation in tumors remains unclear. Here, we report that acetylcholinesterase is aberrantly expressed in non-small cell lung cancer and is an evolutionarily conserved functional target of miR-212. Acetylcholinesterase expression was negatively regulated by miR-212 in vitro and was inversely correlated with miR-212 expression in vivo. In addition, acetylcholinesterase levels were increased, and miR-212 levels decreased, in non-small cell lung cancer cells during cisplatin-induced apoptosis. We further determined that acetylcholinesterase acted as a pro-apoptotic gene in non-small cell lung cells; and attenuated the growth of xenografts in nude mice when upregulated. In contrast, elevated miR-212 levels preserved the protective effect of acetylcholinesterase silencing by RNA interference against cisplatin-induced apoptosis, whereas restoration of miR-212-resistant synaptic acetylcholinesterase expression inhibited the miR-212 anti-apoptotic function. The results demonstrated that miR-212 exerted an anti-apoptotic effect through direct repression of synaptic acetylcholinesterase expression in non-small cell lung cancer cells. Taken together, our study revealed that synaptic acetylcholinesterase may be a tumor suppressor and is modulated by miR-212 in non-small cell lung cancer.

Keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; AChE; AChE-E; AChE-R; AChE-S; Acetylcholinesterase; Apoptosis; CDDP; HCC; IHC; ISH; LNA; MMP; MTT; MiR-212; NSCLC; Non-small cell lung cancer; PARP; RNA interference; RNAi; TUNEL; TdT-mediated dUTP nick end labeling; Tumor suppressor; UTR; acetylcholinesterase; cisplatin; erythrocyte acetylcholinesterase; hepatocellular carcinoma; immunohistochemistry; in situ hybridization; locked nucleic acid; mitochondrial membrane permeability; non-small cell lung cancer; poly(ADP-ribose) polymerase; readthrough acetylcholinesterase; siRNA; small interfering RNA; synaptic acetylcholinesterase; untranslated region.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / genetics
  • Acetylcholinesterase / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Base Sequence
  • Carcinoma, Non-Small-Cell Lung / enzymology*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Synapses / drug effects
  • Synapses / enzymology*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • MIRN212 microRNA, human
  • MicroRNAs
  • Tumor Suppressor Proteins
  • Acetylcholinesterase
  • Cisplatin