miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance

Mol Ther. 2018 Apr 4;26(4):1066-1081. doi: 10.1016/j.ymthe.2018.01.023. Epub 2018 Feb 3.

Abstract

This study aimed to identify mechanisms by which microRNA 296-3p (miR-296-3p) functions as a tumor suppressor to restrain nasopharyngeal carcinoma (NPC) cell growth, metastasis, and chemoresistance. Mechanistic studies revealed that miR-296-3p negatively regulated by nicotine directly targets the oncogenic protein mitogen-activated protein kinase-activated protein kinase-2 (Mapkapk2) (MK2). Suppression of MK2 downregulated Ras/Braf/Erk/Mek/c-Myc and phosphoinositide-3-kinase (PI3K)/Akt/c-Myc signaling and promoted cytoplasmic translocation of c-Myc, which activated miR-296-3p expression by a feedback loop. This ultimately inhibited cell cycle progression, epithelial-to-mesenchymal transition (EMT), and chemoresistance of NPC. In addition, nicotine as a key component of tobacco was observed to suppress miR-296-3p and thus elevate MK2 expression by inducing PI3K/Akt/c-Myc signaling. In clinical samples, reduced miR-296-3p as an unfavorable factor was inversely correlated with MK2 and c-Myc expression. These results reveal a novel mechanism by which miR-296-3p negatively regulated by nicotine directly targets MK2-induced Ras/Braf/Erk/Mek/c-Myc or PI3K/AKT/c-Myc signaling to stimulate its own expression and suppress NPC cell proliferation and metastasis. miR-296-3p may thus serve as a therapeutic target to reverse chemotherapy resistance of NPC.

Keywords: MK2; miR-296-3p; nasopharyngeal carcinoma; nicotine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Ectopic Gene Expression
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Middle Aged
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Nicotine / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Interference
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 3' Untranslated Regions
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Intracellular Signaling Peptides and Proteins
  • MIRN296 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • Nicotine
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt