Reciprocal regulation of miR-206 and IL-6/STAT3 pathway mediates IL6-induced gefitinib resistance in EGFR-mutant lung cancer cells

J Cell Mol Med. 2019 Nov;23(11):7331-7341. doi: 10.1111/jcmm.14592. Epub 2019 Sep 10.

Abstract

Persistently activated IL-6/STAT3 pathway promotes acquired resistance to targeted therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC) treatment. miR-206 has been verified to be dysregulated and plays as a negative regulator in lung cancer. However, whether miR-206 may overcome IL6-induced gefitinib resistance in EGFR-mutant lung cancer remains elusive. In this study, we investigated the role of miR-206 in IL6-induced gefitinib-resistant EGFR-mutated lung cancer cell lines. We showed that forced miR-206 expression restored gefitinib sensitivity in IL6-induced gefitinib-resistant EGFR-mutant lung cancer cells by inhibiting IL6/JAK1/STAT3 pathway. Specifically, mechanistic investigations revealed that miR-206 blocked IL-6/STAT3 signalling via directly targeting the 3'-UTR of intracellular IL-6 messenger RNA. Moreover, IL-6 induced miR-206 down-regulation by reducing the cropping process of primary miR-206 (pri-miR-206) into the Drosha/DGCR8 complex. Taken together, our findings reveal a direct role of miR-206 in regulating IL-6/STAT3 pathway and contrarily activated IL-6/STAT3 signalling mediates the miR-206 maturation process in gefitinib-resistant EGFR-mutant lung cancer cells.

Keywords: IL-6; STAT3; gefitinib; miR-206.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Aged
  • Cell Line, Tumor
  • Down-Regulation / genetics
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / genetics
  • Female
  • Gefitinib / pharmacology
  • Humans
  • Interleukin-6 / genetics*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction / genetics*

Substances

  • 3' Untranslated Regions
  • IL6 protein, human
  • Interleukin-6
  • MIRN206 microRNA, human
  • MicroRNAs
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib