The MRVI1-AS1/ATF3 signaling loop sensitizes nasopharyngeal cancer cells to paclitaxel by regulating the Hippo-TAZ pathway

Oncogene. 2019 Aug;38(32):6065-6081. doi: 10.1038/s41388-019-0858-7. Epub 2019 Jul 4.

Abstract

Long non-coding RNA (lncRNA) plays an important role in malignant tumor occurrence, development, and chemoresistance, but the mechanism of how they affect nasopharyngeal cancer (NPC) paclitaxel chemosensitivity is unclear. In this study, lncRNA array of CNE-1 and HNE-2 paclitaxel-resistant cells and their parental strains revealed that the paclitaxel-resistant strains had significantly lower MRVI1-AS1 (murine retrovirus integration site 1 homolog antisense RNA 1) expression than the parental strains, and that MRVI1-AS1 overexpression in vitro and in vivo increased paclitaxel chemosensitivity. Further, MRVI1-AS1 upregulated ATF3 (activating transcription factor 3) by simultaneously inhibiting miR-513a-5p (microRNA-513a-5p) and miR-27b-3p expression levels to increase NPC paclitaxel chemosensitivity. Chromatin immunoprecipitation and quantitative real-time PCR showed that ATF3 could feed-back MRVI1-AS1 regulation positively. Furthermore, MRVI1-AS1 and ATF3 could form a positive feedback loop, which promoted the expression of RASSF1 (Ras association domain family member 1), a Hippo-TAZ (tafazzin) signaling pathway regulatory factor, thereby inhibiting TAZ expression. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay and flow cytometry showed that the decreased TAZ increased NPC cell paclitaxel chemosensitivity. Overall, the results indicate that the MRVI1-AS1/ATF3 signaling pathway can increase NPC paclitaxel chemosensitivity by modulating the Hippo-TAZ signaling pathway. Therefore, targeting the loop may be a new NPC treatment strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Activating Transcription Factor 3 / genetics*
  • Activating Transcription Factor 3 / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics*
  • Nasopharyngeal Carcinoma / drug therapy*
  • Nasopharyngeal Carcinoma / genetics
  • Nasopharyngeal Carcinoma / pathology
  • Nasopharyngeal Neoplasms / drug therapy*
  • Nasopharyngeal Neoplasms / genetics
  • Nasopharyngeal Neoplasms / pathology
  • Paclitaxel / therapeutic use*
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Antisense / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • ATF3 protein, human
  • Activating Transcription Factor 3
  • IRAG1 protein, human
  • Membrane Proteins
  • Phosphoproteins
  • RNA, Antisense
  • TAZ protein, human
  • Transcription Factors
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • Paclitaxel