Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p-MFF axis

Oncotarget. 2015 Jun 20;6(17):14885-904. doi: 10.18632/oncotarget.3659.

Abstract

Cisplatin has been widely employed as a cornerstone chemotherapy treatment for a wide spectrum of solid neoplasms; increasing tumor responsiveness to cisplatin has been a topic of interest for the past 30 years. Strong evidence has indicated that mitochondrial fission participates in the regulation of apoptosis in many diseases; however, whether mitochondrial fission regulates cisplatin sensitivity remains poorly understood. Here, we show that MFF mediated mitochondrial fission and apoptosis in tongue squamous cell carcinoma (TSCC) cells after cisplatin treatment and that miR-593-5p was downregulated in this process. miR-593-5p attenuated mitochondrial fission and cisplatin sensitivity by targeting the 3' untranslated region sequence of MFF and inhibiting its translation. In exploring the underlying mechanism of miR-593-5p downregulation, we observed that BRCA1 transactivated miR-593-5p expression and attenuated cisplatin sensitivity in vitro. The BRCA1-miR-593-5p-MFF axis also affected cisplatin sensitivity in vivo. Importantly, in a retrospective analysis of multiple centers, we further found that the BRCA1-miR-593-5p-MFF axis was significantly associated with cisplatin sensitivity and the survival of patients with TSCC. Together, our data reveal a model for mitochondrial fission regulation at the transcriptional and post-transcriptional levels; we also reveal a new pathway for BRCA1 in determining cisplatin sensitivity through the mitochondrial fission program.

Keywords: BRCA1; MFF; cisplatin sensitivity; miR-593-5p; mitochondrial fission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Cell Line, Tumor
  • Cisplatin / therapeutic use*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoblotting
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics*
  • Microscopy, Confocal
  • Middle Aged
  • Mitochondrial Dynamics / genetics*
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Multivariate Analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Analysis
  • Tongue Neoplasms / drug therapy*
  • Tongue Neoplasms / genetics
  • Tongue Neoplasms / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • BRCA1 Protein
  • BRCA1 protein, human
  • MIRN593 microRNA, human
  • Membrane Proteins
  • Mff protein, human
  • MicroRNAs
  • Mitochondrial Proteins
  • Cisplatin