The impact of miRNA-based molecular diagnostics and treatment of NRF2-stabilized tumors

Shinsuke Yamamoto, Jun Inoue, Tatsuyuki Kawano, Ken Ichi Kozaki, Ken Omura, Johji Inazawa

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

NF-E2-related factor 2 (NRF2) is a master transcriptional regulator that integrates cellular stress responses and is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1) at the posttranslational level. In human cancers, aberrantly stabilized NRF2, either by mutation of NRF2 or KEAP1, plays a vital role in chemoresistance and tumor cell growth through the transcriptional activation of target genes, suggesting that targeted inhibition of NRF2 is a potential therapy for NRF2-stabilized tumors. MicroRNAs (miRNA) are endogenous small noncoding RNAs that can negatively regulate gene expression by interfering with the translation or stability of target transcripts. Moreover, tumor-suppressor miRNAs have been suggested to be useful for cancer treatment. Here, a reporter-coupled miRNA library screen identified four miRNAs (miR-507, -634, -450a, and -129-5p) that negatively regulate the NRF2-mediated oncogenic pathway by directly targeting NRF2. Importantly, downregulation of these miRNAs, in addition to the somatic mutation of NRF2 or KEAP1, is associated with stabilized NRF2 and poor prognosis in esophageal squamous cell carcinoma (ESCC). Furthermore, administration of a miR-507 alone or in combination with cisplatin inhibited tumor growth in vivo. Thus, these findings reveal that miRNA-based therapy is effective against NRF2-stabilized ESCC tumors.

Original languageEnglish
Pages (from-to)58-68
Number of pages11
JournalMolecular Cancer Research
Volume12
Issue number1
DOIs
Publication statusPublished - Jan 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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