title: The impact of miRNA-based molecular diagnostics and treatment of NRF2-stabilized tumors.
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.
  
  
  CONCLUSIONS
  This study determines the potential of miRNA-based molecular diagnostics and therapeutics in NRF2-stablized tumors.
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. johinaz.cgen@mri.tmd.ac.jp.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Kawano
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kozaki
authors.forename: Ken
authors.initials: K
authors.lastname: Omura
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D002945:Cisplatin