Abstract 2532: High expression of MiR-432-3p is associated with the chemoresistance by NRF2 stabilization via directly targeting KEAP1

Abstract

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 post-translational level. In human cancers, aberrantly stabilized NRF2, either by mutation of NRF2 or KEAP1, plays a vital role in chemoresistance through the 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. Previously, we identified miRNAs negatively regulating NRF2 pathway via directly targeting NRF2 itself by a reporter-coupled miRNA library screening and demonstrated the potential of miRNA-based therapy against NRF2-stabilized tumors in esophageal squamous cell carcinoma (ESCC) (Mol. Cancer Res 2014, Cancer Res 2015). In the present study, we further identified miR-432-3p as a miRNA positively regulating NRF2 pathway. MiR-432-3p could directly targeted KEAP1 via binding to its seed sequence within the cording region. Overexpression of miR-432-3p resulted in enhanced resistance to cisplatin via activation of NRF2 in ESCC cell lines. Furthermore, miR-432-3p was overexpressed in 55 of 84 primary ESCC tumors, compared with that of corresponding non-cancerous esophageal mucosa (65.5%). Importantly, we showed the negative correlation between the expression level of KEAP1 and miR-432-3p in primary ESCC tumors. Taken together, these findings suggest that the high expression of miR-432-3p may contribute to the chemoresistance by NRF2 stabilization via down-regulation of KEAP1 expression in ESCC. Citation Format: Burak Akdemir, Jun Inoue, Tatsuyuki Kawano, Johji Inazawa. High expression of MiR-432-3p is associated with the chemoresistance by NRF2 stabilization via directly targeting KEAP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2532. doi:10.1158/1538-7445.AM2017-2532