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MicroRNA-based diagnosis and therapy in NRF2-stabilized tumor
Jun Inoue,Johji Inazawa 한의병리학회 2015 대한동의병리학회 학술대회논문집 Vol.2015 No.10
NRF2 is a master transcriptional regulator that integrates cellular stress responses and is negatively regulated by 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. Some tumorsuppressing microRNAs (miRNAs) target multiple oncogenes concurrently and therefore may be useful as cancer therapeutic agents. Further, such miRNAs may be useful to address chemotherapeutic resistance in cancer, which remains a primary clinical challenge in need of solutions. Thus, cytoprotective processes upregulated in cancer cells that are resistant to chemotherapy are a logical target for investigation. By using a reporter-coupled miRNA library screening, we have recently identified four miRNAs (miR-507, -634, -450a, and - 129-5p) that negatively regulate the NRF2 activity by directly targeting. 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). Interestingly, we found that overexpression of miR-634 activates the mitochondrial apoptotic pathway by direct concurrent targeting of genes associated with mitochondrial homeostasis, antiapoptosis, and autophagy, together with NRF2-mediated antioxidant ability. In particular, we showed how enforced expression of miR-634 enhanced chemotherapy-induced cytotoxicity in a model of ESCC, where resistance to chemotherapy remains clinically problematic. Our findings illustrate how reversing miRNA-mediated cytoprotective processes may offer a broadly useful approach to improving cancer therapy. (Cancer Res. 75 3890-3901 2015, Mol Cancer Res. 12 58-68 2014)
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