Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Mol Cancer Res. 2014 Jan;12(1):58-68. doi: 10.1158/1541-7786.MCR-13-0246-T. Epub 2013 Dec 4.
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.
This study determines the potential of miRNA-based molecular diagnostics and therapeutics in NRF2-stablized tumors.
NF-E2 相关因子 2（NRF2）是一种主要的转录调节因子，它整合了细胞应激反应，并在翻译后水平上受到 Kelch 样 ECH 相关蛋白 1（KEAP1）的负调控。在人类癌症中，NRF2 的异常稳定，无论是通过 NRF2 或 KEAP1 的突变，通过靶基因的转录激活，在化疗耐药性和肿瘤细胞生长中起着至关重要的作用，这表明靶向抑制 NRF2 是 NRF2 稳定肿瘤的潜在治疗方法。microRNAs（miRNA）是内源性的小非编码 RNA，可以通过干扰靶转录物的翻译或稳定性来负调控基因表达。此外，肿瘤抑制 miRNA 已被认为对癌症治疗有用。在这里，一个报告基因偶联的 miRNA 文库筛选鉴定了四个 miRNA（miR-507、-634、-450a 和-129-5p），它们通过直接靶向 NRF2 来负调控 NRF2 介导的致癌途径。重要的是，除了 NRF2 或 KEAP1 的体细胞突变外，这些 miRNA 的下调与稳定的 NRF2 和食管鳞状细胞癌（ESCC）的不良预后相关。此外，单独或联合顺铂给药 miR-507 可抑制体内肿瘤生长。因此，这些发现表明 miRNA 为基础的治疗方法对 NRF2 稳定的 ESCC 肿瘤有效。
本研究确定了 miRNA 为基础的分子诊断和治疗在 NRF2 稳定肿瘤中的潜力。
