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, by the mutation of either NRF2 or KEAP1 or by the potential inhibition of autophagy, plays a vital role in tumor growth and chemoresistance through the activation of target genes. MicroRNAs (miRNA) are endogenous small noncoding RNAs that can negatively regulate gene expression by interfering with translation and/or stability of target transcripts. However, miRNA-mediated regulation of the NRF2-KEAP1 pathway under physiological conditions is poorly understood. Here, miR-432-3p positively regulates NRF2 activity through the downregulation of KEAP1 by a direct-binding mechanism to the coding region of KEAP1. Overexpression of miR-432-3p resulted in a decreased sensitivity of esophageal squamous cell carcinoma (ESCC) cells to chemotherapy drugs including cisplatin (CDDP). Conversely, the inhibition of miR-432-3p expression by the CRISPR/Cas9 system resulted in an increased sensitivity of ESCC cells to CDDP. Furthermore, miR-432-3p was overexpressed in primary ESCC tumors (55 of 84, 65.5%) and a negative correlation between the expression level of KEAP1 and miR-432-3p in primary ESCC tumors was observed.Implications: These findings provide novel insights into the mechanism of NRF2 stabilization in human cancers. Mol Cancer Res; 15(11); 1570-8. ©2017 AACR.

译文

:NF-E2相关因子2(NRF2)是整合细胞应激反应的主要转录调节因子,在翻译后水平受Kelch样ECH相关蛋白1(KEAP1)负调节。在人类癌症中,通过NRF2或KEAP1的突变或潜在的自噬抑制,异常稳定的NRF2通过激活靶基因在肿瘤生长和化学抗性中起着至关重要的作用。微小RNA(miRNA)是内源性小非编码RNA,可通过干扰目标转录本的翻译和/或稳定性来负面调节基因表达。然而,在生理条件下,miRNA介导的NRF2-KEAP1途径的调控知之甚少。在这里,miR-432-3p通过与KEAP1编码区的直接结合机制,通过下调KEAP1来正向调节NRF2活性。 miR-432-3p的过表达导致食管鳞状细胞癌(ESCC)细胞对化疗药物(包括顺铂(CDDP))的敏感性降低。相反,CRISPR / Cas9系统对miR-432-3p表达的抑制导致ESCC细胞对CDDP的敏感性增加。此外,miR-432-3p在原发性ESCC肿瘤中过表达(55 of 84,65.5%),并且在原发性ESCC肿瘤中观察到KEAP1和miR-432-3p的表达水平呈负相关。对人类癌症中NRF2稳定机制的见解。分子癌症研究; 15(11); 1570-8。 ©2017 AACR。

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