Zhang Mingxin, Zhang Lingmin, Cui Manli, Ye Wenguang, Zhang Pengjiang, Zhou Suna, Wang Jingjie
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, Shaanxi Province, China.
Department of Anesthesiology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
Oncotarget. 2017 Jul 25;8(30):49053-49063. doi: 10.18632/oncotarget.17041.
Cancer related inflammation (CRI) plays an important role in the development of esophageal cancer (EC), and the target gene analysis shows that miR-302b potential target genes closely correlated to CRI important signaling pathways. The present study was to evaluate the inhibition of miR-302b on CRI in EC and its mechanism. We found that the expression levels of miR-302b in EC cells were lower than that in Het-1A cells, while TE11 with the lowest expression and OE33 with the highest. Inflammatory stimuli at 48 h significantly reduced expression of miR-302b in EC cells, but had no effect in Het-1A. After up-regulation of miR-302b in TE11 and down-regulation of miR-302b in OE33, it was found that miR-302b reduced CRI key transcription factors and representative cytokines. Then, over-expressed of miR-302b significantly altered potential target genes protein expressions and there was a negative correlation between miR-302b and potential target genes protein expressions (ERBB4, IRF2 and CXCR4) in EC tissues. Then reporter gene analysis revealed that miR-302b post-transcriptionally regulated expression of target genes by specific area of 3'-UTR. Transfected by target genes shRNA plasmids together could get the same effects of miR-302b on protein expression of CRI key transcription factors. Furthermore, miR-302b was able to repress tumor growth and transcription factors protein expression in vivo. These finding suggests that miR-302b inhibits key transcription factors and cytokines by targeting ERBB4, IRF2 and CXCR4, implicating its role in the inhibition of CRI in EC.
癌症相关炎症（CRI）在食管癌（EC）的发生发展中起重要作用，靶基因分析表明，miR-302b的潜在靶基因与CRI重要信号通路密切相关。本研究旨在评估miR-302b对EC中CRI的抑制作用及其机制。我们发现，EC细胞中miR-302b的表达水平低于Het-1A细胞，其中TE11表达最低，OE33表达最高。48小时的炎症刺激显著降低了EC细胞中miR-302b的表达，但对Het-1A细胞无影响。在TE11中上调miR-302b并在OE33中下调miR-302b后，发现miR-302b降低了CRI关键转录因子和代表性细胞因子。然后，miR-302b的过表达显著改变了潜在靶基因的蛋白表达，并且在EC组织中miR-302b与潜在靶基因蛋白表达（ERBB4、IRF2和CXCR4）之间存在负相关。然后报告基因分析表明，miR-302b通过3'-UTR的特定区域在转录后调控靶基因的表达。与靶基因shRNA质粒一起转染可获得与miR-302b对CRI关键转录因子蛋白表达相同的效果。此外，miR-302b能够在体内抑制肿瘤生长和转录因子蛋白表达。这些发现表明，miR-302b通过靶向ERBB4、IRF2和CXCR4抑制关键转录因子和细胞因子，提示其在抑制EC中CRI的作用。
