MicroRNA-7/NF-κB signaling regulatory feedback circuit regulates gastric carcinogenesis

MicroRNAs play essential roles in gene expression regulation during carcinogenesis. Here, we investigated the role of miR-7 and the mechanism by which it is dysregulated in gastric cancer (GC). We used genome-wide screenings and identified RELA and FOS as novel targets of miR-7. Overexpression of mi...

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Bibliographic Details
Published in:The Journal of cell biology 2015-08, Vol.210 (4), p.613-627
Main Authors: Zhao, Xiao-Di, Lu, Yuan-Yuan, Guo, Hao, Xie, Hua-Hong, He, Li-Jie, Shen, Gao-Fei, Zhou, Jin-Feng, Li, Ting, Hu, Si-Jun, Zhou, Lin, Han, Ya-Nan, Liang, Shu-Li, Wang, Xin, Wu, Kai-Chun, Shi, Yong-Quan, Nie, Yong-Zhan, Fan, Dai-Ming
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Animals
Base Sequence
Binding Sites
Carcinogenesis - genetics
Carcinogenesis - metabolism
Cell Line, Tumor
Cell Proliferation
Feedback, Physiological
Female
Gene Expression Regulation, Neoplastic
Helicobacter pylori
Humans
I-kappa B Kinase - metabolism
Male
Mice, Nude
MicroRNAs - physiology
Middle Aged
Neoplasm Transplantation
Proteome - genetics
Proteome - metabolism
Proto-Oncogene Proteins c-fos - genetics
Proto-Oncogene Proteins c-fos - metabolism
RNA Interference
Signal Transduction
Stomach Neoplasms - genetics
Stomach Neoplasms - metabolism
Stomach Neoplasms - mortality
Transcription Factor RelA - genetics
Transcription Factor RelA - metabolism
Transcriptome
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Summary:MicroRNAs play essential roles in gene expression regulation during carcinogenesis. Here, we investigated the role of miR-7 and the mechanism by which it is dysregulated in gastric cancer (GC). We used genome-wide screenings and identified RELA and FOS as novel targets of miR-7. Overexpression of miR-7 repressed RELA and FOS expression and prevented GC cell proliferation and tumorigenesis. These effects were clinically relevant, as low miR-7 expression was correlated with high RELA and FOS expression and poor survival in GC patients. Intriguingly, we found that miR-7 indirectly regulated RELA activation by targeting the IκB kinase IKKε. Furthermore, IKKε and RELA can repress miR-7 transcription, which forms a feedback circuit between miR-7 and nuclear factor κB (NF-κB) signaling. Additionally, we demonstrate that down-regulation of miR-7 may occur as a result of the aberrant activation of NF-κB signaling by Helicobacter pylori infection. These findings suggest that miR-7 may serve as an important regulator in GC development and progression.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201501073