A novel AP-1/miR-101 regulatory feedback loop and its implication in the migration and invasion of hepatoma cells. Issue 19 (26th September 2014)

• Record Type: Journal Article
• Authors: Liu, Jing-Jing; Lin, Xue-Jia; Yang, Xiao-Jing; Zhou, Liangji; He, Shuai; Zhuang, Shi-Mei; Yang, Jine
• Is Part Of: Nucleic acids research. Volume 42:Issue 19(2014)
• Page Start: 12041
• Page End: 12051
• Publication Date: 2014-09-26
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gku872
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: MicroRNA-101 (miR-101) is frequently downregulated in various cancers. To date, the regulatory networks of miR-101 remain obscure. In this study, we demonstrated that miR-101 was mainly transcribed from human miR-101-2 and mouse miR-101b gene loci. Subsequent analyses revealed that activator protein-1 (AP-1) directly binded to the −17.4 to −16.4 k region upstream of pre-miR-101-2 and activated the expression of miR-101. On the other hand, miR-101 could inhibit the expression of ERK2 and c-Fos, two key factors of the AP-1 pathway, by binding to their 3′-UTRs. Furthermore, reintroduction of miR-101 efficiently suppressed the AP-1 activity and pri-miR-101-2 transcription. These data thus suggest a novel AP-1/miR-101 regulatory circuitry, that is, AP-1 promotes the transcription of miR-101, whereas the expression of miR-101 reduces the level of ERK2 and c-Fos and thereby attenuates the AP-1 signaling. Further investigation disclosed that the AP-1 activator TPA-induced MMP9 activity and the TPA-promoted migration and invasion of hepatoma cells were significantly attenuated by miR-101 but were enhanced by miR-101 inhibitor. Our results suggest that the AP-1/miR-101 feedback loop may prevent the excessive activation of metastatic signals imposed by ERK2/AP-1 and highlight the biological significance of miR-101 downregulation in cancer metastasis.