A novel AP-1/miR-101 regulatory feedback loop and its implication in the migration and invasion of hepatoma cells

• Published in: Nucleic acids research Vol. 42; no. 19; pp. 12041 - 12051
• Main Authors: Liu, Jing-Jing, Lin, Xue-Jia, Yang, Xiao-Jing, Zhou, Liangji, He, Shuai, Zhuang, Shi-Mei, Yang, Jine
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 29.10.2014
• Subjects: Animals; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Movement - genetics; Enhancer Elements, Genetic; Feedback, Physiological; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice, Inbred C57BL; MicroRNAs - biosynthesis; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Biology; Neoplasm Invasiveness; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - metabolism; Transcription, Genetic
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gku872

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-101bgene 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.