SS18-SSX-regulated miR-17 promotes tumor growth of synovial sarcoma by inhibiting p21WAF1/CIP1
Version of Record online: 3 SEP 2014
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Volume 105, Issue 9, pages 1152–1159, September 2014
How to Cite
Cancer Sci 105 (2014) 1152–1159
This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology, from the Japan Society for the Promotion of Science, and from the Ministry of Health, Labor, and Welfare of Japan, as well as a grant from the Japan Science and Technology Agency.
- Issue online: 23 SEP 2014
- Version of Record online: 3 SEP 2014
- Accepted manuscript online: 2 JUL 2014 10:06PM EST
- Manuscript Accepted: 29 JUN 2014
- Manuscript Revised: 27 JUN 2014
- Manuscript Received: 27 FEB 2014
- Japan Society for the Promotion of Science
- Ministry of Health, Labor, and Welfare of Japan
- Cyclin-dependent kinase inhibitor p21;
- drug resistance;
- hsa-mir-17 microRNA;
- SS18-SSX fusion protein;
- synovial sarcoma
MicroRNA (miRNA) can function as tumor suppressors or oncogenes, and also as potential specific cancer biomarkers; however, there are few published studies on miRNA in synovial sarcomas, and their function remains unclear. We transfected the OncomiR miRNA Precursor Virus Library into synovial sarcoma Fuji cells followed by a colony formation assay to identify miRNAs to confer an aggressive tumorigenicity, and identified miR-17-5p from the large colonies. MiR-17 was found to be induced by a chimeric oncoprotein SS18-SSX specific for synovial sarcoma, and all examined cases of human synovial sarcoma expressed miR-17, even at high levels in several cases. Overexpression of miR-17 in synovial sarcoma cells, Fuji and HS-SYII, increased colony forming ability in addition to cell growth, but not cell motility and invasion. Tumor volume formed in mice in vivo was significantly increased by miR-17 overexpression with a marked increase of MIB-1 index. According to PicTar and Miranda algorithms, which predicted CDKN1A (p21) as a putative target of miR-17, a luciferase assay was performed and revealed that miR-17 directly targets the 3′-UTR of p21 mRNA. Indeed, p21 protein level was remarkably decreased by miR-17 overexpression in a p53-independent manner. It is noteworthy that miR-17 succeeded in suppressing doxorubicin-evoked higher expression of p21 and conferred the drug resistance. Meanwhile, introduction of anti-miR-17 in Fuji and HS-SYII cells significantly decreased cell growth, consistent with rescued expression of p21. Taken together, miR-17 promotes the tumor growth of synovial sarcomas by post-transcriptional suppression of p21, which may be amenable to innovative therapeutic targeting in synovial sarcoma.