Cooperation between SS18-SSX1 and miR-214 in Synovial Sarcoma Development and Progression

• Main Authors: Miwa Tanaka, Mizuki Homme, Yukari Yamazaki, Keisuke Ae, Seiichi Matsumoto, Subbaya Subramanian, Takuro Nakamura
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Cancers
• Subjects: synovial sarcoma; ss18-ssx1; mouse model; insertional mutagenesis; mir-214
• Online Access: https://www.mdpi.com/2072-6694/12/2/324

SS18-SSX fusion proteins play a central role in synovial sarcoma development, although, the genetic network and mechanisms of synovial sarcomagenesis remain unknown. We established a new ex vivo synovial sarcoma mouse model through retroviral-mediated gene transfer of <i>SS18-SSX1</i> into mouse embryonic mesenchymal cells followed by subcutaneous transplantation into nude mice. This approach successfully induced subcutaneous tumors in 100% recipients, showing invasive proliferation of short spindle tumor cells with occasional biphasic appearance. Cytokeratin expression was observed in epithelial components in tumors and expression of TLE1 and BCL2 was also shown. Gene expression profiling indicated SWI/SNF pathway modulation by <i>SS18-SSX1</i> introduction into mesenchymal cells and <i>Tle1</i> and <i>Atf2</i> upregulation in tumors. These findings indicate that the model exhibits phenotypes typical of human synovial sarcoma. Retroviral tagging of the tumor identified 15 common retroviral integration sites within the <i>Dnm3</i> locus as the most frequent in 30 mouse synovial sarcomas. <i>miR-199a2</i> and <i>miR-214</i> upregulation within the <i>Dnm3</i> locus was observed. <i>SS18-SSX1</i> and <i>miR-214</i> cointroduction accelerated sarcoma onset, indicating that <i>miR-214</i> is a cooperative oncomiR in synovial sarcomagenesis. <i>miR-214</i> functions in a cell non-autonomous manner, promoting cytokine gene expression (e.g., <i>Cxcl15/IL8</i>). Our results emphasize the role of <i>miR-214</i> in tumor development and disease progression.