miR-193b-regulated signaling networks serve as tumor suppressors in liposarcoma and promote adipogenesis in adipose-derived stem cells

Well-differentiated and dedifferentiated liposarcomas (WDLS/DDLS) account for approximately 13% of all soft tissue sarcoma in adults and cause substantial morbidity or mortality in the majority of patients. In this study, we evaluated the functions of miRNA (miR-193b) in liposarcoma in vitro and in vivo. Deep RNA sequencing on 93 WDLS, 145 DDLS and 12 normal fat samples demonstrated that miR-193b was significantly underexpressed in DDLS compared to normal fat. Re-introduction of miR-193b induced apoptosis in liposarcoma cells and promoted adipogenesis in human adipose-derived stem cells (ASC). Integrative transcriptomic and proteomic analysis of miR-193b-target networks identified novel direct targets including CRK-like proto-oncogene (CRKL) and focal adhesion kinase (FAK). miR-193b was found to regulate FAK-SRC-CRKL signaling through CRKL and FAK. miR-193b also stimulated ROS signaling by targeting the antioxidant methionine sulfoxide reductase A (MSRA) to modulate liposarcoma cell survival and ASC differentiation state. Expression of miR-193b in liposarcoma cells was downregulated by promoter methylation resulting at least in part from increased expression of the DNA methyltransferase DNMT1 in WDLS/DDLS. In vivo, miR-193b mimetics and FAK inhibitor (PF-562271) each inhibited liposarcoma xenograft growth. In summary, miR-193b not only functions as a tumor suppressor in liposarcoma, but also promotes adipogenesis in ASC. Furthermore, this study reveals key tyrosine kinase and DNA methylation pathways in liposarcoma, some with immediate implications for therapeutic exploration.

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