MiR-193b-Regulated Signaling Networks Serve as Tumor Suppressors in Liposarcoma and Promote Adipogenesis in Adipose-Derived Stem Cells.

Ying Z Mazzu,Li-Xuan Qin,Samuel Singer,Ronald C Hendrickson,Thomas Tuschl,Kelly M Mojica,Rajesh K Soni,Nicholas D Socci,Zachary M Waxman,Yulan Hu,Phaedra Agius,Aleksandra Mihailovic

doi:10.1158/0008-5472.can-16-2253

Abstract

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 with normal fat. Reintroduction 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 reactive oxygen species signaling by targeting the antioxidant methionine sulfoxide reductase A 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. Cancer Res; 77(21); 5728-40. ©2017 AACR.

Highlights

Liposarcomas account for about 20% of adult sarcomas [1, 2]
Similar regulation was observed with focal adhesion kinase (FAK) knockdown (Fig. 4G). These results suggest that miR-193b regulates oncogenic FAK–SRC–BCAR1 signaling in liposarcoma through directly targeting FAK
We demonstrated the significance of miR-193b in liposarcoma. miR-193b, by directly targeting FAK, CRK-like proto-oncogene (CRKL), and methionine sulfoxide reductase A (MSRA), regulates focal adhesion signaling and reactive oxygen species (ROS) signaling, which play pivotal roles in liposarcomagenesis and adipogenic differentiation (Fig. 7D)

Summary

Introduction

Liposarcomas account for about 20% of adult sarcomas [1, 2]. Well-differentiated liposarcomas (WDLS) and dedifferentiated liposarcomas (DDLS), characterized by chromosome 12q13– 15 amplification, represent the most common biologic group of liposarcoma [3]. Primary WDLS, a low-grade disease, can evolve to DDLS, the high-grade form. Over 60% of patients with retroperitoneal WDLS and DDLS eventually have recurrence and die of disease [4]. Once advanced disease develops and surgery is no longer possible, conventional chemotherapy is largely palliative with few long-term responses [5]. There is pressing need to understand the molecular

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Conclusion