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miR-193b regulates tumorigenesis in liposarcoma cells via PDGFR, TGFβ, and Wnt signaling
Ying Z Mazzu1, Yulan Hu1, Yawei Shen1
1Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abstract:
Liposarcoma is the most common soft tissue sarcoma. Molecularly targeted therapeutics have had limited efficacy in liposarcomas, in part because of inadequate knowledge of the complex molecular alterations in these tumors. Our recent study revealed the tumor suppressive function of miR-193b in liposarcoma. Considering the biological and clinical heterogeneity of liposarcoma, here, we confirmed the under-expression of miR-193b in additional patient liposarcoma samples and cell lines. Based on STRING analysis of protein-protein interactions among the reported putative miR-193b targets, we validated three: PDGFRβ, SMAD4, and YAP1, belonging to strongly interacting pathways (focal adhesion, TGFβ, and Hippo, respectively). We show that all three are directly targeted by miR-193b in liposarcoma. Inhibition of PDGFRβ reduces liposarcoma cell viability and increases adipogenesis. Knockdown of SMAD4 promotes adipogenic differentiation. miR-193b targeting of the Hippo signaling effector YAP1 indirectly inhibits Wnt/β-catenin signaling. Both a PDGFR inhibitor (CP-673451) and a Wnt/ β-catenin inhibitor (ICG-001) had potent inhibitory effects on liposarcoma cells, suggesting their potential application in liposarcoma treatment. In summary, we demonstrate that miR-193b controls cell growth and differentiation in liposarcoma by targeting multiple key components (PDGFRβ, SMAD4, and YAP1) in several oncogenic signaling pathways.
Insights
MicroRNA-193b (miR-193b) suppresses liposarcoma growth by targeting PDGFRβ, SMAD4, and YAP1. Inhibiting these targets shows potential for new liposarcoma treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Liposarcoma is the most common soft tissue sarcoma.
- Current molecularly targeted therapies for liposarcoma show limited efficacy due to complex tumor alterations.
- MicroRNA-193b (miR-193b) has been identified as a tumor suppressor in liposarcoma.
Purpose of the Study:
- To confirm the under-expression of miR-193b in liposarcoma.
- To identify and validate direct targets of miR-193b in liposarcoma.
- To investigate the therapeutic potential of targeting miR-193b pathways in liposarcoma.
Main Methods:
- Confirmation of miR-193b under-expression in patient samples and cell lines.
- STRING analysis to predict protein-protein interactions of miR-193b targets.
- Validation of PDGFRβ, SMAD4, and YAP1 as direct miR-193b targets.
- Assessment of the effects of inhibiting PDGFRβ, SMAD4, and YAP1 on liposarcoma cells.
Main Results:
- miR-193b is significantly under-expressed in liposarcoma.
- PDGFRβ, SMAD4, and YAP1 were validated as direct targets of miR-193b.
- Inhibition of PDGFRβ reduced cell viability and increased adipogenesis.
- SMAD4 knockdown promoted adipogenic differentiation.
- miR-193b targeting of YAP1 indirectly inhibited Wnt/β-catenin signaling.
- PDGFR and Wnt/β-catenin inhibitors demonstrated potent anti-liposarcoma effects.
Conclusions:
- miR-193b acts as a tumor suppressor in liposarcoma by targeting multiple key signaling pathways.
- Targeting PDGFRβ and Wnt/β-catenin signaling pathways holds promise for liposarcoma treatment.
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