transforming-growth-factor-beta and Liposarcoma

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.

Topics: Adaptor Proteins, Signal Transducing; Adipogenesis; Base Sequence; Carcinogenesis; Cell Differentiation; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Liposarcoma; MicroRNAs; Receptors, Platelet-Derived Growth Factor; Smad4 Protein; Transcription Factors; Transforming Growth Factor beta; Wnt Signaling Pathway; YAP-Signaling Proteins

A rare case of primary pleomorphic liposarcoma of the thigh with a myxoid component, in which divergent differentiation to a well-differentiated chondrosarcoma was focally present, is described. Presence of heterologous elements has mainly been recognized in the context of dedifferentiated liposarcomas. Few cases of benign mesenchymal tissue have also been reported in well-differentiated and myxoid liposarcomas, while divergent sarcomatous differentiation in liposarcomas appears to be also rare in the absence of dedifferentiation. Positive immunostaining of transforming growth factor-beta, which seems to play a role in the formation of bone and cartilage, was demonstrated in our case. Review of the existing literature on the subject has been carried out.

Topics: Aged; Biomarkers, Tumor; Cell Differentiation; Chondrosarcoma; Humans; Immunohistochemistry; Liposarcoma; Male; Neoplasms, Multiple Primary; Soft Tissue Neoplasms; Thigh; Transforming Growth Factor beta