Abstract 3426: miR-133a function in the pathogenesis of dedifferentiated liposarcoma

Abstract

Abstract Background: Sarcomas are malignant heterogeneous tumors of mesenchymal derivation. Dedifferentiated liposarcoma (DDLPS) exhibits aggressive biological behavior with an 80% local recurrence rate and the development of metastasis in approximately 20% of patients. To identify and characterize the molecular alterations that contribute to the development and progression of DDLPS, our laboratory characterized a unique miRNA expression signature associated with human DDLPS tissue compared to paired subjacent normal tissue. We found that several muscle-specific miRNAs (myomiRs), miR-1, -133a, and -206, were significantly underexpressed in liposarcoma tissues. Interestingly, these miRNAs have recently been shown to have tumor suppressor functions in many human cancers. The objective of this study is to characterize the biological and molecular consequences of miR-133a in DDLPS. Methods: Taqman real-time PCR was used to evaluate expression levels of myomiRs in human DDLPS tissue, normal fat tissue, and available human DDLPS cell lines. To evaluate the effects of miR-133a expression on DDLPS cell line behavior in vitro, cells were stably transduced with miR-133a vector or empty lentiviral vector and the effects on cell cycle, proliferation, apoptosis, and migration were assessed. Agilent Seahorse Bioanalyzer system was used to assess metabolism. We performed an in silico search for predicted targets of miR-133a using target prediction databases and compared these target genes to known genes that are highly expressed in human DDLPS tissue. Results: The expression levels of myomiRs were significantly decreased in human DDLPS tissue compared to normal human fat as well as in human DDLPS cell lines compared to a human preadipocyte cell lines. Overexpression of miR-133a decreased cell proliferation, decreased glycolysis, and increased spare respiratory capacity. There was no significant effect on cell cycle, apoptosis, or migration. Using in silico target gene analysis, we identified 18 potential targets of miR-133a. These preliminary results suggest that miR-133a regulates metabolism and proliferation, and its dysregulation might contribute to the oncogenic phenotype of DDLPS. Significance: We have demonstrated that enforced expression of miR-133a decreased proliferation and metabolism in human DDLPS cells. We have identified putative gene targets of miR-133a and are currently dissecting the molecular mechanism by which miR-133a may mediate proliferation and metabolism in DDLPS cell lines. Taken together, these data suggest that miR-133a might play a tumor suppressor role in DDLPS, thereby generating new potential targets for therapeutic intervention to alter the course of this disease. Citation Format: Peter Y. Yu, Hans Iwenofu, Raphael E. Pollock, Denis C. Guttridge. miR-133a function in the pathogenesis of dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3426. doi:10.1158/1538-7445.AM2017-3426