miR-133a function in the pathogenesis of dedifferentiated liposarcoma

Abstract

BackgroundSarcomas are malignant heterogeneous tumors of mesenchymal derivation. Dedifferentiated liposarcoma (DDLPS) is aggressive with recurrence in 80% and metastasis in 20% of patients. We previously found that miR-133a was significantly underexpressed in liposarcoma tissues. As this miRNA has recently been shown to be a tumor suppressor in many cancers, the objective of this study was to characterize the biological and molecular consequences of miR-133a underexpression in DDLPS.MethodsReal-time PCR was used to evaluate expression levels of miR-133a in human DDLPS tissue, normal fat tissue, and human DDLPS cell lines. DDLPS cells were stably transduced with miR-133a vector to assess the effects in vitro on proliferation, cell cycle, cell death, migration, and metabolism. A Seahorse Bioanalyzer system was also used to assess metabolism in vivo by measuring glycolysis and oxidative phosphorylation (OXPHOS) in subcutaneous xenograft tumors from immunocompromised mice.ResultsmiR-133a expression was significantly decreased in human DDLPS tissue and cell lines. Enforced expression of miR-133a decreased cell proliferation, impacted cell cycle progression kinetics, decreased glycolysis, and increased OXPHOS. There was no significant effect on cell death or migration. Using an in vivo xenograft mouse study, we showed that tumors with increased miR-133a expression had no difference in tumor growth compared to control, but did exhibit an increase in OXPHOS metabolic respiration.ConclusionsBased on our collective findings, we propose that in DDPLS, loss of miR-133a induces a metabolic shift due to a reduction in oxidative metabolism favoring a Warburg effect in DDLPS tumors, but this regulation on metabolism was not sufficient to affect DDPLS.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0583-2) contains supplementary material, which is available to authorized users.

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“…Conversely, the most downregulated miRNAs were miR-6503-5p, miR-196b-3p, miR-196b-5p, miR-133a-3p, and miR-5584-5p. The mature miRNA miR-196b functions as a tumor suppressor during lung carcinogenesis (37), and well-characterized miR-133a has been found to function in a tumor-suppressive manner in as many as five cancers, including breast and colorectal cancer (38).…”

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“…In dedifferentiated liposarcoma (DDLPS), loss of miR-133a could reduce oxidative metabolism, supporting the tumor Warburg effect. Braggio, D. first found that overexpression of miR-133a could increase glycolysis and OXPHOS both in vitro and in vivo ; however, the metabolic change was not sufficient to suppress DDLPS cell proliferation and progression 27 . It was known that glycogen metabolism contributed to cancer development.…”

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“…Similarly, over-expression of miRNA-133a could inhibit the proliferation and regulate mitochondrial function and glycolysis ability of DDL cell lines. However, in vivo experiments showed that exogenous recombinant miRNA-133a had only the ability to regulate cell metabolism, and without proliferation inhibition [61]. Recently, Mazzu et al [62] has found that miR-193b regulates multiple oncogenic signaling pathways (such as PDGFR, TGF, and Wnt) by targeting PDGFR-β, SMAD4 and YAP1 proteins in vitro, and thus miR-193b plays a tumor-suppressing role in the WDL/DDL cell lines.…”