Yu Peter Y, Lopez Gonzalo, Braggio Danielle, Koller David, Bill Kate Lynn J, Prudner Bethany C, Zewdu Abbie, Chen James L, Iwenofu O Hans, Lev Dina, Strohecker Anne M, Fenger Joelle M, Pollock Raphael E, Guttridge Denis C
1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.
2College of Medicine, The Ohio State University, Columbus, OH USA.
Cancer Cell Int. 2018 Jun 26;18:89. doi: 10.1186/s12935-018-0583-2. eCollection 2018.
Sarcomas 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.
Real-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.
miR-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.
Based 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.
肉瘤是间充质来源的恶性异质性肿瘤。去分化脂肪肉瘤（DDLPS）具有侵袭性，80%的患者会复发，20%的患者会发生转移。我们之前发现miR-133a在脂肪肉瘤组织中显著低表达。由于这种微小RNA最近已被证明在许多癌症中是一种肿瘤抑制因子，本研究的目的是阐明miR-133a低表达在DDLPS中的生物学和分子后果。
采用实时定量PCR评估miR-133a在人DDLPS组织、正常脂肪组织和人DDLPS细胞系中的表达水平。用miR-133a载体稳定转导DDLPS细胞，以评估其对体外增殖、细胞周期、细胞死亡、迁移和代谢的影响。还使用海马生物分析仪系统通过测量免疫缺陷小鼠皮下异种移植瘤中的糖酵解和氧化磷酸化（OXPHOS）来评估体内代谢。
miR-133a在人DDLPS组织和细胞系中的表达显著降低。miR-133a的过表达降低了细胞增殖，影响了细胞周期进程动力学，降低了糖酵解，并增加了OXPHOS。对细胞死亡或迁移没有显著影响。通过体内异种移植小鼠研究，我们发现miR-133a表达增加的肿瘤与对照组相比，肿瘤生长没有差异，但OXPHOS代谢呼吸确实有所增加。
基于我们的总体研究结果，我们提出在DDPLS中，miR-133a的缺失由于氧化代谢减少而导致代谢转变，有利于DDLPS肿瘤中的瓦伯格效应，但这种对代谢的调节不足以影响DDPLS。
