PO.MCB02.02 · 分子与细胞生物学
TRAP1是去分化脂肪肉瘤的线粒体靶点和生物标志物
TRAP1 represents a mitochondrial target and biomarker of dedifferentiated liposarcoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
去分化脂肪肉瘤(DDLPS)是一种罕见且侵袭性强的脂肪细胞恶性肿瘤,局部复发率接近85%,与其他肿瘤相比异常之高,10年生存率仅为10%。目前尚无可靠的生物标志物能够预测复发或治疗反应。目前的管理主要依赖根治性手术,常联合非特异性化疗,但疗效不佳并严重损害患者的生活质量。DDLPS的侵袭性和缺乏有效的全身治疗凸显了对新型分子靶点和治疗方法的迫切需求。
我们鉴定出线粒体伴侣蛋白TRAP1(TNF受体相关蛋白1)作为DDLPS中潜在的致癌驱动因子和治疗靶点。TRAP1是线粒体代谢、氧化应激和凋亡的主要调控因子,但其在DDLPS中的作用仍不明确。我们的初步数据显示,与低级别高分化脂肪肉瘤(WDLPS)和正常邻近组织(NAT)相比,TRAP1的蛋白和mRNA水平在DDLPS中显著过表达,提示其对肿瘤进展有贡献。
为探索其治疗潜力,我们使用siRNA沉默TRAP1,并用MitoQuinone(MitoQ)——一种目前正在非癌症临床试验中评估的TRAP1抑制剂——抑制其活性。如MTS实验和Annexin V/PI实验所示,TRAP1沉默显著降低了DDLPS细胞增殖并增加了细胞死亡。与WDLPS对照细胞相比,MitoQ处理导致DDLPS细胞出现显著的剂量和时间依赖性细胞毒性,并在3D模型中损害球体生长。此外,与对照条件相比,TRAP1敲低显著降低了线粒体膜电位,并触发G1/S细胞周期阻滞,表明线粒体功能受到破坏。
正在进行的研究利用Seahorse代谢通量分析,探究TRAP1调控如何影响ROS产生、线粒体动力学和能量代谢,以明确其对DDLPS代谢重编程和氧化还原平衡的贡献。最后,为确立TRAP1的临床相关性,我们将在更大规模的脂肪肉瘤患者样本队列中评估TRAP1 mRNA表达,以将其水平与复发率和生存结局相关联。这项工作将TRAP1定位为一个线粒体治疗靶点和潜在生物标志物,提供了新的机制见解,并为创新的DDLPS治疗策略铺平道路。
查看英文原文 English abstract
Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive adipocytic malignancy with a nearly 85% local recurrence rate, exceptionally high compared to other tumors, and a 10-year survival rate of only 10%. No reliable biomarkers currently predict recurrence or therapeutic response. Current management relies primarily on radical surgery, often combined with non-specific chemotherapy, which yields poor outcomes and severely compromises patients' quality of life. The aggressiveness of DDLPS and the lack of effective systemic therapies highlight an urgent need for novel molecular targets and treatment approaches.
We identified the mitochondrial chaperone TRAP1 (TNF Receptor-Associated Protein 1) as a potential oncogenic driver and therapeutic target in DDLPS. TRAP1 is a master regulator of mitochondrial metabolism, oxidative stress, and apoptosis, yet its role in DDLPS remains unknown. Our preliminary data show that TRAP1 protein and mRNA levels are significantly overexpressed in DDLPS compared to low grade well-differentiated liposarcoma (WDLPS) and Normal Adjacent Tissue (NAT), suggesting a contribution to tumor progression.
To explore its therapeutic potential, we silenced TRAP1 using siRNA and inhibited its activity with MitoQuinone (MitoQ), a TRAP1 inhibitor currently evaluated in non-cancer clinical trials. TRAP1 silencing significantly reduced DDLPS cell proliferation and increased cell death, as shown by MTS assays and Annexin V/PI assays. MitoQ treatment led to significant, dose- and time-dependent cytotoxicity in DDLPS cells compared to their WDLPS counterpart, and impaired spheroid growth in 3D models. Moreover, TRAP1 knockdown significantly decreased mitochondrial membrane potential compared to control conditions, and triggered G1/S cell-cycle arrest, indicating disruption of mitochondrial function.
Ongoing studies are investigating how TRAP1 modulation affects ROS production, mitochondrial dynamics and energy metabolism using Seahorse metabolic flux analysis, to define its contribution to metabolic reprogramming and redox balance in DDLPS. Finally, to establish TRAP1's clinical relevance, we will assess TRAP1 mRNA expression in a larger cohort of liposarcoma patient samples to correlate its levels with recurrence rates and survival outcomes. This work positions TRAP1 as a mitochondrial therapeutic target and potential biomarker, offering novel mechanistic insight and paving the way for innovative DDLPS treatment strategies.
利益披露 Disclosure
R. Karna, None..
E. Ulker, None..
S. Rentsch, None..
M. Capece, None..
S. Tahara, None..
Q. Zhang, None..
P. Sarchet, None..
G. Nigita, None..
P. Fadda, None..
F. Costas Casal de Faria, None..
V. Grignol, None..
N. C. Denko, None..
F. Calore, None.