Key Laboratory of Saline-alkali Vegetation Ecology Restoration, College of Life Science, Northeast Forestry University, Harbin, China.
Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Biochim Biophys Acta Mol Cell Res. 2020 Dec;1867(12):118826. doi: 10.1016/j.bbamcr.2020.118826. Epub 2020 Aug 15.
Rhabdomyosarcoma (RMS) is a pediatric cancer with rhabdomyoblastic phenotype and mitochondria act as pivotal regulators of its growth and progression. While miR-7-5p (miR-7) is reported to have a tumor-suppressive role, little is yet known about its antitumor activity in RMS.
The effects of miR-7 on RMS were analyzed both in vitro and in vivo. Cell death modalities induced by miR-7 were identified. Influence on mitochondria was evaluated through RNA sequencing data, morphological observation and mitochondrial functional assays, including outer membrane permeability, bioenergetics and redox balance. Dual-luciferase assay and phenotype validation after transient gene silencing were performed to identify miR-7 targets in RMS.
MiR-7 executed anti-tumor effect in RMS beyond proliferation inhibition. Morphologic features and molecular characteristics with apoptosis and necroptosis were found in miR-7-transfected RMS cells. Chemical inhibitors of apoptosis and necroptosis were able to prevent miR-7-induced cell death. Further, we identified that mitochondrial impairment mainly contributed to these phenomena and mitochondrial proteins SLC25A37 and TIMM50 were crucial targets for miR-7 to induce cell death in RMS.
Our results extended the mechanism of miR-7 antitumor role in rhabdomyosarcoma cancer, and provided potential implications for its therapy.
横纹肌肉瘤（RMS）是一种具有横纹肌样表型的儿科癌症，线粒体作为其生长和进展的关键调节因子。虽然 miR-7-5p（miR-7）被报道具有肿瘤抑制作用，但关于其在 RMS 中的抗肿瘤活性知之甚少。
在体外和体内分析了 miR-7 对 RMS 的影响。鉴定了 miR-7 诱导的细胞死亡方式。通过 RNA 测序数据、形态观察和线粒体功能测定（包括外膜通透性、生物能量和氧化还原平衡）评估对线粒体的影响。通过双荧光素酶报告基因检测和瞬时基因沉默后的表型验证，鉴定 RMS 中的 miR-7 靶标。
miR-7 在 RMS 中除了抑制增殖外，还发挥了抗肿瘤作用。在转染 miR-7 的 RMS 细胞中发现了具有凋亡和坏死样特征的形态学特征和分子特征。凋亡和坏死抑制剂能够阻止 miR-7 诱导的细胞死亡。此外，我们发现线粒体损伤主要导致了这些现象，并且线粒体蛋白 SLC25A37 和 TIMM50 是 miR-7 在 RMS 中诱导细胞死亡的关键靶标。
我们的研究结果扩展了 miR-7 在横纹肌肉瘤癌症中的抗肿瘤作用机制，并为其治疗提供了潜在的意义。
