Background

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.

Methods

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.

Results

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.

Conclusion

Our results extended the mechanism of miR-7 antitumor role in rhabdomyosarcoma cancer, and provided potential implications for its therapy.

中文翻译：

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MiR-7介导线粒体损伤，触发横纹肌肉瘤的凋亡和坏死性坏死。

背景

横纹肌肉瘤（RMS）是一种具有横纹母细胞表型的儿童癌症，线粒体是其生长和进展的关键调节因子。虽然据报道miR-7-5p（miR-7）具有肿瘤抑制作用，但对其在RMS中的抗肿瘤活性知之甚少。

方法

在体外和体内均分析了miR-7对RMS的影响。确定了由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，生物能和氧化还原平衡）评估了对线粒体的影响。进行瞬时基因沉默后的双重荧光素酶测定和表型验证，以鉴定RMS中的miR-7靶标。

结果

MiR-7对RMS的抗肿瘤作用超出了抑制增殖的范围。在miR-7转染的RMS细胞中发现了具有凋亡和坏死性坏死的形态学特征和分子特征。细胞凋亡和坏死病的化学抑制剂能够预防miR-7诱导的细胞死亡。此外，我们发现线粒体损伤主要是这些现象的原因，线粒体蛋白SLC25A37和TIMM50是miR-7诱导RMS细胞死亡的关键靶标。

结论

我们的研究结果扩展了miR-7在横纹肌肉瘤中抗肿瘤作用的机制，并为其治疗提供了潜在的启示。