Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) and the underlying mechanisms remain unclear. This study investigated the role of STAT3-microRNA(miRNA)-targeted protein axis in VE against breast cancer-induced cardiac injury.VE for 4 weeks not only improved cardiac function of transgenic breast cancer female mice [mouse mammary tumor virus–polyomavirus middle T antigen (MMTV-PyMT +)] compared with littermate mice with no cancer (MMTV-PyMT −), but also increased myocardial STAT3 tyrosine 705 phosphorylation. Significantly more obvious cardiac fibrosis, smaller cardiomyocyte size, lower cell viability, and higher serum tumor necrosis factor (TNF)-α were shown in MMTV-PyMT + mice compared with MMTV-PyMT − mice, which were ameliorated by VE. However, VE did not influence the tumor growth. MiRNA sequencing identified that miR-181a-5p was upregulated and miR-130b-3p was downregulated in VE induced-cardioprotection. Myocardial injection of Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutations abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a (the precursor of miR-181a-5p) and HOX transcript antisense RNA (HOTAIR, sponged miR-130b-3p) in isolated cardiomyocytes. Furthermore, miR-181a-5p targeting PTEN and miR-130b-3p targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved in AC-16 cells. These findings indicated that VE protects against breast cancer-induced cardiac injury via activating STAT3 to promote miR-181a-5p targeting PTEN and to promote HOTAIR to sponge miR-130b-3p targeting Zbtb20, helping to develop new targets in exercise therapy for breast cancer-induced cardiac injury.

运动在一定程度上是减轻乳腺癌引起的心脏损伤的有效方法。然而，自主运动（VE）是否激活心脏信号转导器和转录激活子3（STAT3）及其潜在机制仍不清楚。本研究探讨了STAT3-microRNA（miRNA）靶向蛋白轴在VE对抗乳腺癌引起的心脏损伤中的作用。VE连续4周不仅改善了转基因乳腺癌雌性小鼠的心脏功能【小鼠乳腺肿瘤病毒-多瘤病毒中T抗原（MMTV-PyMT +）]与没有癌症的同窝小鼠（MMTV-PyMT -）相比，但心肌 STAT3 酪氨酸 705 磷酸化也增加。与 MMTV-PyMT - 小鼠相比，MMTV-PyMT + 小鼠的心脏纤维化明显更明显，心肌细胞尺寸更小，细胞活力更低，血清肿瘤坏死因子（TNF）-α 更高，而 VE 可以改善这些情况。然而，VE并不影响肿瘤的生长。 miRNA 测序发现，在 VE 诱导的心脏保护作用中，miR-181a-5p 上调，miR-130b-3p 下调。心肌注射驱动 STAT3 酪氨酸 705 突变的腺相关病毒血清型 9 消除了上述心脏保护作用。心肌 STAT3 被鉴定为结合分离心肌细胞中 pri-miR-181a（miR-181a-5p 的前体）和 HOX 转录反义 RNA（HOTAIR，海绵 miR-130b-3p）启动子的转录因子。此外，在 AC-16 细胞中证实了靶向 PTEN 的 miR-181a-5p 和靶向锌指和含有 BTB 结构域的蛋白 20 (Zbtb20) 的 miR-130b-3p。 这些研究结果表明，VE通过激活STAT3促进靶向PTEN的miR-181a-5p并促进HOTAIR海绵靶向Zbtb20的miR-130b-3p来预防乳腺癌引起的心脏损伤，有助于开发乳腺癌运动治疗的新靶点诱发的心脏损伤。