Li Zhengmin, He Fang, Yang Zhanjia, Cao Xueming, Dai Shuyang, Zou Jie, Xu Poshi, Zhou Zhou
Department of Medical Laboratory, Fuwai Central China Cardiovascular Hospital Zhengzhou Henan China.
Department of Medical Laboratory, Henan Provincial People's Hospital Zhengzhou Henan China.
RSC Adv. 2019 Jan 11;9(3):1451-1459. doi: 10.1039/c8ra06750c. eCollection 2019 Jan 9.
Hypoxia is a major hallmark of solid tumors and is associated with malignant phenotypes. Exosomal miRNAs derived from hypoxia tumor cells are implicated in the modulation of cancer progression, whereas, the mechanisms underlying the association between hypoxia and exosomal miR-25-3p during breast cancer progression remain to be further clarified. The present study aimed to investigate the role of exosomal miR-25-3p in regulating breast cancer progression. Herein, we found that miR-25-3p expression was increased in hypoxia tumor-derived exosomes a HIF-1α-dependent manner. Hypoxia exosomes markedly stimulated the viability and migration of normoxia breast cancer cells, which was reversed by miR-25-3p depletion. Inhibition of exosomes miR-25-3p lowered hypoxic-induced the expression of IL-6 and NF-κB from THP-1 and RAW264.7 cells in a TLR7/8-dependent way. Treatment of macrophage supernatant (MS) initially incubated with hypoxic-responsed exosomes accelerated the viability and migration of breast cancer cells, and miR-25-3p depletion relieved the stimulatory effects of hypoxic on cell viability and migration. Moreover, miR-25-3p knockdown dramatically suppressed HIF-1α-induced tumor growth inactivation of IL-6/STAT3 signaling pathway, reflected by the abated abundances of IL-6 and p-STAT3. These data suggested that absence of exosomal miR-25-3p rescued breast cancer aggressiveness through inhibiting cell viability and migration by regulation of IL-6 secretion from macrophages, providing a potential biomarker for breast cancer treatment.
缺氧是实体瘤的一个主要特征，与恶性表型相关。源自缺氧肿瘤细胞的外泌体miRNA参与癌症进展的调节，然而，在乳腺癌进展过程中，缺氧与外泌体miR-25-3p之间关联的潜在机制仍有待进一步阐明。本研究旨在探讨外泌体miR-25-3p在调节乳腺癌进展中的作用。在此，我们发现miR-25-3p在缺氧肿瘤来源的外泌体中以HIF-1α依赖的方式表达增加。缺氧外泌体显著刺激常氧乳腺癌细胞的活力和迁移，而miR-25-3p缺失可逆转这种作用。抑制外泌体miR-25-3p以TLR7/8依赖的方式降低缺氧诱导的THP-1和RAW264.7细胞中IL-6和NF-κB的表达。用缺氧反应外泌体预先孵育的巨噬细胞上清液（MS）处理可加速乳腺癌细胞的活力和迁移，而miR-25-3p缺失可减轻缺氧对细胞活力和迁移的刺激作用。此外，miR-25-3p敲低显著抑制HIF-1α诱导的肿瘤生长，IL-6/STAT3信号通路失活，表现为IL-6和p-STAT3丰度降低。这些数据表明，外泌体miR-25-3p的缺失通过调节巨噬细胞分泌IL-6来抑制细胞活力和迁移，从而挽救乳腺癌的侵袭性，为乳腺癌治疗提供了一个潜在的生物标志物。
