Wang Fang, Li Jingruo, Li Lin, Chen Zhuo, Wang Nan, Zhu Mingzhi, Mi Hailong, Xiong Youyi, Guo Guangcheng, Gu Yuanting
Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Erqi District, Zhengzhou, 450000, Henan, China.
Cancer Cell Int. 2022 Feb 14;22(1):81. doi: 10.1186/s12935-022-02497-y.
Breast cancer (BC) threatens the health of women around the world. Researchers have proved that hsa_circ_0005505 (circ_IRAK3) facilitates BC cell invasion and migration, but the regulatory mechanisms of circ_IRAK3 in BC remain mostly unknown. We aim to explore a new mechanism by which circ_IRAK3 promotes BC progression.
Levels of circ_IRAK3, microRNA (miR)-603, and kinesin family member 2A (KIF2A) mRNA in BC tissues and cells were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The cell cycle progression, colony formation, and proliferation of BC cells were evaluated by flow cytometry, plate clone, or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assays. The migration, invasion, and apoptosis of BC cells were determined by transwell or flow cytometry assays. Several protein levels were detected using western blotting. The targeting relationship between circ_IRAK3 or KIF2A and miR-603 was verified via dual-luciferase reporter assay. The role of circ_IRAK3 in vivo was verified by xenograft assay.
We observed higher levels of circ_IRAK3 in BC tissues and cell lines than their respective controls. Functional experiments presented that circ_IRAK3 silencing induced BC cell apoptosis, curbed cell proliferation, migration, and invasion in vitro, and decreased tumor growth in vivo. Mechanistically, circ_IRAK3 could modulate kinesin family member 2A (KIF2A) expression through acting as a microRNA (miR)-603 sponge. miR-603 silencing impaired the effects of circ_IRAK3 inhibition on the malignant behaviors of BC cells. Also, the repressive effects of miR-603 mimic on the malignant behaviors of BC cells were weakened by KIF2A overexpression.
circ_IRAK3 exerted a promoting effect on BC progression by modulating the miR-603/KIF2A axis, providing a piece of novel evidence for circ_IRAK3 as a therapeutic target for BC.
乳腺癌（BC）威胁着全球女性的健康。研究人员已证明hsa_circ_0005505（circ_IRAK3）促进BC细胞的侵袭和迁移，但circ_IRAK3在BC中的调控机制大多仍不清楚。我们旨在探索circ_IRAK3促进BC进展的新机制。
采用定量实时聚合酶链反应（qRT-PCR）检测BC组织和细胞中circ_IRAK3、微小RNA（miR）-603和驱动蛋白家族成员2A（KIF2A）mRNA的水平。通过流式细胞术、平板克隆或3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）试验评估BC细胞的细胞周期进程、集落形成和增殖。通过Transwell或流式细胞术试验测定BC细胞的迁移、侵袭和凋亡。使用蛋白质印迹法检测几种蛋白质水平。通过双荧光素酶报告基因试验验证circ_IRAK3或KIF2A与miR-603之间的靶向关系。通过异种AK3在体内的作用通过异种移植试验验证。
我们观察到BC组织和细胞系中circ_IRAK3水平高于各自的对照。功能实验表明，circ_IRAK3沉默诱导BC细胞凋亡，抑制体外细胞增殖、迁移和侵袭，并降低体内肿瘤生长。机制上，circ_IRAK3可通过充当微小RNA（miR）- AK3抑制对BC细胞恶性行为的影响。此外，KIF2A过表达减弱了miR-603模拟物对BC细胞恶性行为的抑制作用。
circ_IRAK通过调节miR-603/KIF2A轴对BC进展发挥促进作用，为circ_IRAK3作为BC的治疗靶点提供了新的证据。
