Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 170 Xinsong Rd, Shanghai, 201100, China.
Department of Medical Rehabilitation, Heze Domestic Professional College, Middle Xueyuan Road, Shanxian Development Zone, Heze, Shandong, 274300, China.
Environ Toxicol. 2023 Jul;38(7):1712-1722. doi: 10.1002/tox.23799. Epub 2023 Apr 11.
The conjecture of breast cancer is uncertain because of its explosive growth and the complicated molecular mechanisms. Circular RNAs (circRNAs) are regulatory RNA sequences present in the genome and their regulatory mechanism involves the sponging of microRNAs (miRNAs). In this study, we explored the regulation between circular forms of dedicator of cytokinesis 1 (circDOCK1) (hsa_circ_0007142) and miR-128-3p, and its implication on the pathogenesis of breast cancer modulated by never in mitosis (NIMA) related kinase 2 (NEK2). We revealed an increase in circDOCK1 and NEK2 expression, and a decrease in miR-128-3p expression in breast cancer tissues and cell lines. Bioinformatics analysis and experimental validation indicated a positive correlation between circDOCK1 and NEK2 expression but a negative correlation was recorded between miR-128-3p and circDOCK1 or NEK2, respectively. Furthermore, inhibition of circDOCK1 expression was followed by an increase in miR-128-3p and a decrease in NEK2 levels in vitro and in vivo. The luciferase assay concluded that miR-128-3p was a direct target of circDOCK1 while NEK2 was the direct target of miR-128-3p. Furthermore, circDOCK1 inhibition hindered breast cancer development by repressing NEK2 and thus promoting the increased expression of miR-128-3p both in vitro and in vivo. We therefore conclude that circDOCK1 promotes breast cancer progression by targeting miR-128-3p-mediated downregulation of NEK2 and that the circDOCK1/hsa-miR-128-3p/NEK2 axis may be a novel therapeutic target for breast cancer treatment.
乳腺癌的发生机制尚不确定，因为其具有爆发性生长和复杂的分子机制。环状 RNA（circRNA）是基因组中存在的调节性 RNA 序列，其调节机制涉及 microRNA（miRNA）的海绵作用。在本研究中，我们探讨了细胞分裂蛋白 1（circDOCK1）（hsa_circ_0007142）的环状形式与 miR-128-3p 之间的调节关系，以及其对有丝分裂期非必需激酶 2（NEK2）调节的乳腺癌发病机制的影响。我们发现乳腺癌组织和细胞系中 circDOCK1 和 NEK2 的表达增加，miR-128-3p 的表达降低。生物信息学分析和实验验证表明 circDOCK1 与 NEK2 的表达呈正相关，而 miR-128-3p 与 circDOCK1 或 NEK2 的表达呈负相关。此外，体外和体内抑制 circDOCK1 表达后，miR-128-3p 增加，NEK2 水平降低。荧光素酶报告基因实验表明 miR-128-3p 是 circDOCK1 的直接靶标，而 NEK2 是 miR-128-3p 的直接靶标。此外，circDOCK1 抑制通过抑制 NEK2 促进 miR-128-3p 的表达，从而抑制乳腺癌的发展，无论是在体外还是体内。因此，我们得出结论，circDOCK1 通过靶向 miR-128-3p 介导的 NEK2 下调促进乳腺癌的进展，circDOCK1/hsa-miR-128-3p/NEK2 轴可能是治疗乳腺癌的新靶点。
