School of Medicine, Yunnan University, 2 Cuihu Bei Road, Kunming, 650091, Yunnan, People's Republic of China.
The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650031, Yunnan, People's Republic of China.
Mol Cell Biochem. 2018 Feb;439(1-2):95-104. doi: 10.1007/s11010-017-3139-1. Epub 2017 Aug 9.
MicroRNAs (miRNAs) are small noncoding RNAs that exert their functions by targeting specific mRNA sequences. Many studies have demonstrated that miRNAs are crucial for cancer progression, during which they can act as either oncogenes or tumor suppressors. Previous research has shown that miR-335 is downregulated in breast cancer, and it has been shown to be a breast cancer suppressor. In addition, emerging evidence indicates that erythropoietin-producing hepatocellular A4 (EphA4) is implicated in cancer cell proliferation, migration, and invasion. However, little is known about the relationship between miR-335 and EphA4 in breast cancer. In the present study, we used bioinformatic and biochemical analyses to demonstrate that EphA4 is a direct downstream target of miR-335 in human breast cancer MCF-7 and MDA-MB-23 cells and revealed that miR-335 negatively regulates the expression of EphA4 in these cells. Further investigation revealed that miR-335 overexpression inhibits MCF-7 and MDA-MB-231 cell proliferation and that this inhibition is attenuated by EphA4 coexpression. Similarly, miR-335 overexpression also inhibited growth and downregulated EphA4 expression in tumors in nude mice. Moreover, our results demonstrated that miR-335 overexpression suppresses migration and invasion in MCF-7 and MDA-MB-231 cells, an effect that was reversed by EphA4 overexpression. These findings confirmed that EphA4 is a direct target gene of miR-335 and that miR-335 suppresses breast cancer cell proliferation and motility in part by directly inhibiting EphA4 expression.
微小 RNA（miRNAs）是一种小的非编码 RNA，通过靶向特定的 mRNA 序列来发挥其功能。许多研究表明，miRNAs 对癌症的发展至关重要，在这个过程中，它们可以作为癌基因或肿瘤抑制因子发挥作用。以前的研究表明，miR-335 在乳腺癌中下调，并且被证明是乳腺癌的抑制因子。此外，新出现的证据表明，促红细胞生成素产生肝细胞 A4（EphA4）参与了癌细胞的增殖、迁移和侵袭。然而，miR-335 与 EphA4 在乳腺癌中的关系知之甚少。在本研究中，我们使用生物信息学和生化分析来证明 EphA4 是人类乳腺癌 MCF-7 和 MDA-MB-23 细胞中 miR-335 的直接下游靶标，并揭示 miR-335 负调控这些细胞中 EphA4 的表达。进一步的研究表明，miR-335 过表达抑制 MCF-7 和 MDA-MB-231 细胞的增殖，而 EphA4 的共表达则减弱了这种抑制作用。同样，miR-335 过表达也抑制了裸鼠肿瘤的生长并下调了 EphA4 的表达。此外，我们的结果表明，miR-335 过表达抑制 MCF-7 和 MDA-MB-231 细胞的迁移和侵袭，而 EphA4 的过表达则逆转了这种作用。这些发现证实 EphA4 是 miR-335 的直接靶基因，miR-335 通过直接抑制 EphA4 的表达来抑制乳腺癌细胞的增殖和运动。
