Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91 TK33 Galway, Ireland.
Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, 40530 Gothenburg, Sweden.
Int J Mol Sci. 2023 Aug 22;24(17):13034. doi: 10.3390/ijms241713034.
C/EBP homologous protein (CHOP), also known as growth arrest and DNA damage-inducible protein 153 (GADD153), belongs to the CCAAT/enhancer-binding protein (C/EBP) family. CHOP expression is induced by unfolded protein response (UPR), and sustained CHOP activation acts as a pivotal trigger for ER stress-induced apoptosis. MicroRNA-616 is located within an intron of the CHOP gene. However, the regulation of miR-616 expression during UPR and its function in breast cancer is not clearly understood. Here we show that the expression of miR-616 and CHOP (host gene of miR-616) is downregulated in human breast cancer. Both miR-5p/-3p arms of miR-616 are expressed with levels of the 5p arm higher than the 3p arm. During conditions of ER stress, the expression of miR-616-5p and miR-616-3p arms was concordantly increased primarily through the PERK pathway. Our results show that ectopic expression of miR-616 significantly suppressed cell proliferation and colony formation, whereas knockout of miR-616 increased it. We found that miR-616 represses c-MYC expression via binding sites located in its protein coding region. Furthermore, we show that miR-616 exerted growth inhibitory effects on cells by suppressing c-MYC expression. Our results establish a new role for the CHOP locus by providing evidence that miR-616 can inhibit cell proliferation by targeting c-MYC. In summary, our results suggest a dual function for the CHOP locus, where CHOP protein and miR-616 can cooperate to inhibit cancer progression.
C/EBP 同源蛋白（CHOP），也称为生长停滞和 DNA 损伤诱导蛋白 153（GADD153），属于 CCAAT/增强子结合蛋白（C/EBP）家族。CHOP 的表达受未折叠蛋白反应（UPR）诱导，持续激活的 CHOP 作为 ER 应激诱导细胞凋亡的关键触发因素。miR-616 位于 CHOP 基因的内含子中。然而，UPR 期间 miR-616 表达的调节及其在乳腺癌中的功能尚不清楚。在这里，我们发现 miR-616 和 CHOP（miR-616 的宿主基因）的表达在人乳腺癌中下调。miR-616 的 5p/-3p 臂都有表达，其中 5p 臂的水平高于 3p 臂。在 ER 应激条件下，miR-616-5p 和 miR-616-3p 臂的表达通过 PERK 途径一致增加。我们的结果表明，miR-616 的异位表达显著抑制细胞增殖和集落形成，而 miR-616 的敲除则增加了细胞增殖和集落形成。我们发现，miR-616 通过位于其蛋白质编码区的结合位点抑制 c-MYC 的表达。此外，我们发现 miR-616 通过抑制 c-MYC 的表达对细胞发挥生长抑制作用。我们的结果通过提供证据表明，miR-616 可以通过靶向 c-MYC 抑制细胞增殖，为 CHOP 基因座提供了一个新的作用。总之，我们的结果表明 CHOP 基因座具有双重功能，CHOP 蛋白和 miR-616 可以协同抑制癌症进展。
