Wang Li, Hu Zaoxiu, Bai Han, Chang Li, Chen Ceshi, Li Wenhui
Department of Radiotherapy, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, 650000, Yunnan, China.
Department of Pathology, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, 650000, Yunnan, China.
Am J Med Sci. 2025 Apr;369(4):513-523. doi: 10.1016/j.amjms.2024.09.009. Epub 2024 Sep 21.
Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer (BC). Some potential molecular targets have been identified, and miR-105-5p was found to be abnormally expressed in TNBC tissues.
The objective of this study was to probe the effect of miR-105-5p on TNBC via FOXG1/HDAC2-mediated acetylation.
An animal model of TNBC was established by injecting BC cells into the axillary area of nude mice. The levels of miR-105-5p, FOXG1, HDAC2, Bcl-2, Bax, and Ki67 were detected via RT‒qPCR, Western blotting and immunohistochemistry. Flow cytometry, CCK-8, Transwell and colony formation assays were used to measure apoptosis, proliferation and migration, respectively. Total histone acetylation levels were measured by ELISA. The binding of FOXG1 to HDAC2 was detected by co-immunoprecipitation. The binding relationship between miR-105-5p and FOXG1 was verified using a dual-luciferase reporter gene assay.
In this study, miR-105-5p and HDAC2 were highly expressed in the MDA-MB-231 and BT-549 BC cell lines, whereas FOXG1 was expressed at low levels. The inhibition of miR-105-5p inhibited the proliferation and migration of MDA-MB-231 and BT-549 cells and promoted their apoptosis. Bioinformatics analysis revealed that miR-105-5p and FOXG1 had a negative targeting regulatory relationship. FOXG1 overexpression had a similar effect on cancer cells as the inhibition of miR-105-5p. Moreover, experiments revealed that FOXG1 and HDAC2 could bind to each other and that HDAC2 overexpression or treatment with the histone acetyltransferase inhibitor Garcinol weakened the effect of FOXG1 overexpression. In addition, FOXG1 knockdown inhibited the effect of the miR-105-5p inhibitor, while Garcinol treatment further enhanced the effect of FOXG1 knockdown, inhibited histone acetylation, promoted the proliferation and migration of cancer cells, and inhibited apoptosis. Moreover, the in vivo results confirmed the in vitro results.
miR-105-5p promotes HDAC2 expression by reducing FOXG1, inhibits histone acetylation, and aggravates the malignant biological behavior of TNBC cells.
三阴性乳腺癌（TNBC）是乳腺癌（BC）的一种特殊亚型。已确定了一些潜在的分子靶点，且发现miR-105-5p在TNBC组织中异常表达。
本研究旨在探究miR-105-5p通过FOXG1/HDAC2介导的乙酰化对TNBC的影响。
通过将BC细胞注射到裸鼠腋窝区域建立TNBC动物模型。通过RT-qPCR、蛋白质免疫印迹法和免疫组织化学检测miR-105-5p、FOXG1、HDAC2、Bcl-2、Bax和Ki67的水平。分别采用流式细胞术、CCK-8、Transwell和集落形成试验检测细胞凋亡、增殖和迁移情况。通过ELISA检测总组蛋白乙酰化水平。通过免疫共沉淀检测FOXG1与HDAC2的结合情况。使用双荧光素酶报告基因试验验证miR-105-5p与FOXG1之间的结合关系。
在本研究中，miR-105-5p和HDAC2在MDA-MB-231和BT-549 BC细胞系中高表达，而FOXG1表达水平较低。抑制miR-105-5p可抑制MDA-MB-231和BT-549细胞的增殖和迁移，并促进其凋亡。生物信息学分析显示miR-105-5p与FOXG1存在负向靶向调控关系。FOXG1过表达对癌细胞的作用与抑制miR-105-5p相似。此外，实验表明FOXG1与HDAC2可相互结合，且HDAC2过表达或用组蛋白乙酰转移酶抑制剂藤黄菌素处理会削弱FOXG1过表达的作用。此外，敲低FOXG1可抑制miR-105-5p抑制剂的作用，而藤黄菌素处理可进一步增强敲低FOXG1的作用，抑制组蛋白乙酰化，促进癌细胞的增殖和迁移，并抑制细胞凋亡。此外，体内实验结果证实了体外实验结果。
miR-105-5p通过降低FOXG1促进HDAC2表达，抑制组蛋白乙酰化，加重TNBC细胞的恶性生物学行为。
