Liu Heng, Li Xiunan, Wang Gangyue, Ren Yu, Fan Zhenlie, Tang Xin
Department of Breast Surgery, Beijing Obstetrics and Gynecology Hospital, Capital Medical University; Beijing Maternal and Child Health Care Hospital Beijing, China.
Am J Cancer Res. 2025 Apr 15;15(4):1559-1577. doi: 10.62347/AMTI5713. eCollection 2025.
Circular RNA (circRNA) and microRNA (miRNA) play critical roles in regulating proliferation, apoptosis, and invasion in triple-negative breast cancer (TNBC) cells. To investigate their functional significance, we employed quantitative real-time PCR (qRT-PCR) to assess the differential expression of circ_0000190, miR-301a, and mesenchyme homeobox 2 (MEOX2) between TNBC cell lines and normal breast epithelial cells. Subsequently, we established overexpression and knockdown systems for these molecules to examine their effects on TNBC cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT). Additionally, we evaluated the impact of circ_0000190 overexpression on tumor growth using a mouse xenograft model, measuring tumor volume and weight. Our findings revealed that circ_0000190 and MEOX2 expression were significantly downregulated (P<0.05) in TNBC cells compared to normal breast epithelial cells, whereas miR-301a was upregulated (P<0.05). Knockdown of circ_0000190 promoted TNBC cell proliferation, migration, invasion, and EMT, while suppressing apoptosis. Mechanistically, circ_0000190 functioned as a molecular sponge for miR-301a, and its overexpression significantly inhibited miR-301a expression (P<0.001). Notably, miR-301a mimics partially reversed the suppressive effects of circ_0000190 overexpression on proliferation, migration, invasion, and EMT, as well as its pro-apoptotic effects (P<0.001). Furthermore, we identified MEOX2 as a direct target of miR-301a. MEOX2 knockdown attenuated the inhibitory effects of miR-301a silencing on proliferation, migration, invasion, and EMT, while also counteracting its pro-apoptotic function. In vivo experiments demonstrated that circ_0000190 overexpression significantly reduced tumor volume and weight (P<0.001), concomitant with elevated MEOX2 mRNA and protein levels (P<0.001) and decreased miR-301a expression (P<0.001). In conclusion, our study elucidates that circ_0000190 suppresses TNBC progression by downregulating miR-301a and upregulating MEOX2, forming a competitive endogenous RNA (ceRNA) network of circRNA-miRNA-mRNA.
环状RNA（circRNA）和微小RNA（miRNA）在调节三阴性乳腺癌（TNBC）细胞的增殖、凋亡和侵袭中发挥着关键作用。为了研究它们的功能意义，我们采用定量实时PCR（qRT-PCR）来评估circ_0000190、miR-301a和间充质同源盒2（MEOX2）在TNBC细胞系和正常乳腺上皮细胞之间的差异表达。随后，我们建立了这些分子的过表达和敲低系统，以研究它们对TNBC细胞增殖、凋亡、迁移、侵袭和上皮-间质转化（EMT）的影响。此外，我们使用小鼠异种移植模型评估了circ_0000190过表达对肿瘤生长的影响，测量了肿瘤体积和重量。我们的研究结果显示，与正常乳腺上皮细胞相比，TNBC细胞中circ_0000190和MEOX2的表达显著下调（P<0.05），而miR-301a则上调（P<0.05）。敲低circ_0000190可促进TNBC细胞增殖、迁移、侵袭和EMT，同时抑制细胞凋亡。机制上，circ_0000190作为miR-301a的分子海绵发挥作用，其过表达显著抑制miR-301a的表达（P<0.001）。值得注意的是，miR-301a模拟物部分逆转了circ_0000190过表达对增殖、迁移、侵袭和EMT的抑制作用及其促凋亡作用（P<0.001）。此外，我们确定MEOX2是miR-301a的直接靶标。敲低MEOX2减弱了miR-301a沉默对增殖、迁移、侵袭和EMT的抑制作用，同时也抵消了其促凋亡功能。体内实验表明，circ_0000190过表达显著降低了肿瘤体积和重量（P<0.001），同时MEOX2 mRNA和蛋白水平升高（P<0.001），miR-301a表达降低（P<0.001）。总之，我们的研究阐明了circ_0000190通过下调miR-301a和上调MEOX2来抑制TNBC进展，形成了一个circRNA-miRNA-mRNA的竞争性内源RNA（ceRNA）网络。
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