The protein-coding ability of circular RNAs (circRNAs) has recently been a hot topic, but the expression and roles of protein-coding circRNAs in triple-negative breast cancer (TNBC) remain uncertain. By intersecting circRNA sequencing data from clinical samples and cell lines, we identified a circRNA, termed circ-EIF6, which predicted a poorer prognosis and correlated with clinicopathological characteristics in a cohort of TNBC patients. Functionally, we showed that circ-EIF6 promoted the proliferation and metastasis of TNBC cells in vitro and in vivo. Mechanistically, we found that circ-EIF6 contains a 675-nucleotide (nt) open reading frame (ORF) and that the −150-bp sequence from ATG functioned as an internal ribosome entry site (IRES), which is required for translation initiation in 5′ cap-independent coding RNAs. circ-EIF6 encodes a novel peptide, termed EIF6-224 amino acid (aa), which is responsible for the oncogenic effects of circ-EIF6. The endogenous expression of EIF6-224aa was further examined in TNBC cells and tissues by specific antibody. Moreover, EIF6-224aa directly interacted with MYH9, an oncogene in breast cancer, and decreased MYH9 degradation by inhibiting the ubiquitin-proteasome pathway and subsequently activating the Wnt/beta-catenin pathway. Our study provided novel insights into the roles of protein-coding circRNAs and supported circ-EIF6/EIF6-224aa as a novel promising prognostic and therapeutic target for tailored therapy in TNBC patients.

环状RNAs（circRNAs）的蛋白质编码能力最近成为热门话题，但蛋白质编码circRNAs在三阴性乳腺癌（TNBC）中的表达和作用仍不确定。通过交叉来自临床样本和细胞系的 circRNA 测序数据，我们鉴定了一种称为 circ-EIF6 的 circRNA，它预测了较差的预后并与一组 TNBC 患者的临床病理学特征相关。在功能上，我们发现 circ-EIF6在体外和体内促进了 TNBC 细胞的增殖和转移. 从机制上讲，我们发现 circ-EIF6 包含一个 675 个核苷酸 (nt) 的开放阅读框 (ORF)，并且来自 ATG 的 −150-bp 序列充当内部核糖体进入位点 (IRES)，这是翻译起始所必需的5'帽独立编码RNA。circ-EIF6 编码一种新的肽，称为 EIF6-224 氨基酸 (aa)，它负责 circ-EIF6 的致癌作用。通过特异性抗体进一步检测了 TNBC 细胞和组织中 EIF6-224aa 的内源性表达。此外，EIF6-224aa 直接与乳腺癌致癌基因 MYH9 相互作用，并通过抑制泛素-蛋白酶体途径并随后激活 Wnt/β-连环蛋白途径来减少 MYH9 的降解。