Timeless-Stimulated miR-5188-FOXO1/β-Catenin-c-Jun Feedback Loop Promotes Stemness via Ubiquitination of β-Catenin in Breast Cancer

• Published in: Molecular therapy 2020-01, Vol.28 (1), p.313-327
• Main Authors: Zou, Yujiao, Lin, Xian, Bu, Junguo, Lin, Zelong, Chen, Yanjuan, Qiu, Yunhui, Mo, Haiyue, Tang, Yao, Fang, Weiyi, Wu, Ziqing
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antagonists; beta Catenin - metabolism; Binding sites; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; c-Jun protein; cancer stem cells; Cancer therapies; Cell cycle; Cell Movement - genetics; Cell Proliferation - genetics; Cell self-renewal; Chemoresistance; Cytoplasm; Epithelial-Mesenchymal Transition - genetics; Female; Forkhead Box Protein O1 - metabolism; FOXO1; FOXO1 protein; Gene expression; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Medical prognosis; Mesenchyme; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; miR-5188; miRNA; Original; Prognosis; Proto-Oncogene Mas; Proto-Oncogene Proteins c-jun - metabolism; Stem cells; stemness; timeless; Transcription factors; Transfection; Ubiquitination; Ubiquitination - genetics; Up-Regulation - genetics; Wnt protein; Xenograft Model Antitumor Assays; Young Adult; β-Catenin
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2019.08.015

MicroRNAs (miRNAs) play an essential role in the self-renewal of breast cancer stem cells (BCCs). Our study aimed to clarify the role of proto-oncogene c-Jun-regulated miR-5188 in breast cancer progression and its association with Timeless-mediated cancer stemness. In the present study, we showed that miR-5188 exerted an oncogenic effect by inducing breast cancer stemness, proliferation, metastasis, and chemoresistance in vitro and in vivo. The mechanistic analysis demonstrated that miR-5188 directly targeted FOXO1, which interacted with β-catenin in the cytoplasm, facilitated β-catenin degradation, and impaired the nuclear accumulation of β-catenin, thus stimulating the activation of known Wnt targets, epithelial-mesenchymal transition (EMT) markers, and key regulators of cancer stemness. Moreover, miR-5188 potentiated Wnt/β-catenin/c-Jun signaling to promote breast cancer progression. Interestingly, c-Jun enhanced miR-5188 transcription to form a positive regulatory loop, and Timeless interacted with Sp1/c-Jun to induce miR-5188 expression by promoting c-Jun-mediated transcription, which further activated miR-5188-FOXO1/β-catenin-c-Jun loop and facilitated breast cancer progression. Importantly, miR-5188 was upregulated in breast cancer and was positively correlated with poor patient prognosis. This study identifies miR-5188 as a novel oncomiR and provides a new theoretical basis for the clinical use of miR-5188 antagonists in the treatment of breast cancer. [Display omitted] Molecular targeting therapy has become the most prevalent strategy for cancer treatment. miR-5188 is a significant inducer of cancer stemness that promotes breast cancer pathogenesis. miR-5188 may be a novel factor for the diagnosis and prognosis of breast cancer and may serve as a useful therapeutic target for breast cancer.