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

Abstract

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 b-catenin in the cytoplasm, facilitated b-catenin degradation, and impaired the nuclear accumulation of b-catenin, thus stimulating the activation of known Wnt targets, epithelialmesenchymal transition (EMT) markers, and key regulators of cancer stemness. Moreover, miR-5188 potentiated Wnt/ b-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/b-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.

Bioinformatics Analysis Reveals Biomarkers With Cancer Stem Cell Characteristics in Lung Squamous Cell Carcinoma

“…However, it is highly expressed in colon cancer and significantly correlated with lymphatic metastasis, satellite metastasis and TNM stage (Top et al, 2016;Ozturk et al, 2017). TIMELESS plays a crucial role in the self-renewal process of breast CSCs and interacts with Sp1/c-jun to induce miR-5188 expression by promoting c-jun-mediated transcription, thus promoting breast cancer progression (Zou et al, 2020). Our research also has the following limitations.…”

miR‐5188 augments glioma growth, migration and invasion through an SP1‐modulated FOXO1‐PI3K/AKT‐c‐JUN‐positive feedback circuit

“…[12][13][14] Recent studies suggested the powerful function of miR-5188 in cancer progression. 15,16 However, the biological effects of miR-5188 in glioma remain insufficiently understood.…”

MicroRNA-4476 promotes glioma progression through a miR-4476/APC/β-catenin/c-Jun positive feedback loop

“…C-Jun is an effector of many important signaling pathways like MAPK signaling and Wnt/β-catenin signaling, and has vital roles in the regulation of cell growth, proliferation, differentiation, and apoptosis 40 . As a well-studied transcription factor, c-Jun can regulate the transcription of several miRNAs through binding to their promoter regions, thereby promoting cancer progression 41,42 . Our study has demonstrated that miR-4476 activates Wnt/β-catenin signaling and upregulates c-Jun expression, which, in turn, enhances the expression of miR-4476.…”