Abstract
Simple SummaryThe C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in various cancer stem/progenitor cells via activation of the epithelial-mesenchymal transition (EMT) program to facilitate tumor cell aggressiveness in the premetastatic niche. Through miRNAs microarray and bioinformatics analysis, we confirmed that miR-139 directly interacted with the 3′-untranslated region (3′-UTR) of CXCR4. Overexpression of miR-139 down-modulated CXCR4/p-Akt axis to attenuate invasion and migration of human breast cancer stem cells both in vitro and in vivo. Furthermore, miR-139 expression assessed by quantitative real-time PCR (qRT-PCR) in laser capture microdissected tumor samples significantly correlated with more advanced tumors in patients with breast cancer. Our findings provide support to account for the preferential role of miR-139 in interrupting breast cancer progression, identifying miR-139 as a potential biomarker in prediction of breast cancer invasiveness.Elevated expression of C-X-C motif chemokine receptor 4 (CXCR4) correlates with chemotaxis, invasion, and cancer stem cell (CSC) properties within several solid-tumor malignancies. Recent studies reported that microRNA (miRNA) modulates the stemness of embryonic stem cells. We aimed to investigate the role of miRNA, via CXCR4-modulation, on CSC properties in breast cancer using cell lines and xenotransplantation mouse model and evaluated miR-193 levels in 191 patients with invasive ductal carcinoma. We validated miR-139 directly targets the 3′-untranslated region of CXCR4. Hoechst 33342 fluorescence-activated cell sorting (FACS) and sphere-forming assay were used to identify CSCs. MiR-139 suppressed breast CSCs with mesenchymal traits; led to decreased migration and invasion abilities through down-regulating CXCR4/p-Akt signaling. In lung cancer xenograft model of nude mice transplanted with human miR-139-carrying MDA-MB-231 cells, metastatic lung nodules were suppressed. Clinically, microdissected breast tumor tissues showed miR-139 reduction, compared to adjacent non-tumor tissues, that was significantly associated with worse clinicopathological features, including larger tumor size, advanced tumor stage and lymph node metastasis; moreover, reduced miR-139 level was predominately occurred in late-stage HER2-overexpression tumors. Collectively, our findings highlight miR-139-mediated suppression of CXCR4/p-Akt signaling and thereby affected mesenchymal stem-cell genesis, indicating its potential as a therapeutic target for invasive breast cancer.
Highlights
Breast cancer is the most common cancer type and the second leading cause of cancer mortality in women in Western countries, with approximately one in nine being affected over their lifetime [1]
2.5. miR-139 Reduced BCSC Through Down-Modulation of CXCR4/p-Akt Signaling As CXCR4-induced Akt phosphorylation upregulates vascular endothelial growth factor (VEGF) expression in tumor m tastasis by enhancing mesenchymal proteins [34], we explored the regulatory action miR-139 on CXCR4/p-Akt axis with respect to stemness and invasiveness properties breast cancer cell linking VEGF-mediated epithelialto-mesenchymal transition (EMT)
CXCR4/p-Akt signaling correlated unfavorable outcome of acute myeloid leukemia patients via upregulation of vascular endothelial growth factor (VEGF) and IL-6 gene expression [36]; in this study, we found decreased protein levels of VEGF and IL-6 coincided with CXCR4 reduction in the xenograft-transplantation model of breast cancer cells carrying miR-139 (Figure 5G)
Summary
Breast cancer is the most common cancer type and the second leading cause of cancer mortality in women in Western countries, with approximately one in nine being affected over their lifetime [1]. Similar to the high prevalence in Western countries, its incidence rate in Taiwan has increased significantly over the last two decades; it is the most common cancer type detected and the fourth leading cause of cancer-related death in Taiwanese women since 2006 [the statistics of The Taiwan Cancer Registry (TCR), Ministry of Health and Welfare, http://tcr.cph.ntu.edu.tw/main.php?Page=N1]. CSCs phenotypically resemble normal progenitor cells and dysregulation of stemness-related signaling pathways, such as Wnt/β-catenin [6], Hedgehog [7], Notch [8], and PI3K/p-Akt [9], are often due to acquired genetic mutations and/or epigenetic changes in the tumor cells that in turn lead to metastasis and chemoresistance. The association between genetic signature of CSC-biological traits and cancer prognosis can serve as a reliable marker for assessing clinical outcomes and developing therapeutic strategies for the disease
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