Abstract
BackgroundExtracellular vesicles (EVs) derived from tumor cells are implicated in the progression of malignancies through the transfer of molecular cargo microRNAs (miRNAs or miRs). We aimed to explore the role of EVs derived from breast cancer cells carrying miR-182-5p in the occurrence and development of breast cancer.MethodsDifferentially expressed miRNAs and their downstream target genes related to breast cancer were screened through GEO and TCGA databases. miR-182-5p expression was examined in cancer tissues and adjacent normal tissues from patients with breast cancer. EVs were isolated from breast cancer cell line MDA-MB-231 cells and identified. The gain- and loss-of function approaches of miR-182-5p and CKLF-like MARVEL transmembrane domain-containing 7 (CMTM7) were performed in MDA-MB-231 cells and the isolated EVs. Human umbilical vein endothelial cells (HUVECs) were subjected to co-culture with MDA-MB-231 cell-derived EVs and biological behaviors were detected by CCK-8 assay, flow cytometry, immunohistochemical staining, Transwell assay and vessel-like tube formation in vitro. A xenograft mouse model in nude mice was established to observe the tumorigenesis and metastasis of breast cancer cells in vivo.ResultsmiR-182-5p was highly expressed in breast cancer tissues and cells, and this high expression was associated with poor prognosis of breast cancer patients. miR-182-5p overexpression was shown to promote tumor angiogenesis in breast cancer. Moreover, our data indicated that miR-182-5p was highly enriched in EVs from MDA-MD-231 cells and then ultimately enhanced the proliferation, migration, and angiogenesis of HUVECs in vitro and in vivo. Moreover, we found that CMTM7 is a target of miR-182-5p. EVs-miR-182-5p promotes tumorigenesis and metastasis of breast cancer cells by regulating the CMTM7/EGFR/AKT signaling axis.ConclusionsTaken altogether, our findings demonstrates that EVs secreted by breast cancer cells could carry miR-182-5p to aggravate breast cancer through downregulating CMTM7 expression and activating the EGFR/AKT signaling pathway.
Highlights
Breast cancer is the most frequently diagnosed cancer worldwide (Harbeck and Gnant 2017) and represents a leading cause of premature mortality among women, Lu et al Mol Med (2021) 27:78 risk factors for which include race, ethnicity, family history and genetic traits, along with excess alcohol consumption, physical inactivity and exogenous hormones (Coughlin 2019)
Results miR‐182‐5p is highly expressed in breast cancer tissues and cells, which is associated with poor prognosis of breast cancer patients Analysis on the GSE26659, GSE35412-1, GSE35412-2, GSE45666 and GSE58027 (Fig. 1A, B) revealed 104, 83, 47, 205 and 356 differentially expressed miRNAs, respectively
The results of In situ hybridization (ISH) showed that the expression of miR-182-5p in breast cancer tissue samples was elevated compared to adjacent normal tissues (Fig. 1F, Additional file 2: Fig. S1), and the expression of miR-182-5p in breast cancer tissues with distant metastasis was significantly higher than that in breast cancer tissues without distant metastasis (Fig. 1G, H)
Summary
Breast cancer is the most frequently diagnosed cancer worldwide (Harbeck and Gnant 2017) and represents a leading cause of premature mortality among women, Lu et al Mol Med (2021) 27:78 risk factors for which include race, ethnicity, family history and genetic traits, along with excess alcohol consumption, physical inactivity and exogenous hormones (Coughlin 2019). Tumor cellderived EVs hold great potential for clinical application in cancer early diagnosis, prognosis, and treatment response due to their properties to transferring the one of bioactive cargoes microRNAs (miRNAs) to recipient cells (Rahbarghazi 2019). MiR-182 inhibition contributes to suppressed epithelial-mesenchymal transition, invasion and migration of breast cancer cells in vitro along with tumor growth in vivo (Mao 2020). The inhibited EGFR/AKT signaling pathway is responsible for the anti-proliferative and anti-migration activities of actein on breast cancer cells (Wu 2018). On the basis of above literature and findings, we proposed the hypothesis that breast cancer cell derived-encapsulated miR-182-5p regulates the CMTM7/EGFR/AKT signaling pathway, contributing to the development and progression of breast cancer. Extracellular vesicles (EVs) derived from tumor cells are implicated in the progression of malignancies through the transfer of molecular cargo microRNAs (miRNAs or miRs). We aimed to explore the role of EVs derived from breast cancer cells carrying miR-182-5p in the occurrence and development of breast cancer
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