Breast cancer cell-derived extracellular vesicles transfer miR-182-5p and promote breast carcinogenesis via the CMTM7/EGFR/AKT axis

Abstract

Background 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. Methods Differentially 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. Results miR-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. Conclusions Taken 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.

Insights into the Steps of Breast Cancer–Brain Metastases Development: Tumor Cell Interactions with the Blood–Brain Barrier

“…EVs contain bioalogical molecules, such as nucleic acids (DNA, mRNA, microRNA, and other noncoding RNAs), proteins (receptors, transcription factors, enzymes, and extracellular matrix proteins), and lipids that can influence target cells such as brain endothelial cells [47,48]. Several studies already described the composition of the EVs for both the parental cell line MDA-MB-231 [49,50] and the brain-seeking subline MDA-MB-231-BR [51] to demonstrate a possible EV-dependent brain-metastatic-specific effect. Rodrigues et al reveal only twenty proteins to be differentially expressed in brain-seeking breast cancer cell EVs (MDA-MB-231-BR) compared to the corresponding parental cell line EVs (MDA-MB-231).…”

Comprehensive Analyses of miRNAs Revealed miR-92b-3p, miR-182-5p and miR-183-5p as Potential Novel Biomarkers in Melanoma-Derived Extracellular Vesicles

“…Several functional studies in different entities have shown that miR-183-5p, miR-182-5p, miR-221-3p and the miR-17-92 cluster induce angiogenesis when taken up by epithelial or endothelial cells. This was achieved through the inhibition of factors as FOXO1 ( 71 ), CMTM7 ( 69 ), VASH1 ( 17 ), THBS2 ( 73 ), SOCS3 ( 75 ), PIK3R1 ( 76 ), TSP-1 and CTGF ( 77 ).…”

Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches

“…Growing evidence points to the role of tumor-derived extracellular vesicles in tumor angiogenesis of breast cancer. Lu et al recently reported that extracellular vesicles derived from breast cancer cells are highly enriched with miRNA-182-5p which enhanced proliferation and migration of endothelial cells in vitro and angiogenesis and metastasis of breast cancer in vivo (Lu et al, 2021). Microvesicles rich in a special VEGF isoform activated VEGFR and induced angiogenesis while being resistant to bevacizumab (Feng et al, 2017).…”