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MiR-200-containing extracellular vesicles promote breast cancer cell metastasis.

ABSTRACT: Metastasis is associated with poor prognosis in breast cancer patients. Not all cancer cells within a tumor are capable of metastasizing. The microRNA-200 (miR-200) family, which regulates the mesenchymal-to-epithelial transition, is enriched in the serum of patients with metastatic cancers. Ectopic expression of miR-200 can confer metastatic ability to poorly metastatic tumor cells in some settings. Here, we investigated whether metastatic capability could be transferred between metastatic and nonmetastatic cancer cells via extracellular vesicles. miR-200 was secreted in extracellular vesicles from metastatic murine and human breast cancer cell lines, and miR-200 levels were increased in sera of mice bearing metastatic tumors. In culture, murine and human metastatic breast cancer cell extracellular vesicles transferred miR-200 microRNAs to nonmetastatic cells, altering gene expression and promoting mesenchymal-to-epithelial transition. In murine cancer and human xenograft models, miR-200-expressing tumors and extracellular vesicles from these tumors promoted metastasis of otherwise weakly metastatic cells either nearby or at distant sites and conferred to these cells the ability to colonize distant tissues in a miR-200-dependent manner. Together, our results demonstrate that metastatic capability can be transferred by the uptake of extracellular vesicles.

SUBMITTER: Le MT

PROVIDER: S-EPMC4348969 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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miR-200-containing extracellular vesicles promote breast cancer cell metastasis.

Le Minh T N MT Hamar Peter P Guo Changying C Basar Emre E Perdigão-Henriques Ricardo R Balaj Leonora L Lieberman Judy J

The Journal of clinical investigation 20141117 12

Metastasis is associated with poor prognosis in breast cancer patients. Not all cancer cells within a tumor are capable of metastasizing. The microRNA-200 (miR-200) family, which regulates the mesenchymal-to-epithelial transition, is enriched in the serum of patients with metastatic cancers. Ectopic expression of miR-200 can confer metastatic ability to poorly metastatic tumor cells in some settings. Here, we investigated whether metastatic capability could be transferred between metastatic and ...[more]

PMID: 25401471

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Project description: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.

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MiR-200-containing extracellular vesicles promote breast cancer cell metastasis.

Publications

miR-200-containing extracellular vesicles promote breast cancer cell metastasis.

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