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Exosomal miR-34b inhibits proliferation and the epithelial-mesenchymal transition by targeting Notch2 in ovarian cancer.

ABSTRACT: Exosomal microRNA (miR) can affect signaling pathways in various physiological and pathological conditions, including ovarian cancer (OC). miR-34b, the first microRNA targeted in a human clinical trial for cancer treatment, exhibited decreased expression in several cancer types. However, the biological function of exosomal miR-34b in OC has not been elucidated. In the present study, using reverse transcription-quantitative PCR, it was reported that exosomal miR-34b is downregulated in OC cells. Exosomal miR-34b reduced cell proliferation and epithelial-mesenchymal transition (EMT) in the OC cell line SKOV3. In addition, it was confirmed that Notch2, which is upregulated in SKOV3 cells, is a target of miR-34b. Moreover, exosomal miR-34b and Notch2 levels were found to be negatively correlated. The present data highlights the importance of exosomal miR-34b-mediated inhibition of cell proliferation and EMT, suggesting that exosomal miR-34b has value as a diagnostic biomarker and a potential molecular target for the treatment of OC.

SUBMITTER: Lu S

PROVIDER: S-EPMC7400462 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Exosomal miR-34b inhibits proliferation and the epithelial-mesenchymal transition by targeting Notch2 in ovarian cancer.

Lu Shenglian S Liu Wuxia W Shi Hong H Zhou Han H

Oncology letters 20200709 3

Exosomal microRNA (miR) can affect signaling pathways in various physiological and pathological conditions, including ovarian cancer (OC). miR-34b, the first microRNA targeted in a human clinical trial for cancer treatment, exhibited decreased expression in several cancer types. However, the biological function of exosomal miR-34b in OC has not been elucidated. In the present study, using reverse transcription-quantitative PCR, it was reported that exosomal miR-34b is downregulated in OC cells. ...[more]

PMID: 32782588

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Project description:Purpose: Circular RNAs (circRNAs) have been reported to regulate the incidence of tumor by regulating the transcriptional level and post-transcriptional level of tumor-related genes, and are significantly correlated with tumor metastasis and progression. CircRNA_100395 (circ_100395) has been reported to suppress lung cancer cell proliferation, and might act as an oncogene in deveopment of various cancers. However, the expression and function of circ_100395 in ovarian cancer has not been systematically researched. Methods: The expression of circ_100395 in ovarian cancer tissues was detected by Real-time Quantitative polymerase chain reaction (RT-qPCR), while the relationship between circ_100395 expression and clinicopathological characteristics was further analyzed. After increasing the expression of circ_100395 by plasmid transfection in ovarian cancer cells, we further investigated the cell proliferation, invasion and migration by cell counting kit-8 (CCK-8), and Transwell assays. Epithelial-mesenchymal transition (EMT) pathway was also measured by western blotting. In addition, the relationship among circ_100395, miR-1228 and p53 in ovarian cancer, was explored by luciferase reporter assay. Results: The expression of circ_100395 was found to be significantly down-regulated in ovarian cancer, while low expression of circ_100395 was highly correlated with the poor outcomes. In addition, upregulation of circ_100395 could significantly inhibit tumor growth, metastasis and EMT signaling pathway in ovarian cancer. Furthermore, the expression level of circ_100395 was negatively correlated with the expression of miR-1228, and with the addition of miR-1228 could reverse anti-cell proliferation effect induced by circ_100395 in ovarian cancer cells. In addition, p53 might be the key target of circ_100395 / miR-1228 axis in ovarian cancer. Conclusion: CircRNA_100395 could inhibit cell growth and metastasis of ovarian cancer cells via regulating the miR-1228/p53/EMT axis.

Project description:The limb-bud and heart (LBH) gene was reported to suppress nasopharyngeal carcinoma (NPC) progression in our previous study. Distant metastasis predominantly accounts for the unsatisfactory prognosis of NPC treatment, in which epithelial-mesenchymal transition (EMT) and tumor angiogenesis are of great significance. The roles of exosomes in mediating NPC progression have been highlighted in recent researches, and attempts have been made to explore the clinical application of NPC exosomes. Here we investigated the function of the LBH gene in NPC exosomes, and its potential mechanism. NPC xenografts were constructed, showing that vascular endothelial growth factor A (VEGFA) expression and neovascularity were attenuated by LBH overexpression, together with diminished EMT progression. NPC-derived exosomes were isolated, identified and applied for in vitro/in vivo experiments, and the exosomal distribution of LBH was elevated in exosomes derived from LBH-upregulated cells. Ectopic LBH, αB-crystallin (CRYAB) and VEGFA expression was induced by lentiviral infection or plasmid transfection to explore their functions in modulating EMT and angiogenesis in NPC. The addition of LBH+ NPC exosomes during a Matrigel plug assay in mice suppressed in vivo angiogenesis, and the treatment of human umbilical vein endothelial cells (HUVECs) with LBH+ NPC exosomes inhibited cellular proliferation, migration and tube formation. The interactions among LBH, CRYAB and VEGFA were confirmed by colocalization and fluorescence resonance energy transfer (FRET) assays, and extracellular VEGFA secretion from both HUVECs and NPC cells under the treatment with LBH+ NPC exosomes was diminished according to ELISA results. We concluded that exosomal LBH inhibits EMT progression and angiogenesis in the NPC microenvironment, and that its effects are partially implemented by modulation of VEGFA expression, secretion and related signaling. Thus, LBH could serve as a promising therapeutic target in VEGFA-focused NPC treatment.

Dataset Information

Exosomal miR-34b inhibits proliferation and the epithelial-mesenchymal transition by targeting Notch2 in ovarian cancer.

Publications

Exosomal miR-34b inhibits proliferation and the epithelial-mesenchymal transition by targeting Notch2 in ovarian cancer.

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