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Exosomes Derived from miR-143-Overexpressing MSCs Inhibit Cell Migration and Invasion in Human Prostate Cancer by Downregulating TFF3.

ABSTRACT: Exosomes are membrane-enclosed nanovesicles that shuttle active cargoes, such as mRNAs and microRNAs (miRNAs), between different cells. Mesenchymal stem cells (MSCs) are able to migrate to the tumor sites and exert complex functions over tumor progress. We investigated the effect of human bone marrow-derived MSC (BMSC)-derived exosomal miR-143 on prostate cancer. During the co-culture experiments, we disrupted exosome secretion by the inhibitor GW4869 and overexpressed exosomal miR-143 using miR-143 plasmid. miR-143 was involved in the progression of prostate cancer via trefoil factor 3 (TFF3). Moreover, miR-143 was downregulated while TFF3 was upregulated in prostate cancer cells and tissues, and miR-143 was found to specifically inhibit TFF3 expression. Human MSC-derived exosomes enriched miR-143 and transferred miR-143 to prostate cancer cells. Furthermore, elevated miR-143 or exosome-miR-143 or silencing TFF3 inhibited the expression of TFF3, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase (MMP)-2, and MMP-9 and PC3 cell proliferation, migration, invasion, and tumor growth, whereas it promoted apoptosis. In conclusion, hMSC-derived exosomal miR-143 directly and negatively targets TFF3 to suppress prostate cancer.

SUBMITTER: Che Y

PROVIDER: S-EPMC6796755 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Exosomes Derived from miR-143-Overexpressing MSCs Inhibit Cell Migration and Invasion in Human Prostate Cancer by Downregulating TFF3.

Che Yuanyuan Y Shi Xu X Shi Yunpeng Y Jiang Xiaoming X Ai Qing Q Shi Ying Y Gong Fengyan F Jiang Wenyan W

Molecular therapy. Nucleic acids 20190816

Exosomes are membrane-enclosed nanovesicles that shuttle active cargoes, such as mRNAs and microRNAs (miRNAs), between different cells. Mesenchymal stem cells (MSCs) are able to migrate to the tumor sites and exert complex functions over tumor progress. We investigated the effect of human bone marrow-derived MSC (BMSC)-derived exosomal miR-143 on prostate cancer. During the co-culture experiments, we disrupted exosome secretion by the inhibitor GW4869 and overexpressed exosomal miR-143 using miR ...[more]

PMID: 31563120

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Project description:BackgroundMalignant behavior and radioresistance, which severely limits the efficacy of radiation therapy (RT) in nasopharyngeal carcinoma (NPC), are associated with tumor progression and poor prognosis. Mesenchymal stem cells (MSCs) are used as a therapeutic tool in a variety of tumors. The aim of this study was to reveal the effect of tumor suppressor microRNA-34c-5p (miR-34c) on NPC development and radioresistance, as well as to confirm that exosomes derived from MSCs overexpressing miR-34c restore the sensitivity to radiotherapy in NPCs.MethodsPotentially active microRNAs were screened by cell sequencing, Gene Expression Omnibus (GEO) database analysis, and analysis of clinical serum samples from 70 patients. The expression of genes and proteins was detected by Western blotting, quantitative reverse transcription PCR (qRT-PCR), and immunohistochemistry (IHC). Proliferation, apoptosis, invasion, migration and radioresistance of NPC were detected. Luciferase reporter assays were used to verify the interactions of microRNAs with their downstream targets. MSCs exosomes were isolated by ultrafiltration and verified by electron microscopy and nanoparticle tracking technology.ResultsThe expression of miR-34c was associated with the occurrence and radiation resistance of NPC. In vitro and in vivo experiments indicated that overexpression of miR-34c inhibit malignant behavior such as invasion, migration, proliferation and epithelial-mesenchymal transition (EMT) in NPCs by targeting β-Catenin. In addition, we found alleviated radioresistance upon miR-34c overexpression or β-catenin knockdown in NPCs. Exosomes derived from miR-34c-transfected MSCs attenuated NPC invasion, migration, proliferation and EMT. Moreover, miR-34c-overexpressing exosomes drastically increased radiation-induced apoptosis in NPC cells.ConclusionmiR-34c is a tumor suppressor miR in NPC, which inhibits malignant behavior as well as radioresistance of tumor. Therefore, exogenous delivery of miR-34c to NPCs via MSC exosomes inhibits tumor progression and increases the efficiency of RT. Combination IR with miR-34c-overexpressing exosomes may be effective treatment for radioresistant NPCs.

Project description:Background:MicroRNAs (miRNAs) serve as important regulators of the tumorigenesis and progression of many human cancers. Therefore, we evaluated the biological function and underlying mechanism of miR-363 in clear cell renal cell carcinoma (ccRCC). Methods:The expression of miR-363 in ccRCC tissues compared with adjacent normal renal tissues was detected by quantitative real-time polymerase chain reaction, and the association between miR-363 levels and prognosis of ccRCC patients was analyzed. The candidate target gene of miR-363 was determined by in silico analysis and luciferase reporter assays. The effects of miR-363 on the proliferation, migration and invasion of ccRCC cells in vitro were determined by MTS assay, colony formation assay, Transwell assay and wound healing assay. We also investigated the roles of miR-363 in vivo by a xenograft tumour model. The mechanism of miR-363 on the proliferation, migration and invasion of ccRCC was determined by gain- and loss-of-function analyses. Results:we demonstrated that miR-363 expression was obviously downregulated in ccRCC tissues and that reduced miR-363 expression was correlated with poor disease-free survival (DFS) in ccRCC patients after surgery. S1PR1 expression was inversely correlated with the level of miR-363 in human ccRCC samples. Luciferase reporter assays suggested that S1PR1 was a direct functional target of miR-363. miR-363 downregulated S1PR1 expression and suppressed the proliferation, migration and invasion abilities of ccRCC cells in vitro and suppressed xenograft tumour growth in vivo. Importantly, miR-363 exerted its biological function by inhibiting S1PR1 expression in ccRCC cells, leading to the repression of ERK activation. Moreover, we found that the levels of downstream effectors of ERK, including PDGF-A, PDGF-B, and epithelial-mesenchymal transition (EMT)-related genes, were decreased after miR-363 overexpression. Conclusions:Our results suggest that miR-363 acts as a tumour suppressor by directly targeting S1PR1 in ccRCC and may be a potential new therapeutic target for ccRCC.

Dataset Information

Exosomes Derived from miR-143-Overexpressing MSCs Inhibit Cell Migration and Invasion in Human Prostate Cancer by Downregulating TFF3.

Publications

Exosomes Derived from miR-143-Overexpressing MSCs Inhibit Cell Migration and Invasion in Human Prostate Cancer by Downregulating TFF3.

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