Human umbilical cord mesenchymal stem cells-derived exosomes deliver microRNA-375 to downregulate ENAH and thus retard esophageal squamous cell carcinoma progression

He, Zhao; Li, Weihao; Zheng, Tianliang; Liu, Donglei; Zhao, Song

doi:10.1186/s13046-020-01631-w

Cited by 73 publications

(42 citation statements)

References 41 publications

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“…Exosomes secreted from HeLa cells can destroy endothelial barriers to facilitate tumor metastasis by inducing endoplasmic reticulum stress in endothelial cells (52). Exosomal miR-375 has also been validated to serve as a communicator mediating the crosstalk between different cells in the tumor microenvironment, thus affected the biological functions of exosome-recipient cells such as tumor cells (31) and fibroblasts (30). In our research, we revealed that miR-375-3p was enwrapped into exosomes by SCLC cells and delivered to vascular endothelial cells, and this communication was visualized under a fluorescence microscope.…”

Section: Discussionmentioning

confidence: 99%

“…Besides, exosomal miR-375 secreted by Merkel cell carcinoma could induce fibroblast polarization to construct a pro-tumorigenic microenvironment by targeting RBPJ and p53 (30). Exosomal miR-375 derived from umbilical cord mesenchymal stem cells could inhibit esophageal squamous cell carcinoma progression via inhibiting ENAH (31). These researches underlined the importance of exosomal miR-375 in cell communications and tumor progressions, but its role in SCLC has never been explored.…”

Section: Introductionmentioning

confidence: 99%

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Exosomal miR-375-3p breaks vascular barrier and promotes small cell lung cancer metastasis by targeting claudin-1

Mao

Zheng

et al. 2021

Transl Lung Cancer Res

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Background: High incidence of metastasis is the main cause of death for small cell lung cancer (SCLC), with its underlying molecular mechanisms remain unclear. Exosomal miRNAs are important regulators in metastatic processes of various tumors, but their specific role in SCLC metastasis is unknown.Methods: Small RNA sequencing followed by qRT-PCR verification was used to screen the potential exosomal miRNAs that might mediate SCLC metastasis. SCLC-cell-secreted exosomes were labeled followed by incubating with vascular endothelial cells to evaluate exosome-mediated communication between SCLC cells and vascular endothelial cells. In vitro permeability assay and transendothelial migration assay were applied to investigate the function of exosomal miRNA on vascular endothelial cells. In vivo permeability assay and mouse lung colonization assay were used to verify the effects of exosomal miRNA on vascular barriers and SCLC metastasis in vivo. Proteomics technology, dual-luciferase reporter system together with rescue assays were conducted to excavate the downstream pathways of miRNA.Results: Compared with 57 healthy volunteers and 46 non-small cell lung cancer patients, we identified that the level of exosomal miR-375-3p in 126 SCLC patients was obviously higher and was positively correlated with patient TNM stages. In vitro functional experiments found that SCLC-cell-secreted exosomal miR-375-3p could increase the permeability of vascular endothelial cells and facilitate the transendothelial migration of SCLC cells. In vivo, miR-375-3p-enriched exosomes also destroyed the barrier structure of lung, liver and brain tissues of mice, leaded to an increased blood vessel permeability and finally promoted SCLC metastasis.Mechanistically, SCLC-cell-secreted exosomal miR-375-3p was transferred to vascular endothelial cells. The internalized miR-375-3p broke the tight junction of vascular endothelial cells by directedly binding to the 3'UTR of tight junction protein claudin-1 and negatively regulating its expression. Overexpressing claudin-1 in vascular endothelial cells could rescue the broken vascular barriers induced by miR-375-3p.Conclusions: Our findings underline the crucial roles of exosomal miRNA-375-3p in regulating vascular endothelial barrier integrity and SCLC metastasis. miRNA-375-3p has a great potential to be a novel biomarker monitoring metastasis and guiding clinical therapeutics of SCLC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exosomal miR-375-3p breaks vascular barrier and promotes small cell lung cancer metastasis by targeting claudin-1

Mao

Zheng

et al. 2021

Transl Lung Cancer Res

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“…Based on the existing literature, there is no “gold standard” exosomal miRNA or ideal endogenous molecule for RT-qPCR normalization in body fluids; some studies recommend spiked-in controls, i.e., Caenorhabditis elegans (cel)-miR-39 or cel-miR-54 ( 50 , 51 ). As a classical internal control, U6 is still used to normalize miRNA expression levels in blood or other fluids ( 52 – 54 ). In our study, we used U6 as an internal control, without spiked-in controls.…”

Section: Discussionmentioning

confidence: 99%

MiR-1539 and Its Potential Role as a Novel Biomarker for Colorectal Cancer

Cui

Ding

et al. 2021

Front. Oncol.

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PurposeWe investigated microRNA (miR) 1539 as a potential biomarker for predicting the risk and pathobiological behavior of colorectal cancer (CRC).MethodsOur strategy consisted of analyzing 100 serum samples from 51 CRC patients, 49 healthy controls (HCs), and another 56 CRC tissue and matched normal adjacent to tumor (NAT) samples. The relative expression levels of miR-1539 in exosomes, serum and tissues were detected and compared in the different groups, using reverse transcription-polymerase chain reaction (RT-qPCR). The diagnostic value and potential function of miR-1539 were investigated using clinicopathological data combined with bioinformatics analysis.ResultsMiR-1539 expression was significantly up-regulated in exosomes (p = 0.003) and cancer tissue (p < 0.001) from CRC patients. MiR-1539 expression levels in serum varied according to different tumor sites (right-sided vs. left-sided, p = 0.047; left-side CRC vs. HCs, p = 0.031). In terms of diagnostic efficacy, miR-1539 expression in exosomes may help distinguish CRC cases from HCs with a sensitivity of 92.2%, and miR-1539 expression in serum may improve the specificity to 96.6% for left-sided CRC diagnosis. When combined with clinicopathological data, serum miR-1539 levels were positively associated with vascular endothelial growth factor (VEGF) expression (p = 0.028), whilst levels in CRC tissue were positively associated with increased Ki-67 levels (p = 0.035). Poorer pathologic differentiation was potentially related to an increased tendency of miR-1539 expression in CRC tissue (p = 0.071). Based on our bioinformatics analysis, miR-1539 may have a significant mechanistic influence on CRC genesis and progression.ConclusionsCirculating or tissue based miR-1539 may be used as a novel potential biomarker for CRC screening, and a predictor of poor clinicopathological behavior in tumors.

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“…In addition to these technical and biological challenges facing this research field, another important concern should be taken in consideration regarding the potential protumoral function of MSC-EVs due to their contents of a spectrum of biological factors (e.g., IL-6) that can promote proliferation, angiogenic activity, and motility of cancer cells and foster the immunosuppressive and metastatic niches (DeNardo and Ruffell 2019; Ren et al 2019; Valenzuela Alvarez et al 2019). Interestingly, recent studies have shown that MSC-EVs inhibit angiogenesis, tumor growth, and progression in oral and esophageal squamous cell carcinoma (Rosenberger et al 2019; He et al 2020). According to these important findings, it is worthwhile to further explore the potential effects of GMSC-EVs on tumor growth, angiogenesis, and metastasis both in vitro and in vivo so as to guarantee the biosafety before translation into clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles of GMSCs Alleviate Aging-Related Cell Senescence

et al. 2020

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Healthy aging is a complex biological process with progressive accumulation of senescent cells characterized by stable cell cycle arrest, resulting in impaired homeostasis, regenerative potential, and gradual functional decline in multiple tissues and organs, whereby the aberrant activation of mammalian target of rapamycin (mTOR) signaling networks plays a central role. Herein, we explored the effects of extracellular vesicles (EVs) released by gingiva-derived mesenchymal stem cells (GMSC-EVs) on oxidative stress–induced cellular senescence in human endothelial cells and skin fibroblasts and their antiaging potentials. Our results showed that GMSC-EVs robustly abrogated oxidative stress–induced upregulation in the expression of cellular senescence-related genes, such as β-galactosidase, p21, p53, and γH2AX, and mTOR/pS6 signaling pathway, in human umbilical vein endothelial cells (HUVECs) and skin fibroblasts. Meanwhile, GMSC-EVs restored oxidative stress–induced impairment in proliferation and tube formation by HUVECs. Systemic administration of GMSC-EVs attenuated aging-associated elevation in the expression levels of p21, mTOR/pS6, interleukin 6, and tumor necrosis factor α in skin and heart tissues of aged mice. These findings suggest that GMSC-EVs could be a potential alternative source of cell-free product for attenuation of aging-related skin and vascular dysfunctions due to their potent inhibitory effects on oxidative stress–induced cellular senescence in endothelial cells and skin fibroblasts.

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Human umbilical cord mesenchymal stem cells-derived exosomes deliver microRNA-375 to downregulate ENAH and thus retard esophageal squamous cell carcinoma progression

Cited by 73 publications

References 41 publications

Exosomal miR-375-3p breaks vascular barrier and promotes small cell lung cancer metastasis by targeting claudin-1

Exosomal miR-375-3p breaks vascular barrier and promotes small cell lung cancer metastasis by targeting claudin-1

MiR-1539 and Its Potential Role as a Novel Biomarker for Colorectal Cancer

Extracellular Vesicles of GMSCs Alleviate Aging-Related Cell Senescence

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