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Tumor-derived exosomal miR-3157-3p promotes angiogenesis, vascular permeability and metastasis by targeting TIMP/KLF2 in non-small cell lung cancer.

ABSTRACT: Metastasis is the main cause of death in patients with advanced lung cancer. The exosomes released by cancer cells create tumor microenvironment, and then accelerate tumor metastasis. Cancer-derived exosomes are considered to be the main driving force for metastasis niche formation at foreign sites, but the mechanism in Non-small cell lung carcinoma (NSCLC) is unclear. In metastatic NSCLC patients, the expression level of miR-3157-3p in circulating exosomes was significantly higher than that of non-metastatic NSCLC patients. Here, we found that miR-3157-3p can be transferred from NSCLC cells to vascular endothelial cells through exosomes. Our work indicates that exosome miR-3157-3p is involved in the formation of pre-metastatic niche formation before tumor metastasis and may be used as a blood-based biomarker for NSCLC metastasis. Exosome miR-3157-3p has regulated the expression of VEGF/MMP2/MMP9 and occludin in endothelial cells by targeting TIMP/KLF2, thereby promoted angiogenesis and increased vascular permeability. In addition, exosome miR-3157-3p promoted the metastasis of NSCLC in vivo.

SUBMITTER: Ma Z

PROVIDER: S-EPMC8426367 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Tumor-derived exosomal miR-3157-3p promotes angiogenesis, vascular permeability and metastasis by targeting TIMP/KLF2 in non-small cell lung cancer.

Ma Zijian Z Wei Ke K Yang Fengming F Guo Zizhang Z Pan Chunfeng C He Yaozhou Y Wang Jun J Li Zhihua Z Chen Liang L Chen YiJiang Y Xia Yang Y

Cell death & disease 20210908 9

Metastasis is the main cause of death in patients with advanced lung cancer. The exosomes released by cancer cells create tumor microenvironment, and then accelerate tumor metastasis. Cancer-derived exosomes are considered to be the main driving force for metastasis niche formation at foreign sites, but the mechanism in Non-small cell lung carcinoma (NSCLC) is unclear. In metastatic NSCLC patients, the expression level of miR-3157-3p in circulating exosomes was significantly higher than that of ...[more]

PMID: 34497265

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Project description:BackgroundHigh 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.MethodsSmall 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.ResultsCompared 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.ConclusionsOur 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.

Project description:BackgroundMetastasis is the main cause of death in colorectal cancer (CRC). Circulating tumour cells (CTCs) are regarded as the precursor cells of metastasis. The CTCs, which underwent epithelial-mesenchymal transition (EMT), are associated with metastasis and responsible for poor prognosis. EMT cancer cells modulate endothelial permeability in the invasive front and facilitate cancer cell intravasation, resulting in CTCs-mediated distant metastasis. Exosomes derived from cancer cells are key mediators of cancer-host intercommunication. However, the mechanism by which EMT-tumour cells-derived exosomes modulate vascular permeability and promote CTCs generation has remained unclear.MethodsExosomes isolation and purification were conducted by ultra-centrifugation. Exosomal miRNA was identified by sequencing followed by quantitative PCR. In vitro co-culture assay experiments were conducted to evaluate the effect of exosomal miR-27b-3p on the permeability of blood vessel endothelium. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) and RNA immunoprecipitation (RIP) were performed to investigate the underlying mechanism by which miR-27b-3p is packaged into exosomes. A mouse model was established to determine the role of exosomal miR-27b-3p in blood vessel permeability modulation in vivo.ResultsWe found that EMT-CRC cells attenuate the blood vessel barrier by transferring miR-27b-3p to human umbilical vein endothelial cells (HUVECs) in exosomes. Mechanically, miR-27b-3p atteuated the expression of vascular endothelial cadherin (VE-Cad) and p120 at the post-transcriptional level by binding to 3'-untranslated region of VE-Cad and p120 directly. The packaging of miR-27b-3p into exosomes was induced by heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which activated by STAT3. Clinically, miR-27b-3p up-regulated in CRC tissues. Plasma exosomal miR-27b-3p was positively correlated with malignant progression and CTC count in CRC patients. Our study reveals a novel mechanism by which EMT-CRC cells promote metastasis, increasing blood vessel permeability and facilitating the generation of CTCs.ConclusionExosomal miR-27b-3p secreted by EMT-CRC cells increases blood vessel permeability and facilitates the generation of CTCs. Exosomal miR-27b-3p may become a promising biomarker for CRC metastasis.

Project description:BackgroundmiR-103a-3p has been reported to be a factor leading to poor prognosis in several human malignancies, including nasopharyngeal carcinoma (NPC). Secreted microRNAs containing exosomes may mediate the communication between cancer and stromal cells. The purpose of the current work was to learn more about miR-103a-3p's function in NPC exosomes.MethodsTransmission electron microscopy and NanoSight analysis were used to verify the existence of exosomes. To determine the relationship between exosomal miR-103a-3p and carcinogenesis in NPC, gain- and loss-of-function studies were carried out. Cell Counting Kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay, colony formation, flow cytometry, trans-endothelial invasion assays, endothelial permeability and cellular immunofluorescence were used to identify roles of exosomal miR-103a-3p in vitro. Zebrafish assay was used to disclose the effect of exosomal miR-103a-3p in vivo. Bioinformatics and dual-luciferase reporter assay were applied to clarify the mechanism of exosomal miR-103a-3p regulating the crosstalk between NPC cells and human umbilical vein endothelial cells (HUVECs).ResultsIn the present study, we first demonstrated that the overexpression of exosomal miR-103a-3p improved NPC cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) progression in vitro. Then, we verified that NPC cell-derived exosomal miR-103a-3p destroyed the integrity of the endothelial monolayer in vitro and in vivo by downregulating zonula occludens 1 (ZO-1) expression. Moreover, we revealed that miR-103a-3p containing exosomes facilitated NPC cell proliferation through lipid droplet accumulation by direct target to metabolic enzyme acyl-CoA oxidase 1 (ACOX-1).ConclusionsOur data demonstrate that exosomal miR-103a-3p can facilitate the development of NPC by regulating the crosstalk between NPC cells and HUVECs. Exosomal miR-103a-3p could potentially serve as a therapeutic target for NPC.

Dataset Information

Tumor-derived exosomal miR-3157-3p promotes angiogenesis, vascular permeability and metastasis by targeting TIMP/KLF2 in non-small cell lung cancer.

Publications

Tumor-derived exosomal miR-3157-3p promotes angiogenesis, vascular permeability and metastasis by targeting TIMP/KLF2 in non-small cell lung cancer.

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