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Tumor-derived exosomal miRNA-141 promote angiogenesis and malignant progression of lung cancer by targeting growth arrest-specific homeobox gene (GAX).

ABSTRACT: Previous researches have suggested that exosomal miRNA-141 has association with metastatic lung cancer, however, its role and regulatory mechanism require further study. In this study, exosomes were isolated from lung cancer patients and normal human serum and identified. We found that the expression of miRNA-141 was up-regulated in the lung cancer serum exosomes compared with the normal serum exosomes. When the exosomes were extracted for co-culture with HUVECs, they were absorbed and distributed around the nucleus by confocal microscopy. Moreover, exosomal miRNA-141 from A549 significantly not only promoted the migration and invasion of A549 but also increased the cell proliferation, tube formation of HUVECs. In order to reveal the mechanism of exosomal miRNA-141, bioinformatics analysis revealed that miRNA-141 targeted the binding of Growth arrest-specific homeobox gene (GAX) in the 3'UTR region, and confirmed by MS2-RIP assay and dual-luciferase assay. Exosome miRNA-141 could down-regulate the expression of GAX. Taken together, our results demonstrate that tumor-derived exosomal miRNA-141 promote angiogenesis and malignant progression of lung cancer by targeting GAX. It provides a new possibility for the treatment of lung cancer.

SUBMITTER: Wang W

PROVIDER: S-EPMC8291845 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Angiogenesis, a basic requirement for tumor cell survival, is considered to be a malignant characteristic of small cell lung cancer (SCLC) and is closely related to the poor outcomes of SCLC patients. miR-141 has been found to play pro- and antiangiogenic roles in different cancers, but its role in SCLC angiogenesis has never been explored. METHODS:Total RNA was isolated from plasm exosomes and serum of SCLC patients to examine the expression of miR-141 by qRT-PCR. Cell proliferation, invasion, migration, tube formation assay, aortic ring assay and mouse tumor model were used to investigate the effect of exosomal miR-141 in angiogenesis in vitro and in vivo. Dual-luciferase assay was conducted to explore the target gene of miR-141. RESULTS:Circulating miR-141 was upregulated in samples from 122 SCLC patients compared with those from normal volunteers and that the increase in miR-141 was significantly associated with advanced TNM stages, implying the potential oncogenic role of miR-141 in SCLC malignancy. In vitro, miR-141 that was packaged into SCLC cell-secreted exosomes and delivered to human umbilical vein vascular endothelial cells (HUVECs) via exosomes facilitated HUVEC proliferation, invasion, migration and tube formation and promoted microvessel sprouting from mouse aortic rings. Matrigel plug assays demonstrated that SCLC cell-derived exosomal miR-141 induced neoangiogenesis in vivo. Furthermore, mouse subcutaneous tumor nodules that were developed from miR-141-overexpressing SCLC cells had a higher microvessel density (MVD) and grew faster than those developed from negative control cells. KLF12 was found to be the direct target gene of miR-141 and that the proangiogenic effect of miR-141 on HUVECs was abrogated by KLF12 overexpression. CONCLUSIONS:Our results demonstrate the specific function of the exosomal miR-141/KLF12 pathway in SCLC angiogenesis for the first time and provide potential novel targets for antiangiogenic therapies for SCLC patients.

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Tumor-derived exosomal miRNA-141 promote angiogenesis and malignant progression of lung cancer by targeting growth arrest-specific homeobox gene (GAX).

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