Abstract
BackgroundAngiogenesis, 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.MethodsTotal 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.ResultsCirculating 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.ConclusionsOur 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.
Highlights
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
Our research reveals novel details elaborating the mechanism of exosomal miR141 in SCLC angiogenesis and offers a promising clue for identifying effective antiangiogenic targets to improve the prognosis of SCLC patients
MiR-141 is aberrantly upregulated in the plasma and serum of SCLC patients To better understand the clinical importance of miR-141 in patients with SCLC, we measured the expression of miR-141 in both plasma and serum samples
Summary
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. 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. SCLC is a highly aggressive neuroendocrine tumor characterized by uncontrolled fast tumor growth, abundant neoangiogenesis, early metastasis, drug resistance and early disease relapse, which together lead to extremely poor outcomes for SCLC patients [3, 4]. Further exploration of the molecular mechanisms of SCLC-associated angiogenesis might help to clarify the complex angiogenetic processes in SCLC microenvironment which might broaden our knowledge about SCLC malignancy and have potential value in promoting the development of effective antiangiogenic therapeutics in SCLC patients
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