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Exosomal long non-coding RNA DLX6-AS1 as a potential diagnostic biomarker for non-small cell lung cancer.

ABSTRACT: Distal-less homeobox 6 antisense RNA 1 (DLX6-AS1) is upregulated in various solid tumors and serves a critical role in the tumorigenesis of cancer. However, to the best of our knowledge, the expression of circulating DLX6-AS1 and its role in the diagnosis of non-small cell lung cancer (NSCLC) have not been previously clarified. The aim of the present study was to investigate the expression and clinical significance of circulating DLX6-AS1 using reverse transcription-quantitative PCR in serum and exosomes derived from patients with NSCLC and healthy donors. The diagnostic value of circulating DLX6-AS1 was identified by receiver operating characteristic curve (ROC) analysis. First, it was revealed that the expression levels of DLX6-AS1 were significantly increased in tumor tissues compared with in adjacent normal tissues. In addition, DLX6-AS1 was highly expressed in NSCLC cell lines compared with in BEAS-2B cells. DLX6-AS1-knockdown inhibited cell proliferation and migration in vitro. It was subsequently demonstrated that the serum DLX6-AS1 level was significantly higher in patients with NSCLC compared with in healthy controls. Additionally, the higher DLX6-AS1 expression was associated with advanced disease stage, positive lymph node metastasis and poor tumor differentiation of NSCLC. ROC analysis demonstrated that the sensitivity and specificity of DLX6-AS1 were higher than those of CYFRA21-1, which is a serum marker for NSCLC. Finally, exosomal DLX6-AS1 expression was increased in patients with NSCLC compared with in healthy controls. The present data implied that circulating DLX6-AS1 was mainly incorporated into exosomes, providing a novel potential diagnostic marker for NSCLC.

SUBMITTER: Zhang X

PROVIDER: S-EPMC6781719 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Exosomal long non-coding RNA DLX6-AS1 as a potential diagnostic biomarker for non-small cell lung cancer.

Zhang Xilin X Guo Huihui H Bao Ying Y Yu Huanming H Xie Dong D Wang Xiang X

Oncology letters 20190919 5

Distal-less homeobox 6 antisense RNA 1 (DLX6-AS1) is upregulated in various solid tumors and serves a critical role in the tumorigenesis of cancer. However, to the best of our knowledge, the expression of circulating DLX6-AS1 and its role in the diagnosis of non-small cell lung cancer (NSCLC) have not been previously clarified. The aim of the present study was to investigate the expression and clinical significance of circulating DLX6-AS1 using reverse transcription-quantitative PCR in serum and ...[more]

PMID: 31612030

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Project description:Aim:Traditional non-invasive diagnostic markers for gastric cancer (GC) exhibit insufficient sensitivity and specificity. Circulating exosomes are clinically useful non-invasive biomarkers for tumor diagnosis. In addition to their potential role in cancer biology, circulating long non-coding RNAs (lncRNAs) are a new class of promising cancer biomarkers. In the present study, we aimed to identify lncRNAs in circulating exosomes with potential as biomarkers for GC detection. Methods:We compared the expression of CEBPA-AS1 between GC cells and gastric epithelial cells. The biological function of exosomal CEBPA-AS1 was determined by cell phenotype experiments and rescue assays. We also compared the expression of CEBPA-AS1 in cancerous tissue from GC patients and corresponding adjacent normal tissues, as well as the expression of CEBPA-AS1 in plasma exosomes of GC patients and healthy controls. Diagnostic accuracy was assessed by the receiver operating characteristic (ROC) curve and area under the curve (AUC). Results:CEBPA-AS1 was highly expressed in both GC cells and in exosomes secreted by GC cells. In addition, CEBPA-AS1-containing exosomes secreted by GC cells could promote cell proliferation and inhibit apoptosis, thereby inducing the malignant behavior of GC cells. The level of CEBPA-AS1 was also significantly increased in tissues and plasma exosomes of GC patients. Stability tests showed that most plasma CEBPA-AS1 was encased in exosomes, thus avoiding degradation by RNases. We evaluated the diagnostic accuracy of exosome-derived CEBPA-AS1. The AUC value of CEBPA-AS1 in discriminating GC patients from healthy controls was 0.824, which was higher than the diagnostic accuracy of other traditional tumor biomarkers. Conclusion:CEBPA-AS1-containing exosomes secreted from GC cells could promote cell proliferation, inhibit apoptosis, and induce GC progression, indicating that exosomal CEBPA-AS1 is involved in cell-to-cell communication in GC carcinogenesis. Exosomal CEBPA-AS1 is a promising new biomarker for clinical diagnosis of GC.

Project description:Recent evidence has proven that long noncoding RNAs (lncRNAs) play important roles in cancer biology, while few lncRNAs have been characterized in NSCLC. Here, we characterized a novel lncRNA, SBF2 antisense RNA 1 (SBF2-AS1), in non-small cell lung cancer (NSCLC).Quantitative real-time PCR was used to quantify SBF2-AS1 expression in NSCLC tissues and cell lines. The correlation of SBF2-AS1 expression with clinicopathologic features was analyzed in a cohort NSCLC patient. Loss of function and gain of function studies were performed to determine the effects of SBF2-AS1 on proliferation and metastasis of NSCLC cells. RNA immunoprecipitation and chromosome immunoprecipitation assay was performed to confirm the interaction between SBF2-AS1 with protein and chromosome.We confirmed that SBF2-AS1 was significantly upregulated in NSCLC compared with corresponding non-tumor tissues, and a high expression level of SBF2-AS1 was correlated with lymph node metastasis and advanced TNM stage. Using siRNAs specifically targeting SBF2-AS1 and plasmid vector, we successfully silenced and overexpressed SBF2-AS1 in NSCCLC cell lines and investigated its biological function both in vitro and in vivo. After the silencing of SBF2-AS1, the metastasis of NSCLC cells was significantly inhibited, the silencing of SBF2-AS1 decreased the proliferation of NSCLC cells, and the cell cycle was arrested at the G1 phase; while overexpression promoted proliferation ability. Xenograft tumor models revealed that the silencing of SBF2-AS1 inhibited tumor growth in vivo. We speculated that SBF2-AS1 might negatively regulate P21. RNA immunoprecipitation discovered that SBF2-AS2 could bind with a core component of polycomb repressive complex2, SUZ12. Additionally chromatin immunoprecipitation assay demonstrated that, after silencing SBF2-AS1, the enrichment of SUZ12 and trimethylation of histone 3 lysine 27 decreased at the promoter region of P21.We demonstrated that SBF2-AS1 is upregulated in NSCLC and promotes proliferation of NSCLC tumor cells. SBF2-AS1 may serve as a novel biomarker and potential therapeutic target for NSCLC patients.

Project description:BackgroundAcquired drug resistance is a constraining factor in clinical treatment of glioblastoma (GBM). However, the mechanisms of chemoresponsive tumors acquire therapeutic resistance remain poorly understood. Here, we aim to investigate whether temozolomide (TMZ) resistance of chemoresponsive GBM was enhanced by long non-coding RNA SBF2 antisense RNA 1 (lncRNA SBF2-AS1) enriched exosomes.MethodLncSBF2-AS1 level in TMZ-resistance or TMZ-sensitive GBM tissues and cells were analyzed by qRT-PCR and FISH assays. A series of in vitro assay and xenograft tumor models were performed to observe the effect of lncSBF2-AS1 on TMZ-resistance in GBM. CHIP assay were used to investigate the correlation of SBF2-AS1 and transcription factor zinc finger E-box binding homeobox 1 (ZEB1). Dual-luciferase reporter, RNA immunoprecipitation (RIP), immunofluorescence and western blotting were performed to verify the relation between lncSBF2-AS1, miR-151a-3p and XRCC4. Comet assay and immunoblotting were performed to expound the effect of lncSBF2-AS1 on DNA double-stand break (DSB) repair. A series of in vitro assay and intracranial xenografts tumor model were used to determined the function of exosomal lncSBF2-AS1.ResultIt was found that SBF2-AS1 was upregulated in TMZ-resistant GBM cells and tissues, and overexpression of SBF2-AS1 led to the promotion of TMZ resistance, whereas its inhibition sensitized resistant GBM cells to TMZ. Transcription factor ZEB1 was found to directly bind to the SBF2-AS1 promoter region to regulate SBF2-AS1 level and affected TMZ resistance in GBM cells. SBF2-AS1 functions as a ceRNA for miR-151a-3p, leading to the disinhibition of its endogenous target, X-ray repair cross complementing 4 (XRCC4), which enhances DSB repair in GBM cells. Exosomes selected from temozolomide-resistant GBM cells had high levels of SBF2-AS1 and spread TMZ resistance to chemoresponsive GBM cells. Clinically, high levels of lncSBF2-AS1 in serum exosomes were associated with poor response to TMZ treatment in GBM patients.ConclusionWe can conclude that GBM cells remodel the tumor microenvironment to promote tumor chemotherapy-resistance by secreting the oncogenic lncSBF2-AS1-enriched exosomes. Thus, exosomal lncSBF2-AS1 in human serum may serve as a possible diagnostic marker for therapy-refractory GBM.

Dataset Information

Exosomal long non-coding RNA DLX6-AS1 as a potential diagnostic biomarker for non-small cell lung cancer.

Publications

Exosomal long non-coding RNA DLX6-AS1 as a potential diagnostic biomarker for non-small cell lung cancer.

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