Abstract
BackgroundIncreasing evidence indicates that the aberrant expression of circular RNAs (circRNAs) is involved in the pathogenesis and progression of lung adenocarcinoma (LUAC). However, the function and molecular mechanisms of hsa_circ_0002483 (circ_0002483) in LUAC remain unclear.MethodsThe association between circ_0002483 expression and clinicopathological characteristics and prognosis in patients with LUAC was analyzed by fluorescence in situ hybridization. The functional experiments such as CCK-8, colony formation and Transwell assays and a subcutaneous tumor model were conducted to determine the role of circ_0002483 in LUAC cells. The specific binding between circ_0002483 and miR-125a-3p was validated by RNA immunoprecipitation, luciferase gene report and qRT-PCR assays. The effects of circ_0002483 on miR-125a-3p-mediated C-C motif chemokine ligand 4 (CCL4)-CCR5 axis were assessed by Western blot analysis.ResultsWe found that circ_0002483 was upregulated in LUAC tissue samples and associated with Tumor Node Metastasis (TNM) stage and poor survival in patients with LUAC. Knockdown of circ_0002483 inhibited proliferation, colony formation and invasion of A549 and PC9 cells in vitro, whereas overexpression of circ_0002483 harbored the opposite effects. Furthermore, circ_0002483 sponged miR-125a-3p and negatively regulated its expression. CCL4 was identified as a direct target of miR-125a-3p. The rescue experiments showed that miR-125a-3p mimics reversed the tumor-promoting effects of circ_0002483 by targeting CCL4-CCR5 axis in A549 and PC9 cells. In addition, the in vivo experiment further validated that knockdown of circ_0002483 repressed tumor growth.ConclusionsOur findings demonstrated that circ_0002483 could act as a sponge of miR-125a-3p to upregulate CCL4-CCR5 axis, contributing to the tumorigenesis of LUAC, and represent a potential therapeutic target for LUAC.
Highlights
Lung cancer is one of the most malignant tumors and its incidence and mortality are increasing rapidly, threatening to the public health and human life [1]
Upregulation of circ_0002483 was associated with poor survival in patients with LUACThe Gene Expression Omnibus (GEO) dataset (GSE101684) was used to screen the differentially-expressed Circular RNA (circRNA) between lung adenocarcinoma (LUAC) and non-cancerous tissue samples and top 10 upregulated or downregulated circRNAs were identified according to the FC > 2 and P < 0.01, of which hsa_circ_0002483 harbored a remarkable elevation in LUAC (Fig. 1A)
The similar result was shown in LUAC patients with stage III–IV (n = 42) as compared with those with stage I–II (n = 38) (Fig. 1C; P = 0.02)
Summary
Lung cancer is one of the most malignant tumors and its incidence and mortality are increasing rapidly, threatening to the public health and human life [1]. With the development of treatment methods, lung adenocarcinoma (LUAC) as a subclass of non-small cell lung cancer (NSCLC) has been well-treated, but the advanced cases still harbor a poor prognosis duo to its distant metastasis [2]. Accumulating data display that the aberrant expression of noncoding RNAs is associated with the prognosis and progression of LUAC [3,4,5]. Identification of cancer-related noncoding RNAs may provide potential biomarkers for the early detection of LUAC. Circular RNA (circRNA) as a subclass of noncoding RNAs is characterized by covalently closed loop structures and RNA stability owing to resistance to RNase R [6]. Increasing evidence indicates that the aberrant expression of circular RNAs (circRNAs) is involved in the pathogenesis and progression of lung adenocarcinoma (LUAC). The function and molecular mechanisms of hsa_circ_0002483 (circ_0002483) in LUAC remain unclear
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