Abstract
BackgroundCancer metastasis is responsible for 90% of cancer‐related deaths. Recently, circular RNA (circRNA) is deemed to be an important regulator of cancer progression. However, little is known about the role of circRNA in the metastasis of lung adenocarcinoma (LUAD). Herein, we investigated the clinical implication and regulatory effect of circ‐TSPAN4 (hsa_circ_0020732) in LUAD.MethodsGene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE104854) was used to identify the aberrantly expressed circRNAs in LUAD. The expression levels of circ‐TSPAN4, miR‐4731‐5p, miR‐665, and ZEB1 were determined by quantitative reverse transcription PCR (qRT‐PCR). The functional experiments were carried out with wound healing and transwell assays. And, the luciferase reporter and RNA pull‐down assays were employed to examine the crosstalk between circ‐TSPAN4, miR‐665, and ZEB1. In vivo metastasis experiment was tested by the lung metastasis model.ResultsCirc‐TSPAN4 was significantly upregulated in LUAD tissues and cell lines. The increased circ‐TSPAN4 was linked to advanced tumor‐node‐metastasis stage, lymph node and distant metastasis, and poor outcome. Lentivirus‐mediated stably circ‐TSPAN4 knockdown dramatically attenuated the metastatic ability of LUAD cells both in vitro and in vivo. Mechanistically, circ‐TSPAN4 directly interacted with miR‐665, but not miR‐4731‐5p, to increase the expression of ZEB1, which is a well‐known metastasis trigger. Importantly, the reduced metastatic capacity caused by circ‐TSPAN4 depletion was partially rescued by miR‐665 silencing or ZEB1 overexpression.ConclusionsCirc‐TSPAN4 plays a pivotal metastasis‐promoting role in LUAD through acting as a sponge for miR‐665 and upregulating ZEB1.
Highlights
Lung adenocarcinoma (LUAD), the most common type of primary lung cancer, is the leading cause of cancer‐related mortality worldwide (Myers & Wallen, 2019)
The overall survival time of patients with high circ‐TSPAN4 expression was significantly shorter than patients with low circ‐TSPAN4 expression (Figure 1e), and the prognostic utility of circ‐TSPAN4 for lung adenocarcinoma (LUAD) patients was highly considerable with an AUC value of 0.907 (Figure 1f)
We identified a novel dysregulated circular RNA (circRNA), circ‐TSPAN4, which was markedly increased in LUAD and closely related to metastatic properties and poor survival
Summary
Lung adenocarcinoma (LUAD), the most common type of primary lung cancer (accounting for approximately 40%), is the leading cause of cancer‐related mortality worldwide (Myers & Wallen, 2019). Multiple lines of evidence show that circRNA is closely related to human diseases, including cancer (Kristensen, Hansen, Veno, & Kjems, 2018; Rong et al, 2017). Several functions of circRNA have been proposed, such as acting as a molecular sponge of microRNAs (miRNAs), interacting with proteins, regulating host gene, and even translating proteins, and the most widely known of which is its role as a miRNA sponge (Shang, Yang, Jia, & Ge, 2019; Zhong et al, 2018). Subsequent numerous studies confirmed the miRNA sponge function of circRNA and found that circRNA was capable of tightly controlling cancer progression through this mechanism (Panda, 2018). The regulatory role of circRNA in LUAD progression, especially in metastasis, remains largely unknown. We identified a novel circRNA, circ‐ TSPAN4 (hsa_circ_0020732), which was highly expressed in LUAD tissues and cells and linked to the metastatic clinical characteristics. We addressed the underlying mechanism through which circ‐TSPAN4 facilitated LUAD metastasis
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