RETRACTED: Hypoxic tumor-derived exosomal circular RNA SETDB1 promotes invasive growth and EMT via the miR-7/Sp1 axis in lung adenocarcinoma

Abstract

Hypoxia is a common feature of solid tumors and has been associated with tumor aggressiveness and poor prognosis. Exosomes are involved in mediating cellular-environment interactions. Circular RNAs (circRNAs) are a class of non-coding RNA broadly found in cells and exosomes. However, the functions and regulatory mechanisms of exosomal circRNAs induced by hypoxia remain poorly understood in lung adenocarcinoma (LUAD) development. Differentially expressed circRNAs were identified between exosomes extracted from hypoxic and normoxic conditions through microarray analysis. We focused on hsa-circ-0003439 found on chromosome 1 and derived from SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), and thus we named it circSETDB1. We discovered that exosomes obtained from hypoxic LUAD cells improved the migration, invasion, and proliferation capacity of normoxic LUAD cells. circSETDB1 was found to be significantly upregulated in hypoxia-induced exosomes from LUAD cell lines compared with exosomes in the normal condition. Moreover, knockdown of circSETDB1 significantly inhibited cell malignant growth in vitro. Importantly, we showed that circSETDB1 was upregulated in serum exosomes in LUAD patients, and exosomal circSETDB1 levels were closely associated with disease stage. Finally, using RNA immunoprecipitation (RIP), bioinformatics, and luciferase reporter assays, we elucidated the implication of a circSETDB1/miR-7/specificity protein 1 (Sp1) axis in the development and epithelial-mesenchymal transition (EMT) of lung adenocarcinoma.

Exosome-transported circRNA_0001236 enhances chondrogenesis and suppress cartilage degradation via the miR-3677-3p/Sox9 axis

“…Bioinformatics analysis of exosomal circRNA microarray data to explore the ceRNA regulation network revealed that ceRNA essentially operates in an miRNA-target mechanism [ 36 ]. The number of MREs is the key determinant of the range and strength of ceRNA regulation [ 37 , 38 ]. Several validated ceRNA networks participate in the initiation and progression of various diseases [ 39 , 40 ].…”

Tumor-Derived Extracellular Vesicles Regulate Cancer Progression in the Tumor Microenvironment

“…Moreover, RT-qPCR analysis showed that the concentrations of those increased miRNAs were 1000-fold above the cellular level, which may better distinguish acute myeloid leukemia from healthy volunteers with high sensitivity and specificity ( Hornick et al, 2015 ). High levels of circular RNA SETDB1 and miR-31-5P are observed in lung adenocarcinoma patients ( Xu et al, 2021 ; Yu et al, 2021 ). Serum vesicular circular RNA SETDB1 level is closely correlated with the T stage and lymph node metastasis ( Xu et al, 2021 ).…”

“…High levels of circular RNA SETDB1 and miR-31-5P are observed in lung adenocarcinoma patients ( Xu et al, 2021 ; Yu et al, 2021 ). Serum vesicular circular RNA SETDB1 level is closely correlated with the T stage and lymph node metastasis ( Xu et al, 2021 ). In addition, zinc finger antisense 1 (ZFAS1), belonging to competing endogenous lncRNA, is enriched in the serum EVs of gastric cancer patients ( Pan et al, 2017 ).…”

Structure, Activity and Function of the SETDB1 Protein Methyltransferase

“…In Non-Small Cell Lung Cancers (NSCLC), upregulated SETDB1 expression favors tumor progression through interaction and methylation of p53 and Akt (AKT Serine/Threonine Kinase 1) [ 68 , 69 , 70 ], resulting in poorer prognosis and tumor recurrence in patients with stage I NSCLC [ 71 , 72 ]. According to a recent study, SETDB1-derived circular RNA (circSETDB1) was significantly increased in lung adenocarcinoma hypoxia-induced exosomes and was associated with disease stage, whereas circSETDB1 knockdown notably inhibited in vitro malignant growth [ 73 ]. SETDB1 also activates the Wingless-related integration site (WNT) pathway, causing the accumulation of nuclear β-catenin and induction of a cancerous phenotype [ 74 ].…”