CircNEIL3 regulatory loop promotes pancreatic ductal adenocarcinoma progression via miRNA sponging and A-to-I RNA-editing

Abstract

Background A growing number of studies have focused on investigating circRNAs as crucial regulators in the progression of multiple cancer types. Nevertheless, the biological effects and underlying mechanisms of circRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Methods Differentially expressed circRNAs between cancerous tissue and adjacent normal tissues were identified by RNA sequencing in PDAC. Subsequently, in vitro and in vivo functional experiments were performed to investigate the functional roles of circNEIL3 in PDAC tumour growth and metastasis. Furthermore, RNA pull-down, dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, fluorescent in situ hybridization (FISH) and Sanger sequencing assays were performed to examine the circular interaction among circNEIL3, miR-432-5p and adenosine deaminases acting on RNA 1 (ADAR1). Results CircNEIL3 was upregulated in PDAC and promoted the progression of PDAC cells both in vitro and in vivo. Mechanistically, circNEIL3 was shown to regulate the expression of ADAR1 by sponging miR-432-5p to induce RNA editing of glioma-associated oncogene 1 (GLI1), ultimately influencing cell cycle progression and promoting epithelial-to-mesenchymal transition (EMT) in PDAC cells. Moreover, we discovered that the circNEIL3/miR-432-5p/ADAR1 axis was correlated with the PDAC clinical stage and overall survival of PDAC patients, while ADAR1 may reduce the biogenesis of circNEIL3. Conclusions Our findings reveal that circNEIL3 facilitates the proliferation and metastasis of PDAC through the circNEIL3/miR-432-5p/ADAR1/GLI1/cell cycle and EMT axis and that its expression is regulated by ADAR1 through a negative feedback loop. Therefore, circNEIL3 may serve as a prognostic marker and a therapeutic target for PDAC.

Circular RNA CircEYA3 induces energy production to promote pancreatic ductal adenocarcinoma progression through the miR-1294/c-Myc axis

“…Existing studies have demonstrated that many circRNAs exert their biological effects by sponging miRNAs and subsequently regulating miRNA expression in PDAC [ 13 , 14 , 25 ]. Given that circEYA3 exhibited high stability and was localized mainly in the cytoplasm, as described above, we hypothesized that circEYA3 facilitated malignant biological behaviours of PDAC cells by sponging miRNAs.…”

“…For example, according to previous reports, circBFAR acts as a miR-34b-5p sponge to facilitate the proliferation and metastasis of PDAC cells by activating MET signalling [ 13 ]. More recently, Shen et al revealed that a negative feedback loop was formed between circNEIL3 and ADAR1 that can promote the progression of PDAC through the miR-432-5p/ADAR1/GLI1 axis [ 14 ]. To the best of our knowledge, although some dysregulated circRNAs have been reported to play crucial roles in the initiation and development of PDAC [ 15 ], here are still many unknowns that need exploration and study to elucidate the underlying mechanisms of circRNAs in PDAC.…”

Higher circular RNA_0015278 correlates with absence of extrathyroidal invasion, lower pathological tumor stages, and prolonged disease‐free survival in papillary thyroid carcinoma patients

“…Circular RNA (circRNA) is a type of non‐coding RNA that regulates various biological processes through sponging microRNAs and regulating RNA binding proteins 6,7 . Meanwhile, recent studies reveal that circRNAs regulate various signaling to modulate the pathogenesis and progression of cancers 8–10 . Besides, circRNA is regarded as a potential, clinical biomarker for it is stable and easy to extract 11,12 .…”

“… 6 , 7 Meanwhile, recent studies reveal that circRNAs regulate various signaling to modulate the pathogenesis and progression of cancers. 8 , 9 , 10 Besides, circRNA is regarded as a potential, clinical biomarker for it is stable and easy to extract. 11 , 12 In PTC, previous studies suggest that several circRNAs, including circ_0002111, circ_0006156, and circ_0137287, serve as clinical biomarkers and possess the potential to improve the management of PTC patients.…”

A Nomogram Based On A-To-I RNA Editing Predicting The Overall Survival of Patients With Lung Squamous Carcinoma

“…In cancer studies, a lot of A-to-I editing events such as A-to-I-edited GABRA3[18], AZIN1 [19], and miRNA-379-5p [20] have signi cant effects on cancer survival. Other studies have also shown that A-to-I editing regulates cancer progression [21,22], metastasis [23], tumorigenesis [24][25][26], drug resistance [27]. However, the extent to which A-to-I editing predicts cancer survival is not known.…”