Identification of the tumor‑suppressive function of circular RNA FOXO3 in non‑small cell lung cancer through sponging miR‑155

Abstract

Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that have been demonstrated to be potential regulators in the development and progression of various types of human cancer. However, little is known about their roles in cancer initiation and progression, particular in non-small cell lung cancer (NSCLC). In the present study, the expression level of circRNA-forkhead box O3 class (FOXO3) in NSCLC specimens was determined and its functional role was investigated in NSCLC cells. By performing Taq-man based RT-qPCR, it was identified that circRNA-FOXO3 was downregulated in NSCLC tissues and cell lines. Receiver operating curve analysis indicated that circRNA-FOXO3 had a relatively higher diagnostic accuracy. The functional relevance was further examined by biological assays. circRNA-FOXO3 significantly promoted the ability of cell proliferation, migration and invasion of NSCLC cells. The linear isomer of circRNA-FOXO3, FOXO3 gene, was identified as a downstream target. RNA immunoprecipitation indicated that circRNA-FOXO3 sequestering miR-155, which further promoted linear FOXO3 expression. In addition, gain and loss functional assays indicated that circRNA-FOXO3 served an anti-oncogenic role through sequestering miR-155 and enhancing FOXO3 expression. These results suggest that circRNA-FOXO3 is a tumor-suppressor in NSCLC and may serve as a promising therapeutic target. Therefore, restoration of circRNA-FOXO3 expression could be a future approach to develop a novel treatment strategy.

Circular RNA circFOXO3 promotes prostate cancer progression through sponging miR‐29a‐3p

“…Accumulating studies showed that circFOXO3 was involved in progression of diseases, such as cardiac senescence 21 and nonsmall-cell lung cancer. 22 Moreover, Burton Yang et al reported circFOXO3 interacted with p21 and CDK2, and retarded cell cycle progression. 15 They also detected that circFOXO3 induced tumour apoptosis though enhancing FOXO3 activity.…”

Potential Diagnostic and Prognostic Biomarkers of Circular RNAs for Lung Cancer in China

“…After abstract and full article review, 24 published articles were enrolled for the final analysis. Among them, 5 articles investigated diagnostic value of circRNAs in lung cancer [24,[33][34][35][36], and 19 studies examined prognostic information related to overall survival [32,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. The period of the eligible studies ranged from 2017 to 2018 with a total of 2122 individuals.…”

“…CircRNAs Are Diagnostic Biomarkers for Lung Cancer. We retrieved 5 published articles pertaining to the expression levels of different circRNAs in human lung cancer, including 1 downregulated circRNA [24] and 4 upregulated circRNAs [33][34][35][36]. Furthermore, in the selection process for eligible articles, results of studies were considered acceptable only based on the expression of circRNAs in tissue, while consequences of studies based on the expression levels of circRNAs in serum, plasma, or peripheral blood samples were not taken into account.…”

“…What is more, circFOXO3, a putative tumor suppressor, was significantly downregulated in lung cancer and breast cancer [24,25]. Zhang et al reported that circFOXO3 served as a novel biomarker for early diagnosis with AUC of 0.782 in lung cancer and in vitro investigations implied inversely correlation with migration and invasion of nonsmall cell lung cancer through sponging miR-155 and releasing FOXO3 gene [24]. Besides, CiRS-7 (circular RNA sponge for miR-7), also termed CDR1as (cerebellar degeneration-related protein 1 transcript), harbors more than 70 conventional miR-7 binding sites and directly suppresses activity of miR-7 [26].…”

“…They further investigated 5 circRNAs by bioinformatic analysis and reported that these circRNAs might function as diagnostic markers in cancer. What is more, circFOXO3, a putative tumor suppressor, was significantly downregulated in lung cancer and breast cancer [24,25]. Zhang et al reported that circFOXO3 served as a novel biomarker for early diagnosis with AUC of 0.782 in lung cancer and in vitro investigations implied inversely correlation with migration and invasion of nonsmall cell lung cancer through sponging miR-155 and releasing FOXO3 gene [24].…”