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Critical function of circular RNAs in lung cancer

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Abstract Lung cancer is one of the main causes of cancer‐related death in the world, especially due to its frequency and ineffective therapeutically approaches in the late stages of the disease. Despite the recent advent of promising new targeted therapies, lung cancer diagnostic strategies still have difficulty in identifying the disease at an early stage. Therefore, the characterizations of more sensible and specific cancer biomarkers have become an important goal for clinicians. Circular RNAs (circRNAs), a type of RNA with covalently closed continuous loop structures that display high structural resistance and tissue specificity pointed toward a potential biomarker role. Current investigations have identified that circRNAs have a prominent function in the regulation of oncogenic pathways, by regulating gene expression both at transcriptional and post‐transcriptional level. The aim of this review is to provide novel information regarding the implications of circRNAs in lung cancer, with an emphasis on the role in disease development and progression. Initially, we explored the potential utility of circRNAs as biomarkers, focusing on function, mechanisms, and correlation with disease progression in lung cancer. Further, we will describe the interaction between circRNAs and other non‐coding species of RNA (particularly microRNA) and their biological significance in lung cancer. Describing the nature of these interactions and their therapeutic potential will provide additional insight regarding the altered molecular landscape of lung cancer and consolidate the potential clinical value of these circular transcripts. This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development
Overview of circRNA biogenesis and general functions. The production of circRNAs is dependent on the splicing machinery. Events that facilitate transcript circularization are the presence of flanking inverted repeats that promote intron pairing, RBP dimerization subsequent to RNA binding. Additionally, lariat structures are created which circularize and, in some cases, can generate intronic or exon‐containing circRNA, depending on the size and composition of the skipped region. The main identified functions of circRNAs are described as follows: miRNA sponging (a) consisting in the complementary binding and inactivation of a miRNA that displays a compatible MRE sequence. Peptide coding (b) properties have been recorded in several circRNAs that contain exons containing a functional open‐reading frame and start/stop codons; RBP binding and complex scaffolding (c), circRNAs have been proven to directly interact with several RBPs and regulate their activity by either promoting or inhibiting the formation of ternary protein structures. It is important to mention that a circRNA is unlikely to exhibit all presented functions simultaneously, as they are dependent on intronic/exonic composition and sequences. circRNA, circular RNA; RBP, RNA binding protein
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Examples of altered circRNA expression patterns and their biological effects in lung cancer. circRNA, circular RNA
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Overview of the FOXO3‐miR‐155 regulatory loop. Tumor suppressor FOXO3 has is largely considered as downregulated in lung cancer. This might come due to other genomic alterations identified, such as the overexpression of specific miRNAs. In the case of FOXO3, miR‐155 can target its mRNA at a small seven nucleotide region in the mRNAs 3′ UTR region, thus inhibiting translation. In an opposite manor, circFOXO3, the circular transcript originating from the same pre‐mRNA as the mature FOXO3 mRNA can act as a competitive binding site for miR‐155, acting as a molecular sponge for miRNA. This hinders the binding of miR‐155 to the FOXCO3 mRNA and allows it to be further translated into a functional protein, thus allowing it to carry out its tumor suppressor effect upon the cell
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RNA in Disease and Development > RNA in Development
RNA in Disease and Development > RNA in Disease
RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems

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