The functions and clinical significance of circRNAs in hematological malignancies
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REVIEW
The functions and clinical significance of circRNAs in hematological malignancies Xiangxiang Zhou1,2,3,4,5,6*† , Linquan Zhan1†, Kai Huang7 and Xin Wang1,2,3,4,5,6*
Abstract With covalently closed circular structures, circular RNAs (circRNAs) were once misinterpreted as by-products of mRNA splicing. Being abundant, stable, highly conserved, and tissue-specific, circRNAs are recently identified as a type of regulatory RNAs. CircRNAs bind to certain miRNAs or proteins to participate in gene transcription and translation. Emerging evidence has indicated that the dysregulation of circRNAs is closely linked to the tumorigenesis and treatment response of hematological malignancies. CircRNAs play critical roles in various biological processes, including tumorigenesis, drug resistance, tumor metabolism, autophagy, pyroptosis, and ferroptosis. The N6-methyladenosine modification of circRNAs and discovery of fusion-circRNAs provide novel insights into the functions of circRNAs. Targeting circRNAs in hematological malignancies will be an attractive treatment strategy. In this review, we systematically summarize recent advances toward the novel functions and molecular mechanisms of circRNAs in hematological malignancies, and highlight the potential clinical applications of circRNAs as novel biomarkers and therapeutic targets for future exploration. Keywords: Circular RNAs, Hematological malignancies, Tumorigenesis, Drug-resistance, Biomarker Background Circular RNAs (circRNAs) are a novel type of competing endogenous RNAs (ceRNAs) of the non-coding RNA (ncRNA) families. Without 5′ and 3′ ends, they are hallmarked by covalently closed continuous loops and are more stable than linear RNAs in vivo [1]. CircRNAs are abundant in biological cells, highly conserved, and expressed in a tissue-specific pattern [2]. CircRNAs are classified into four categories, including exon circRNAs (ecRNAs), circular intron RNAs (ciRNAs), exon-intron circRNAs (EIciRNAs), and tRNA intronic circular RNAs (tricRNAs) (Fig. 1). Accumulating evidence has revealed various biological functions of circRNAs, which have attracted widespread attention [3]. Localized in miRNA *Correspondence: [email protected]; [email protected] † Xiangxiang Zhou and Linquan Zhan have contributed equally to this work 1 Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, People’s Republic of China Full list of author information is available at the end of the article
binding sites, circRNAs could directly sponge miRNAs through miRNA response elements (MREs), thereby negatively regulating the inhibition of target mRNAs [4]. CircRNAs also regulate gene expression and bind to RNA-binding proteins (RBPs), playing critical roles in gene transcription and translation [5, 6]. In addition, the translation potential of circRNAs as protein templates related to tumorigenesis and development has been proved [7]. Since circRNAs are abundant in human peripheral blood and tissues, making th
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