Exosomal circRNAs as novel cancer biomarkers: Challenges and opportunities

Abstract

Identifying high specificity and sensitivity biomarkers has always been the focus of research in the field of non-invasive cancer diagnosis. Exosomes are extracellular vesicles with a lipid bilayer membrane that can be released by all types of cells, which contain a variety of proteins, lipids, and a variety of non-coding RNAs. Increasing research has shown that the lipid bilayer can effectively protect the nucleic acid in exosomes. In cancers, tumor cell-derived exosomal circRNAs can act on target cells or organs through the transport of exosomes, and then participate in the regulation of tumor development and metastasis. Since exosomes exist in various body fluids and circRNAs in exosomes exhibit high stability, exosomal circRNAs have the potential as biomarkers for early and minimally invasive cancer diagnosis and prognosis judgment. In this review, we summarized circRNAs and their biological roles in cancers, with the emerging value biomarkers in cancer diagnosis, disease judgment, and prognosis observation. In addition, we briefly compared the advantages of exosomal circRNAs as biomarkers and the current obstacles in the exosome isolation technology, shed light to the future development of this technology.

Keywords: CircRNAs; biomarkers; exosomal circRNAs; exosomes; liquid biopsy.

Figure 1

The formation process and classification of circRNA. (A) Intron-pairing-driven circularization:The formation of the loop structure occurs through the pairing of flanking introns and reverse complementary sequences or the action of RBPs, and then removing or retaining the introns and connecting the exons to form EcRNAs or EIciRNAs, respectively. (B) Lariat-driven circularization: This process is associated with exon skipping or intron removal, in which one or more exons of the transcript are skipped, and it contributes to an exon-containing lariat. The formed lasso intermediate produces circRNA by further splicing. (C) Splicing of pre-tRNA: CircRNA derived from pre-tRNA.

Figure 2

The regulatory role of exosomal circRNA in tumors. Donor cells secrete exosomal circRNA into recipient cells, which can affect the tumor microenvironment and tumor growth and metastasis by competitively binding miRNA and acting on downstream target genes. (A) Angiogenesis: Exosomal circRNAs can regulate tumor angiogenesis and permeability of vascular endothelial cells through miRNA sponge action or direct binding to proteins. (B) EMT: Exosomal circRNAs can enter different tumor cells and participate in the regulation of EMT and invasive growth of tumor cells. (C) Regulating tumor immunity: Exosomal circRNA can participate in the regulation of tumor immune microenvironment through multiple channels. (D) Regulating drug resistance: Exosomal circRNA participates in the regulation of drug resistance of multiple chemotherapeutics through multiple channels.

Figure 3

Detection of cancer-related exosomal circRNA. Tumor-derived exosomes contain a large number of tumor-specific nucleic acids and proteins. Exosomes function as an information carrier; by detecting the differentially expressed circRNAs in exosomes released into the body fluids, they can be important for the diagnosis of tumors. Rather than extracting circRNA directly from body fluids, extracting exosomes first and then extracting circRNA will result in a higher abundance and more differential expression of circRNA.