circRNAs and Exosomes: A Mysterious Frontier for Human Cancer

Abstract

Exosomes are nano-sized membrane-bound vesicles and contain active substances (DNA, noncoding RNA [ncRNA], protein), which provide a novel method of transferring effector messages between cells. Circular RNAs (circRNAs), a kind of ncRNA, have attracted increasing attention over the last decade given advances in whole-genome and transcriptome sequencing technologies. It has become increasingly clear that circRNAs regulate gene expression through various actions and play diverse roles in many fields of human cancer biology. Notably, several studies reported that circRNAs are enriched in exosomes and that exosomal circRNAs play an important role in cancer biology. Exosomal circRNAs can be taken up by neighboring or distant cells and affect many aspects of physiological and pathological conditions of the recipient cells, potentially promoting cell communication and tumor metastasis. Herein, we briefly review the molecular mechanisms of circRNAs and recent findings regarding exosomal circRNAs, and highlight the specific roles of exosomal circRNAs in human cancer.

<p>Biological Roles and Mechanisms of Circular RNA in Human Cancers</p>

“…Upon complete elucidation of exosomal circRNA functionality and molecular mechanisms relevant to human cancer, avenues of new insight will be opened, providing novel therapeutic approaches in malignant tumors. 11 CircRNAs may also play a key role in the development of drug resistance. Recently, multiple studies have highlighted the key roles of ncRNAs in chemoresistance of cancer, such as HCC, 142,249 lung cancer, 250,251 gastric cancer, 252,253 breast cancer, 254,255 multiple myeloma, 256 acute myeloid leukemia, 234 prostate cancer, 257 bladder cancer, 258 among others.…”

“…The long introns containing flank regions that will become circRNAs usually contain specific sequences which induce circRNA formation either by complementarity and/or by binding to circRNA-promoting factors, and are generally expressed in cell type-specific and tissue-specific manners. 10,11 Based on the different structures, and cycling mechanisms, circRNA molecules are divided into four categories: exonic circRNAs (ecRNAs), intronic circRNAs (ciRNAs), exon-intron circRNAs (eIciRNAs), and intergenic circRNAs. Unlike linear RNAs, circRNAs are stable and resistant to exonucleases (including RNase R) due to the lack of a poly(A) tail and have longer median half-life than that of their linear mRNAs due to the lack of free 3′ or 5′ ends, which makes them resistant to regular mechanisms of linear RNA decay.…”

“…Unlike linear RNAs, circRNAs are stable and resistant to exonucleases (including RNase R) due to the lack of a poly(A) tail and have longer median half-life than that of their linear mRNAs due to the lack of free 3′ or 5′ ends, which makes them resistant to regular mechanisms of linear RNA decay. [10][11][12] Functions of cirRNAs Acting as miRNA Sponges…”

Emerging landscape of circular RNAs as biomarkers and pivotal regulators in osteosarcoma

“…Exosomes refers to a class of membrane‐bound extracellular vesicles (EVs) released by most cell types with sizes ranging from 30 to 100 nm (Shi et al, 2019). Exosome could facilitate intercellular communication by transferring active components, including DNA, RNA, protein and lipid from the donor cells to recipient cells (Tu et al, 2019).…”

“…B. Zhou et al, 2019), and cancer (Cui et al, 2019; Fu, Jiang, Li, Hu, & Guo, 2018; X. Huang, Zhang, et al, 2019; Q. Zhong, Huang, Wei, & Wu, 2019). Of note, circRNAs are reported to exert diverse functions in cancer tumorigenesis (S. Meng, Zhou, et al, 2017), metastasis (Shi et al, 2019; Wei et al, 2019) and even chemoresistance (W. Huang, Yang, et al, 2019). Characteristics including high stability, abundance and tissue‐specific expression indicate that circRNAs may serve as ideal biomarkers in multiple cancers for clinical treatment and research (J.‐F.…”