Circular RNAs in body fluids as cancer biomarkers: the new frontier of liquid biopsies

Abstract

Cancer is a leading cause of death worldwide, particularly because of its high mortality rate in patients who are diagnosed at late stages. Conventional biomarkers originating from blood are widely used for cancer diagnosis, but their low sensitivity and specificity limit their widespread application in cancer screening among the general population. Currently, emerging studies are exploiting novel, highly-accurate biomarkers in human body fluids that are obtainable through minimally invasive techniques, which is defined as liquid biopsy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs generated mainly by pre-mRNA splicing. Following the rapid development of high-throughput transcriptome analysis techniques, numerous circRNAs have been recognized to exist stably and at high levels in body fluids, including plasma, serum, exosomes, and urine. CircRNA expression patterns exhibit distinctly differences between patients with cancer and healthy controls, suggesting that circRNAs in body fluids potentially represent novel biomarkers for monitoring cancer development and progression. In this study, we summarized the expression of circRNAs in body fluids in a pan-cancer dataset and characterized their clinical applications in liquid biopsy for cancer diagnosis and prognosis. In addition, a user-friendly web interface was developed to visualize each circRNA in fluids ( https://mulongdu.shinyapps.io/circrnas_in_fluids/ ).

Keywords: Cancer biomarker; Circular RNA; Liquid biopsy.

Fig. 1

The potential biogenetic and functional mechanisms of circRNAs. Schematic showing the biogenesis of circRNAs through the noncanonical back-splicing process and their reported functional mechanisms. CircRNAs are generated by a process called back-splicing from linear pre-messenger RNA. During this process, the 3′ and 5′ ends are ligated to form a covalently closed, uninterrupted loop. Unlike linear RNAs, circRNAs are relatively stable and not easily degraded by endonucleases. CircRNAs function as miRNA sponges, bind RBPs, and are translated due to the existence of an internal ribosome entry site. This schematic was generated at https://app.biorender.com/gallery/illustrations

Fig. 2

CircRNAs identified in patients with the 10 most common cancers. The ten most common cancers are shown according to “cancer statistics in 2020”[1], including lung cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, cervical cancer, thyroid cancer, and bladder cancer. Ovarian cancer-related circRNAs are listed in this figure because of its increasing morbidity and mortality rates in females. This figure was generated at https://app.biorender.com/gallery/illustrations

Fig. 3

A user-friendly interface to visualize the database of circRNAs in body fluids. The shiny package in R was utilized to develop this interface, and this interface is accessible in a user-friendly format at https://mulongdu.shinyapps.io/circrnas_in_fluids/. Moreover, some useful links are listed in this interface and users can click them to obtain more information. More detailed information can be acquired by navigating to this website or clicking on the hyperlink in the electronic version of this manuscript