Functions and potential clinical applications of circular RNAs in hepatocellular carcinoma

Hepatocellular carcinoma (HCC), which accounts for 75%-80% of primary liver cancers, is recognized worldwide as a highly lethal cancer. Adjunctive diagnostic biomarkers for HCC are α-fetoprotein (AFP), induced by the absence of vitamin K or its antagonist (PIVKA-II), and AFP-L3. Using multiple biomarkers, or biomarkers in combination with other clinical tests, is recommended from the perspective of sensitivity and specificity; however, this approach does not lend itself to early detection. Therefore, novel biomarkers are needed urgently. Non-coding RNAs, mainly circular RNAs (circRNAs), are key players in the progression and suppression of diseases, including cancer. Unlike linear RNAs, circRNAs are cyclic RNAs generated by 3’ to 5’ back-splicing. Advancements in RNA sequencing technology and bioinformatic pipelines mean that numerous circRNAs have been predicted and identified. These RNA molecules play a role in the progression/suppression of cancer through direct or indirect epigenetic regulation via microRNAs and proteins in cancer cells, as well as in the surrounding tumor microenvironment. Some circRNAs are tissue- or cell line-specific and are detected in exosomes, blood, and saliva. Importantly, circRNAs are more stable than linear cognate RNAs in vivo . This unique characteristic positions circRNAs as versatile materials with potential for use as biomarkers, in clinical tests, and as therapeutic applications. In the context of HCC, numerous circRNAs have been identified. Here, we describe the functions of circRNAs in HCC, the experimental methods in which they can be used, and their potential clinical applications.