Emerging roles of circular RNAs in liver cancer

Hepatocellular carcinoma and cholangiocarcinoma are the most common liver primary tumors and showed an increased incidence and mortality over the last decades. Due to a frequent late diagnosis, liver cancer is associated with limited curative therapeutic options. Characterizing new molecular determinants of liver carcinogenesis is required to develop innovative treatments and to identify clinically relevant biomarkers. Recently, circular RNAs (circRNAs) emerged as promising regulatory molecules involved in cancer onset and progression, thus opening new opportunities. Mechanistically, circRNAs are currently mainly described for their capability to sponge and to regulate the activity of microRNAs and RNA binding proteins, although other functions are emerging (e.g. transcriptional and post-transcriptional regulation, protein scaffolding). In liver cancer, circRNAs are described to regulate tumor cell proliferation, migration, invasion and cell death resistance. Their role in regulating angiogenesis, genome instability, immune surveillance and metabolic switching is emerging. Importantly, circRNAs are detected in body fluids. Due to their circular structure, circRNAs are often more stable than mRNAs or miRNAs and could therefore serve as promising biomarkers quantifiable with high specificity and sensitivity though minimally invasive methods. This review focuses on the role and the clinical relevance of circRNAs in liver cancer, including the development of innovative biomarkers and therapeutic strategies.