Abstract
Simple SummaryCircular RNAs (circRNAs) belong to a new class of non-coding RNAs implicated in cellular physiological functions but also in the evolution of various human pathologies. Due to their circular shape, circRNAs are resistant to degradation by exonuclease activity, making them more stable than linear RNAs. Several findings reported that circRNAs are aberrantly modulated in human cancer tissues, thus affecting carcinogenesis and metastatization. We aim to report the most recent and relevant results about novel circRNA functions and molecular regulation, to dissert about their role as reliable cancer biomarkers, and to hypothesize their contribution to multiple hallmarks of cancer.Next generation RNA sequencing techniques, implemented in the recent years, have allowed us to identify circular RNAs (circRNAs), covalently closed loop structures resulting in RNA molecules that are more stable than linear RNAs. This class of non-coding RNA is emerging to be involved in a variety of cell functions during development, differentiation, and in many diseases, including cancer. Among the described biological activities, circRNAs have been implicated in microRNA (miRNA) sequestration, modulation of protein–protein interactions and regulation of mRNA transcription. In human cancer, circRNAs were implicated in the control of oncogenic activities such as tumor cell proliferation, epithelial-mesenchymal transition, invasion, metastasis and chemoresistance. The most widely described mechanism of action of circRNAs is their ability to act as competing endogenous RNAs (ceRNAs) for miRNAs, lncRNAs and mRNAs, thus impacting along their axis, despite the fact that a variety of additional mechanisms of action are emerging, representing an open and expanding field of study. Furthermore, research is currently focusing on understanding the possible implications of circRNAs in diagnostics, prognosis prediction, effectiveness of therapies and, eventually, therapeutic intervention in human cancer. The purpose of this review is to discuss new knowledge on the mechanisms of circRNA action, beyond ceRNA, their impact on human cancer and to dissect their potential value as biomarkers and therapeutic targets.
Highlights
Many in vivo and in vitro studies and, more recently, analysis of liquid biopsy from cancer patients have shown that non-coding RNA, such as microRNA and long ncRNA, can be considered as good biomarkers for the diagnosis, prognosis and treatment of various human cancers [1,2]
We show here two examples referring, respectively, to gastric (GC) and liver (HCC) cancer. circDONSON is a circRNA able to directly control the expression of SOX4, a transcription factor often elevated in human cancers, where it generally correlates with tumor-progression and poor disease outcome
Elevated circ_0020710 expression correlates with cytotoxic lymphocyte exhaustion, and, of note, a combination of a CXCL12/CXCR4 axis inhibitor and anti-PD-1 significantly attenuates tumor growth [45]. Another interesting example is circMET, a circRNA enclosed in chromosome region 7q21-7q31, the amplification of which is associated with tumor recurrence and multidrug resistance in hepatocellular carcinoma (HCC). circMET expression promotes Hepatocellular Carcinoma (HCC) development by inducing an epithelial to mesenchymal transition and enhancing an immunosuppressive tumor microenvironment
Summary
Many in vivo and in vitro studies and, more recently, analysis of liquid biopsy from cancer patients have shown that non-coding RNA (ncRNA), such as microRNA (miRNA) and long ncRNA (lncRNA), can be considered as good biomarkers for the diagnosis, prognosis and treatment of various human cancers [1,2]. Another study reports that circGSK3β can promote ESCC migration and invasion by decreasing β-catenin phosphorylation by GSK3β and its sequential ubiquitination [30] These recent evidence shows that circRNAs play a role in the establishment of functional platforms where protein molecules can interact. Data reported by Ding et al (2019) demonstrate that circDONSON activates SOX4 transcription to promote GC progression [31] Another example of a circRNA that impinges on gene transcription is circRHOT1, which regulates the expression of NR2F6 in HCC cells [32]. CircRHOT1 promotes the cell proliferation, migration and progression of HCC through NR2F6 activation [32] These and many other papers strongly suggest that circRNAs may play a transcriptional regulatory role, the detailed mechanisms of which are discussed in the following sub-paragraphs. These studies provide important information for future exploration of the function of circRNAs transcriptional control in cancer
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