Circular RNAs: new biomarkers of chemoresistance in cancer

Abstract

Chemotherapeutics are validated conventional treatments for patients with advanced cancer. However, with continual application of chemotherapeutics, chemoresistance, which is often predictive of poor prognosis, has gradually become a concern in recent years. Circular RNAs (circRNAs), a class of endogenous noncoding RNAs (ncRNAs) with a closed-loop structure, have been reported to be notable targets and markers for the prognosis, diagnosis, and treatment of many diseases, particularly cancer. Although dozens of studies have shown that circRNAs play major roles in drug-resistance activity in tumors, the mechanisms by which circRNAs affect chemoresistance have yet to be explored. In this review, we describe the detailed mechanisms of circRNAs and chemotherapeutics in various cancers and summarize potential therapeutic targets for drug-resistant tumors.

Keywords: Circular RNA; cancer; chemoresistance; drug resistance.

Figure 1

Biogenesis of circRNAs: (A, B) EcircRNAs and EIciRNAs can be generated from an SD site attacking an SA site, with sites with repeat elements close together; (C) Intronic circRNAs can be generated from intronic lariats that escape the debranching step of canonical linear splicing.

Figure 2

Biological functions of circRNAs in cancer: (A) Functions as miRNA sponges: miRNAs can bind miRNA response elements of circRNAs and thereby alleviate repression of downstream mRNAs; (B) Functions through RNA-binding proteins: circRNAs can bind RBPs which have binding sites affecting the expression of associated genes; (C) Functions as transcriptional regulators: circRNAs can regulate transcription by binding polymerase II or U1 snRNP complexes, as well as regulating selective splicing; (D) Functions in protein translation: circRNAs with open reading frames and internal ribosome entry sites can translate protein. Moreover, m⁶A motif, which is sufficient to initiate translation, is recognized rich in some circRNAs, so as to empower these circRNAs to translate protein.

Figure 3

Mechanisms of chemoresistance: (A) Promoting drug excretion: ABC transporters enhance drug excretion, thus leading to low drug accumulation in cells; (B) Regulating apoptosis-related genes: upregulation of anti-apoptotic genes or downregulation of apoptotic genes allows cancer cells to proliferate indefinitely without constraint, thus resisting chemotherapy; (C) Enhancing DNA repair: some proteins contribute to repairing damaged DNA, thus resulting in the failure of drugs that destroy the structure of DNA; (D) Creating the TME: a hypoxic, acidic, inflammatory, and immunosuppressive TME with cancer-related fibroblasts and vessels can protect tumor cells from immune cells and killing by drugs.