Competing endogenous RNAs (ceRNAs) and drug resistance to cancer therapy

Abstract

Competing endogenous RNAs (ceRNAs) are transcripts that possess highly similar microRNA response elements (MREs). microRNAs (miRNAs) are short, endogenous, single-stranded non-coding RNAs (ncRNAs) that can repress gene expression by binding to MREs on the 3' untranslated regions (UTRs) of the target mRNA transcripts to suppress gene expression by promoting mRNA degradation and/or inhibiting protein translation. mRNA transcripts, circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and transcribed pseudogenes could share similar MREs, and they can compete for the same pool of miRNAs. These ceRNAs may affect the level of one another by competing for their shared miRNAs. This interplay between different RNAs constitutes a ceRNA network, which regulates many important biological processes. Cancer drug resistance is a major factor leading to treatment failure in patients receiving chemotherapy. It can be acquired through genetic, epigenetic, and various tumor microenvironment mechanisms. The involvement of ceRNA crosstalk and its disruption in chemotherapy resistance is attracting attention in the cancer research community. This review presents an updated summary of the latest research on ceRNA dysregulation causing drug resistance across different cancer types and chemotherapeutic drug classes. Interestingly, accumulating evidence suggests that ceRNAs may be used as prognostic biomarkers to predict clinical response to cancer chemotherapy. Nevertheless, detailed experimental investigations of the putative ceRNA networks generated by computational algorithms are needed to support their translation for therapeutic and prognostic applications.

Keywords: Alternative mRNA polyadenylation; cancer immunotherapy; ceRNA crosstalk; immune evasion; mRNA 3’untranslated region; microRNA; multidrug resistance; non-coding RNA.

Figure 1

An overview of the dysregulation of ceRNA regulatory network to induce different drug resistance mechanisms (including efflux transporter overexpression, reduced apoptosis, downregulated tumor suppressor, increased angiogenesis, induced autophagy, increased EMT, increased cuproptosis, reduced DNA damage, and immune escape). Representative downstream effectors leading to the different resistance mechanisms are listed in parentheses. RNA molecules could communicate with one another through miRNA and MRE. The expression of one RNA could influence the level and activity of another RNA by sequestering their common miRNA(s). ceRNA: Completing endogenous RNA; EMT: epithelial-mesenchymal transition; miRNA: microRNA; MRE: microRNA response element; circRNA: circular RNA; lncRNA: long non-coding RNA.

Figure 2

Schematic diagram illustrating how mRNA 3’UTR shortening represses its ceRNA partner in trans by releasing the common miRNA(s). 3’UTR shortening of mRNA-X allows its escape from miRNA-mediated repression, therefore increasing mRNA-X expression. However, the release of the common miRNA(s) from binding to the long 3’UTR of mRNA-X will result in the repression of the ceRNA partner mRNA-Y. 3’UTR: 3’ untranslated region; ceRNA: completing endogenous RNA; miRNA: microRNA.

Figure 3

Resistance to cancer immunotherapy due to upregulation of PD-L1 mediated by ceRNA dysregulation in different cancer types. Representative ceRNA networks (miRNA - ncRNA interaction) are shown. PD-L1: Programmed cell death ligand 1; ceRNA: completing endogenous RNA; miRNA: microRNA; ncRNA: non-coding RNA.

Figure 4

Schematic diagram showing a dual mechanism of PD-L1 regulation by a lncRNA TINCR in breast cancer to mediate resistance to cancer immunotherapy. TINCR was shown to increase PD-L1 expression by upregulating the USP20 via a dual mechanism. TINCR is expressed both in the nucleus and cytoplasm of breast cancer cells. In the cytoplasm, TINCR sponges miR-199a-5p and upregulates USP20 mRNA, thus increasing PD-L1 expression by suppressing its ubiquitination. In the nucleus, TINCR recruits DNMT1 to the gene promoter of miR-199-5p and promotes DNA methylation, thereby inhibiting the transcription of miR-199-5p. PD-L1: Programmed cell death ligand 1; lncRNA: long non-coding RNA; TINCR: tissue differentiation-inducing non-protein coding RNA; USP20: ubiquitin-specific protease 20.