The influence of circular RNAs on autophagy and disease progression

Abstract

Circular RNAs (circRNAs) are non-coding RNAs that have attracted considerable attention in recent years. Owing to their distinct circular structure, circRNAs are stable in cells. Autophagy is a catabolic process that helps in the degradation and recycling of harmful or inessential biological macromolecules in cells and enables cells to adapt to stress and changes in the internal and external environments. Evidence has shown that circRNAs influence the course of a disease by regulating autophagy, which indicates that autophagy is involved in the onset and development of various diseases and can affect drug resistance (for example, it affects cisplatin resistance in tumors). In this review, we summarized the role of circRNAs in autophagy and their influence on disease onset and progression as well as drug resistance. The review will expand our understanding of tumors as well as cardiovascular and neurological diseases and also suggest novel therapeutic strategies.Abbreviations: ACR: autophagy-related circRNA; ADSCs: adipogenic mesenchymal stem cells; AMPK: AMP-activated protein kinase; ATG: autophagy related; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; ceRNA: competing endogenous RNA; circRNA: circular RNA; CMA: chaperone-mediated autophagy; EPCs: endothelial progenitor cells; LE/MVBs: late endosomes/multivesicular bodies; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NSCLC: non-small cell lung cancer; PDLSCs: periodontal ligament stem cells; PE: phosphatidylethanolamine; PtdIns: phosphatidylinositol; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate 1,2-dipalmitoyl; PTEN: phosphatase and tensin homolog; RBPs: RNA-binding proteins; SiO₂: silicon dioxide; TFEB: transcription factor EB; ULK: unc-51 like autophagy activating kinase 1.

Keywords: Autophagy; cancer; cardiovascular disease; circRNAs; neurological disease.

Figure 1.

The biological characteristics and functions of circRNAs. (A) Intron pairing-derived cyclization. (B) Lasso-derived cyclization. (C) RNA binding proteins regulate circRNAs formation. (D) circRNAs adsorption of miRNA as a molecular sponge, playing the role of ceRNA. (E) circRNAs direct binding to mRNA. (F) circRNAs binding to proteins. (G) circRNAs binding to transcription factors. (H) circRNAs encoding small peptides.

Figure 2.

Schematic diagram depicting the process of autophagy, the biomolecules involved, and the signaling pathways regulated. Autophagy is primarily divided into four steps, namely the formation of autophagy precursors, the encapsulation of the cell components directed for digestion by the autophagosomes, the interaction of the autophagosomes with lysosomes to form the autolysosomes, and ultimately digestion and degradation of the autolysosomes. Signaling pathways such as AMPK, PI3K-AKT-MTORC1, MAPK, WNT-CTNNB1 regulate autophagy by affecting key proteins like the ULK complex, class III PItd3nsK complex, ATG protein family, and LC3-II.

Figure 3.

circRNAs affect tumor development and drug resistance by regulating autophagy. In tumor cells, circDNMT1, circCDYL, circ0006528, circABCB10, circMUC16, circMTO1, hsa_circ_0023404, circRACGAP1, circIARS, circPVT1, hsa_circ_0085131, circEIF6, hsa_circ_0035483, circ0009910, circPAN3, and circCCNB2 promote autophagy by promoting the functions of key proteins involved in the autophagy process, whereas circHIPK3, circNRIP1, circ0032821, circKHDC4, circCUL2, circMCTP2, CDR1-AS, circ104075, circ0027345, has_circ_0000515, circ0000285, circCRIM1, and circKMT2D inhibit autophagy by inhibiting the functions of key proteins in the autophagy process. Eventually circRNAs lead to the enhancement of tumor cell invasion, metastasis, proliferation, and drug resistance in patients.

Figure 4.

circRNAs affect cardiovascular diseases by regulating autophagy. In cardiovascular diseases, circ101237, circHipk2, and circPan3 promote autophagy whereas circZnf292, Acr, and circPan3 inhibit autophagy, and this ultimately leads to reduced cardiomyocyte apoptosis and a reduced myocardial necrosis area.

Figure 5.

circRNAs affect neuronal diseases by regulating autophagy. In neurological diseases, circ016719, circHectd1, circAkap7, circLrp1b, circDLGAP4, circHipk2, Cdr1-as, and circNf1-419 promote autophagy in neuronal cells or glial cells by promoting the function of autophagy-related proteins; in contrast, circHipk3, circ2837, and Acr inhibit autophagy by inhibiting the functions of autophagy-related proteins. They ultimately affect the apoptosis of nerve cells and the inflammatory response of the nervous system.

Figure 6.

circRNAs affect other diseases by regulating autophagy. In inflammatory cells, circEIF3K promotes autophagy and affects apoptosis. In stem cells, circCDK8, mmu_circ_0000250, mmu_circ_0000623, and hsa_circ_0026827 promote autophagy and affect its function. In cadmium-exposed cells, hsa_circ_0040768 promotes autophagy and apoptosis whereas in fibroblasts, intestinal epithelial cells, and virus-infected cells, circHECTD1, circ012091, circGATAD2A, and circPabpn1 inhibit autophagy and cause cell proliferation, invasion, and migration.