Research status and prospect of circular RNAs in diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Lu Chen ,  Shao Jun

Department of Ophthalmology, Wuxi People’s Hospital of Nanjing Medical University, Wuxi 214023, China;

Corresponding author：

Shao Jun, Email: shaojun1983@hotmail.com

Keywords：

Diabetic retinopathy; Biomarkers, pharmacological; Molecular targeted therapy; Review; circRNA

DOI：

10.3760/cma.j.cn511434-20210416-00197

Video：

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Abstract Full text Figures/Tables Video References Cited by

The mechanisms behind diabetic retinopathy (DR) can be ascribed primarily to retinal microvascular abnormalities, excessive inflammatory response and neurodegeneration. Circular RNA (circRNA) is a type of endogenous non-coding RNA with a special circular structure, which is mainly composed of precursor RNA after shearing and processing. It is widely present in the retina and participates in the occurrence and development of various fundus diseases. CircRNAs express in an abnormal way in retina, serving as “the sponge” for miRNA so as to play roles in dysfunction of retinal vascular, inflammatory response and neurodegeneration in the development of DR. Further studies for circRNAs in DR will illustrate pathophysiology of DR more deeply, shedding light on circRNAs becoming novel biomarkers and molecular targets for diagnosis and treatment, thus achieving the goal of early diagnosis and precise therapy of DR.

Citation： Lu Chen, Shao Jun. Research status and prospect of circular RNAs in diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2022, 38(1): 77-80. doi: 10.3760/cma.j.cn511434-20210416-00197 Copy

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2.	Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency[J]. Nature, 2013, 495(7441): 333-338. DOI: 10.1038/nature11928.
3.	He M, Wang W, Yu H, et al. Comparison of expression profiling of circular RNAs in vitreous humour between diabetic retinopathy and non-diabetes mellitus patients[J]. Acta Diabetol, 2020, 57(4): 479-489. DOI: 10.1007/s00592-019-01448-w.
4.	Chen J, Yang X, Liu R, et al. Circular RNA GLIS2 promotes colorectal cancer cell motility via activation of the NF-kappaB pathway[J/OL]. Cell Death Dis, 2020, 11(9): 788[2020-09-23]. https://pubmed.ncbi.nlm.nih.gov/32968054/. DOI: 10.1038/s41419-020-02989-7.
5.	Hsiao KY, Lin YC, Gupta SK, et al. Noncoding effects of circular RNA CCDC66 promote colon cancer growth and metastasis[J]. Cancer Res, 2017, 77(9): 2339-2350. DOI: 10.1158/0008-5472.CAN-16-1883.
6.	Lukiw WJ. Circular RNA (circRNA) in Alzheimer's disease (AD)[J/OL]. Front Genet, 2013, 4: 307[2013-12-13]. https://pubmed.ncbi.nlm.nih.gov/24427167/. DOI: 10.3389/fgene.2013.00307.
7.	Shen S, Yao T, Xu Y, et al. CircECE1 activates energy metabolism in osteosarcoma by stabilizing c-Myc[J]. Mol Cancer, 2020, 19(1): 151. DOI: 10.1186/s12943-020-01269-4.
8.	Zeng Z, Xia L, Fan S, et al. Circular RNA circMAP3K5 acts as a microRNA-22-3p sponge to promote resolution of intimal hyperplasia via TET2-mediated smooth muscle cell differentiation[J]. Circulation, 2021, 143(4): 354-371. DOI: 10.1161/CIRCULATIONAHA.120.049715.
9.	Wawrzyniak O, Zarebska Z, Rolle K, et al. Circular and long non-coding RNAs and their role in ophthalmologic diseases[J]. Acta Biochim Pol, 2018, 65(4): 497-508. DOI: 10.18388/abp.2018_2639.
10.	Zhang C, Hu J, Yu Y. CircRNA is a rising star in researches of ocular diseases[J/OL]. Front Cell Dev Biol, 2020, 8: 850[2020-09-03]. https://pubmed.ncbi.nlm.nih.gov/33015046/. DOI: 10.3389/fcell.2020.00850.
11.	Guo N, Liu XF, Pant OP, et al. Circular RNAs: novel promising biomarkers in ocular diseases[J]. Int J Med Sci, 2019, 16(4): 513-518. DOI: 10.7150/ijms.29750.
12.	Sun LF, Zhang B, Chen XJ, et al. Circular RNAs in human and vertebrate neural retinas[J]. RNA Biol, 2019, 16(6): 821-829. DOI: 10.1080/15476286.2019.1591034.
13.	Zhang SJ, Chen X, Li CP, et al. Identification and characterization of circular RNAs as a new class of putative biomarkers in diabetes retinopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(14): 6500-6509. DOI: 10.1167/iovs.17-22698.
14.	Liu C, Yao MD, Li CP, et al. Silencing of circular RNA-ZNF609 ameliorates vascular endothelial dysfunction[J]. Theranostics, 2017, 7(11): 2863-2877. DOI: 10.7150/thno.19353.
15.	Liu G, Zhou S, Li X, et al. Inhibition of hsa_circ_0002570 suppresses high-glucose-induced angiogenesis and inflammation in retinal microvascular endothelial cells through miR-1243/angiomotin axis[J]. Cell Stress Chaperones, 2020, 25(5): 767-777. DOI: 10.1007/s12192-020-01111-2.
16.	Shan K, Liu C, Liu BH, et al. Circular noncoding RNA HIPK3 mediates retinal vascular dysfunction in diabetes mellitus[J]. Circulation, 2017, 136(17): 1629-1642. DOI: 10.1161/CIRCULATIONAHA.117.029004.
17.	Wu Z, Liu B, Ma Y, et al. Discovery and validation of hsa_circ_0001953 as a potential biomarker for proliferative diabetic retinopathy in human blood[J]. Acta Ophthalmol, 2021, 99(3): 306-313. DOI: 10.1111/aos.14585.
18.	Kusuhara S, Fukushima Y, Ogura S, et al. Pathophysiology of diabetic retinopathy: the old and the new[J]. Diabetes Metab J, 2018, 42(5): 364-376. DOI: 10.4093/dmj.2018.0182.
19.	Cheung N, Mitchell P, Wong TY. Diabetic retinopathy[J]. Lancet, 2010, 376(9735): 124-136. DOI: 10.1016/S0140-6736(09)62124-3.
20.	Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature, 2013, 495(7441): 384-388. DOI: 10.1038/nature11993.
21.	Zhu K, Hu X, Chen H, et al. Downregulation of circRNA DMNT3B contributes to diabetic retinal vascular dysfunction through targeting miR-20b-5p and BAMBI[J]. EBioMedicine, 2019, 49: 341-353. DOI: 10.1016/j.ebiom.2019.10.004.
22.	Zou J, Liu KC, Wang WP, et al. Circular RNA COL1A2 promotes angiogenesis via regulating miR-29b/VEGF axis in diabetic retinopathy[J/OL]. Life Sci, 2020, 256: 117888[2020-09-01]. https://pubmed.ncbi.nlm.nih.gov/32497630/. DOI: 10.1016/j.lfs.2020.117888.
23.	Geevarghese A, Herman IM. Pericyte-endothelial crosstalk: implications and opportunities for advanced cellular therapies[J]. Transl Res, 2014, 163(4): 296-306. DOI: 10.1016/j.trsl.2014.01.011.
24.	Ferland-McCollough D, Slater S, Richard J, et al. Pericytes, an overlooked player in vascular pathobiology[J]. Pharmacol Ther, 2017, 171: 30-42. DOI: 10.1016/j.pharmthera.2016.11.008.
25.	Jiang Q, Liu C, Li CP, et al. Circular RNA-ZNF532 regulates diabetes-induced retinal pericyte degeneration and vascular dysfunction[J]. J Clin Invest, 2020, 130(7): 3833-3847. DOI: 10.1172/JCI123353.
26.	Liu C, Ge HM, Liu BH, et al. Targeting pericyte-endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction[J]. Proc Natl Acad Sci USA, 2019, 116(15): 7455-7464. DOI: 10.1073/pnas.1814874116.
27.	Tonade D, Kern TS. Photoreceptor cells and RPE contribute to the development of diabetic retinopathy[J/OL]. Prog Retin Eye Res, 2021, 83: 100919[2020-11-12]. https://pubmed.ncbi.nlm.nih.gov/33188897/. DOI: 10.1016/j.preteyeres.2020.100919.
28.	Li Y, Cheng T, Wan C, et al. circRNA_0084043 contributes to the progression of diabetic retinopathy via sponging miR-140-3p and inducing TGFA gene expression in retinal pigment epithelial cells[J/OL]. Gene, 2020, 747: 144653[2020-07-15]. https://pubmed.ncbi.nlm.nih.gov/32259630/. DOI: 10.1016/j.gene.2020.144653.
29.	Sun H, Kang X. hsa_circ_0041795 contributes to human retinal pigment epithelial cells (ARPE 19) injury induced by high glucose via sponging miR-646 and activating VEGFC[J/OL]. Gene, 2020, 747: 144654[2020-07-15]. https://pubmed.ncbi.nlm.nih.gov/32259632/. DOI: 10.1016/j.gene.2020.144654.
30.	Zhou L, Li FF, Wang SM. Circ-ITCH restrains the expression of MMP-2, MMP-9 and TNF-alpha in diabetic retinopathy by inhibiting miR-22[J/OL]. Exp Mol Pathol, 2021, 118: 104594[2020-12-09]. https://pubmed.ncbi.nlm.nih.gov/33309614/. DOI: 10.1016/j.yexmp.2020.104594.
31.	Altmann C, Schmidt MHH. The role of microglia in diabetic retinopathy: inflammation, microvasculature defects and neurodegeneration[J]. Int J Mol Sci, 2018, 19(1): 110. DOI: 10.3390/ijms19010110.
32.	Zhang Y, Liu Q, Liao Q. CircHIPK3: a promising cancer-related circular RNA[J]. Am J Transl Res, 2020, 12(10): 6694-6704.
33.	Li Y, Ge YZ, Xu L, et al. Circular RNA ITCH: a novel tumor suppressor in multiple cancers[J/OL]. Life Sci, 2020, 254: 117176[2019-12-18]. https://pubmed.ncbi.nlm.nih.gov/31843532/. DOI: 10.1016/j.lfs.2019.117176.
34.	Deng Y, Li S, Li S, et al. CircPDE4B inhibits retinal pathological angiogenesis via promoting degradation of HIF-1alpha though targeting miR-181c[J]. IUBMB Life, 2020, 72(9): 1920-1929. DOI: 10.1002/iub.2307.

1. Gu Y, Ke G, Wang L, et al. Altered expression profile of circular RNAs in the serum of patients with diabetic retinopathy revealed by microarray[J]. Ophthalmic Res, 2017, 58(3): 176-184. DOI: 10.1159/000479156.
2. Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency[J]. Nature, 2013, 495(7441): 333-338. DOI: 10.1038/nature11928.
3. He M, Wang W, Yu H, et al. Comparison of expression profiling of circular RNAs in vitreous humour between diabetic retinopathy and non-diabetes mellitus patients[J]. Acta Diabetol, 2020, 57(4): 479-489. DOI: 10.1007/s00592-019-01448-w.
4. Chen J, Yang X, Liu R, et al. Circular RNA GLIS2 promotes colorectal cancer cell motility via activation of the NF-kappaB pathway[J/OL]. Cell Death Dis, 2020, 11(9): 788[2020-09-23]. https://pubmed.ncbi.nlm.nih.gov/32968054/. DOI: 10.1038/s41419-020-02989-7.
5. Hsiao KY, Lin YC, Gupta SK, et al. Noncoding effects of circular RNA CCDC66 promote colon cancer growth and metastasis[J]. Cancer Res, 2017, 77(9): 2339-2350. DOI: 10.1158/0008-5472.CAN-16-1883.
6. Lukiw WJ. Circular RNA (circRNA) in Alzheimer's disease (AD)[J/OL]. Front Genet, 2013, 4: 307[2013-12-13]. https://pubmed.ncbi.nlm.nih.gov/24427167/. DOI: 10.3389/fgene.2013.00307.
7. Shen S, Yao T, Xu Y, et al. CircECE1 activates energy metabolism in osteosarcoma by stabilizing c-Myc[J]. Mol Cancer, 2020, 19(1): 151. DOI: 10.1186/s12943-020-01269-4.
8. Zeng Z, Xia L, Fan S, et al. Circular RNA circMAP3K5 acts as a microRNA-22-3p sponge to promote resolution of intimal hyperplasia via TET2-mediated smooth muscle cell differentiation[J]. Circulation, 2021, 143(4): 354-371. DOI: 10.1161/CIRCULATIONAHA.120.049715.
9. Wawrzyniak O, Zarebska Z, Rolle K, et al. Circular and long non-coding RNAs and their role in ophthalmologic diseases[J]. Acta Biochim Pol, 2018, 65(4): 497-508. DOI: 10.18388/abp.2018_2639.
10. Zhang C, Hu J, Yu Y. CircRNA is a rising star in researches of ocular diseases[J/OL]. Front Cell Dev Biol, 2020, 8: 850[2020-09-03]. https://pubmed.ncbi.nlm.nih.gov/33015046/. DOI: 10.3389/fcell.2020.00850.
11. Guo N, Liu XF, Pant OP, et al. Circular RNAs: novel promising biomarkers in ocular diseases[J]. Int J Med Sci, 2019, 16(4): 513-518. DOI: 10.7150/ijms.29750.
12. Sun LF, Zhang B, Chen XJ, et al. Circular RNAs in human and vertebrate neural retinas[J]. RNA Biol, 2019, 16(6): 821-829. DOI: 10.1080/15476286.2019.1591034.
13. Zhang SJ, Chen X, Li CP, et al. Identification and characterization of circular RNAs as a new class of putative biomarkers in diabetes retinopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(14): 6500-6509. DOI: 10.1167/iovs.17-22698.
14. Liu C, Yao MD, Li CP, et al. Silencing of circular RNA-ZNF609 ameliorates vascular endothelial dysfunction[J]. Theranostics, 2017, 7(11): 2863-2877. DOI: 10.7150/thno.19353.
15. Liu G, Zhou S, Li X, et al. Inhibition of hsa_circ_0002570 suppresses high-glucose-induced angiogenesis and inflammation in retinal microvascular endothelial cells through miR-1243/angiomotin axis[J]. Cell Stress Chaperones, 2020, 25(5): 767-777. DOI: 10.1007/s12192-020-01111-2.
16. Shan K, Liu C, Liu BH, et al. Circular noncoding RNA HIPK3 mediates retinal vascular dysfunction in diabetes mellitus[J]. Circulation, 2017, 136(17): 1629-1642. DOI: 10.1161/CIRCULATIONAHA.117.029004.
17. Wu Z, Liu B, Ma Y, et al. Discovery and validation of hsa_circ_0001953 as a potential biomarker for proliferative diabetic retinopathy in human blood[J]. Acta Ophthalmol, 2021, 99(3): 306-313. DOI: 10.1111/aos.14585.
18. Kusuhara S, Fukushima Y, Ogura S, et al. Pathophysiology of diabetic retinopathy: the old and the new[J]. Diabetes Metab J, 2018, 42(5): 364-376. DOI: 10.4093/dmj.2018.0182.
19. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy[J]. Lancet, 2010, 376(9735): 124-136. DOI: 10.1016/S0140-6736(09)62124-3.
20. Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature, 2013, 495(7441): 384-388. DOI: 10.1038/nature11993.
21. Zhu K, Hu X, Chen H, et al. Downregulation of circRNA DMNT3B contributes to diabetic retinal vascular dysfunction through targeting miR-20b-5p and BAMBI[J]. EBioMedicine, 2019, 49: 341-353. DOI: 10.1016/j.ebiom.2019.10.004.
22. Zou J, Liu KC, Wang WP, et al. Circular RNA COL1A2 promotes angiogenesis via regulating miR-29b/VEGF axis in diabetic retinopathy[J/OL]. Life Sci, 2020, 256: 117888[2020-09-01]. https://pubmed.ncbi.nlm.nih.gov/32497630/. DOI: 10.1016/j.lfs.2020.117888.
23. Geevarghese A, Herman IM. Pericyte-endothelial crosstalk: implications and opportunities for advanced cellular therapies[J]. Transl Res, 2014, 163(4): 296-306. DOI: 10.1016/j.trsl.2014.01.011.
24. Ferland-McCollough D, Slater S, Richard J, et al. Pericytes, an overlooked player in vascular pathobiology[J]. Pharmacol Ther, 2017, 171: 30-42. DOI: 10.1016/j.pharmthera.2016.11.008.
25. Jiang Q, Liu C, Li CP, et al. Circular RNA-ZNF532 regulates diabetes-induced retinal pericyte degeneration and vascular dysfunction[J]. J Clin Invest, 2020, 130(7): 3833-3847. DOI: 10.1172/JCI123353.
26. Liu C, Ge HM, Liu BH, et al. Targeting pericyte-endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction[J]. Proc Natl Acad Sci USA, 2019, 116(15): 7455-7464. DOI: 10.1073/pnas.1814874116.
27. Tonade D, Kern TS. Photoreceptor cells and RPE contribute to the development of diabetic retinopathy[J/OL]. Prog Retin Eye Res, 2021, 83: 100919[2020-11-12]. https://pubmed.ncbi.nlm.nih.gov/33188897/. DOI: 10.1016/j.preteyeres.2020.100919.
28. Li Y, Cheng T, Wan C, et al. circRNA_0084043 contributes to the progression of diabetic retinopathy via sponging miR-140-3p and inducing TGFA gene expression in retinal pigment epithelial cells[J/OL]. Gene, 2020, 747: 144653[2020-07-15]. https://pubmed.ncbi.nlm.nih.gov/32259630/. DOI: 10.1016/j.gene.2020.144653.
29. Sun H, Kang X. hsa_circ_0041795 contributes to human retinal pigment epithelial cells (ARPE 19) injury induced by high glucose via sponging miR-646 and activating VEGFC[J/OL]. Gene, 2020, 747: 144654[2020-07-15]. https://pubmed.ncbi.nlm.nih.gov/32259632/. DOI: 10.1016/j.gene.2020.144654.
30. Zhou L, Li FF, Wang SM. Circ-ITCH restrains the expression of MMP-2, MMP-9 and TNF-alpha in diabetic retinopathy by inhibiting miR-22[J/OL]. Exp Mol Pathol, 2021, 118: 104594[2020-12-09]. https://pubmed.ncbi.nlm.nih.gov/33309614/. DOI: 10.1016/j.yexmp.2020.104594.
31. Altmann C, Schmidt MHH. The role of microglia in diabetic retinopathy: inflammation, microvasculature defects and neurodegeneration[J]. Int J Mol Sci, 2018, 19(1): 110. DOI: 10.3390/ijms19010110.
32. Zhang Y, Liu Q, Liao Q. CircHIPK3: a promising cancer-related circular RNA[J]. Am J Transl Res, 2020, 12(10): 6694-6704.
33. Li Y, Ge YZ, Xu L, et al. Circular RNA ITCH: a novel tumor suppressor in multiple cancers[J/OL]. Life Sci, 2020, 254: 117176[2019-12-18]. https://pubmed.ncbi.nlm.nih.gov/31843532/. DOI: 10.1016/j.lfs.2019.117176.
34. Deng Y, Li S, Li S, et al. CircPDE4B inhibits retinal pathological angiogenesis via promoting degradation of HIF-1alpha though targeting miR-181c[J]. IUBMB Life, 2020, 72(9): 1920-1929. DOI: 10.1002/iub.2307.

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