Study on the mechanism of miRNA expression profile and enrichment analysis on p21 in oxygen-induced retinopathy mice_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Boshi , Han Jindong , Huang Xinyuan , Li Hui , Cao Jingjing , Liang Jingli , Li Xiaorong ,  Dong Lijie

Tianjin Medical University Eye Hospital, Tianjin Medical University Eye Institute, Tianjin Medical University School of Optometry and Ophthalmology, Tianjin 300384, China;
Liu Boshi and Han Jindong are contributed equally to the article;

Corresponding author：

Dong Lijie, Email: aitaomubang@126.com

Keywords：

Retinal neovascularization; MicroRNAs; Cyclin-dependent kinase inhibitor p21; Animal experimentation

DOI：

10.3760/cma.j.cn511434-20201112-00545

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Objective To observe the expression of miRNA in retinal tissue of mice with oxygen-induced retinopathy (OIR), and screen miRNAs related to p21 and retinal neovascularization (RNV) formation. Methods A experimental study. Forty healthy 7-day-old C57BL/6J mice were randomly divided into normal group and OIR group, with 20 mice in each group. The oxygen induced RNV model was constructed in the OIR group, and no treatment was performed in the normal group. At the age of 17 days, the mice were killed and the RNV of mice was observed by retinal fluorescence; the nuclei of vascular endothelium that broke through the inner limiting membrane of retina were counted under light microscope. The retinal tissues were taken for miRNA chip analysis to detect the differentially expressed miRNAs between the normal group and the OIR group. The resulting differential miRNA target genes were subjected to enrichment analysis based on gene annotation (GO) and Kyoto Encyclopedia of genes and genomes (KEGG); miRNAs and pathways that may be related to p21 were screened through Targetscan, MiRanda and MicroT-CDs database alignment. Independent sample t-test was used for pairwise comparison between groups. Results Compared with the normal group, the area of nonperfusion area, RNV and the number of vascular endothelial nuclei that broke through the inner limiting membrane of the retina in the OIR group increased significantly, differences were statistically significant (t=18.800, 9.025; P＜0.05). Compared with the normal group, there were 54 miRNAs that were statistically differentially expressed in the OIR group, of which 47 were up-regulated and 7 were down-regulated. A total of 13 miRNAs related to p21 were screened from the alignment results of the three databases with the obtained differential miRNAs. According to the difference multiples, they were miR-7218-5p, miR-322-5p, miR-224-5p, miR-335-5p, miR-329-3p, miR-362-3p, miR-532-5p, miR-20b-5p, miR-20a-5p, miR-195a-5p, miR-423-5p, miR-497a-5p, and miR-129-5p. Differential miRNA target gene enrichment analysis yielded 1 112 go entries and 50 KEGG pathways, of which 50 go entries and 13 KEGG pathways were related to p21. Conclusion 13 miRNAs related to p21 were screened out in the OIR model.

Citation： Liu Boshi, Han Jindong, Huang Xinyuan, Li Hui, Cao Jingjing, Liang Jingli, Li Xiaorong, Dong Lijie. Study on the mechanism of miRNA expression profile and enrichment analysis on p21 in oxygen-induced retinopathy mice. Chinese Journal of Ocular Fundus Diseases, 2022, 38(9): 762-767. doi: 10.3760/cma.j.cn511434-20201112-00545 Copy

1.	Dong L, Nian H, Shao Y, et al. PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy[J]. Cell Tissue Res, 2015, 360(2): 233-243. DOI: 10.1007/s00441-014-2104-5.
2.	Li W, Dong L, Ma M, et al. Preliminary in vitro and in vivo assessment of a new targeted inhibitor for choroidal neovascularization in age-related macular degeneration[J]. Drug Des Devel Ther, 2016, 10: 3415-3423. DOI: 10.2147/DDDT.S115801.
3.	Shao Y, Dong LJ, Takahashi Y, et al. miRNA-451a regulates RPE function through promoting mitochondrial function in proliferative diabetic retinopathy[J/OL]. Am J Physiol Endocrinol Metab, 2019, 316(3): e443-452[2019-03-01]. https://pubmed.ncbi.nlm.nih.gov/30576241/. DOI: 10.1152/ajpendo.00360.2018.
4.	Li C, Lie H, Sun W. Inhibitory effect of miR-182-5p on retinal neovascularization by targeting angiogenin and BDNF[J]. Mol Med Rep, 2022, 25(2): 61. DOI: 10.3892/mmr.2021.12577.
5.	Chen X, Yao Y, Yuan F, et al. Overexpression of miR-181a-5p inhibits retinal neovascularization through endocan and the ERK1/2 signaling pathway[J]. J Cell Physiol, 2020, 235(12): 9323-9335. DOI: 10.1002/jcp.29733.
6.	El-Deiry WS. p21(WAF1) mediates cell-cycle inhibition, relevant to cancer suppression and therapy[J]. Cancer Res, 2016, 76(18): 5189-5191. DOI: 10.1158/0008-5472.
7.	韩金栋, 袁志刚, 郑华宾, 等. 重组腺病毒介导p21对小鼠视网膜新生血管生成的抑制作用[J]. 中华眼底病杂志, 2012, 28(5): 493-497. DOI: 10.3760/cma.j.issn.1005-1015.2012.05.015.Han JD, Yuan ZG, Zheng HB, et al. Recombined adenovirus mediated delivery of p21 inhibits oxygen-induced retinal neovascularization in mice[J]. Chin J Ocul Fundus Dis, 2012, 28(5): 493-497. DOI: 10.3760/cma.j.issn.1005-1015.2012.05.015.
8.	Han J, Yuan Z, Yan H. Inhibitory effect of adenoviral vector-mediated delivery of p21WAF1/CIP1 on retinal vascular endothelial cell proliferation and tube formation in cultured Rhesus monkey cells (RF/6A)[J]. Curr Eye Res, 2013, 38(6): 670-673. DOI: 10.3109/02713683.2012.746992.
9.	Dong L, Li W, Lin T, et al. PSF functions as a repressor of hypoxia-induced angiogenesis by promoting mitochondrial function[J]. Cell Commun Signal, 2021, 19(1): 14. DOI: 10.1186/s12964-020-00684-w.
10.	Xing X, Huang L, Lyu Y, et al. DL-3-N-butylphthalide protected retinal Müller cells dysfunction from oxidative stress[J]. Curr Eye Res, 2019, 44(10): 1112-1120. DOI: 10.1080/02713683.2019.1624777.
11.	牛瑞, 东莉洁, 马腾, 等. 结缔组织生长因子重组干扰载体慢病毒颗粒的构建及其对视网膜血管内皮细胞内源性结缔组织生长因子表达的抑制作用[J]. 中华眼底病杂志, 2018, 34(6): 580-585. DOI: 10.3760/cma.j.issn.1005-1015.2018.06.011.Niu R, Dong LJ, Ma T, et al. Construction of connective tissue growth factor recombinant interference vector lentiviral particle and its inhibitory effect on endogenous connective tissue growth factor expression in retinal vascular endothelial cells[J]. Chin J Ocul Fundus Dis, 2018, 34(6): 580-585. DOI: 10.3760/cma.j.issn.1005-1015.2018.06.011.
12.	张哲, 刘巨平, 东莉洁, 等. 高糖状态下视网膜血管内皮细胞基因表达谱的RNA-Seq分析[J]. 中华眼底病杂志, 2018, 34(4): 377-381. DOI: 10.3760/cma.j.issn.1005-1015.2018.04.014.Zhang Z, Liu JP, Dong LJ, et al. RNA-Seq analysis of gene expression profiling in retinal vascular endothelial cells under high glucose condition[J]. Chin J Ocul Fundus Dis, 2018, 34(4): 377-381. DOI: 10.3760/cma.j.issn.1005-1015.2018.04.014.
13.	田芳, 东莉洁, 周玉, 等. 重组腺相关病毒-多聚嘧啶序列结合蛋白相关剪接因子对氧诱导视网膜新生血管形成的抑制作用[J]. 中华眼底病杂志, 2014, 30(5): 504-508. DOI: 10.3760/cma.j.issn.1005-1015.2014.05.019.Tian F, Dong LJ, Zhou Y, et al. Inhibition of oxygen induced retinal neovascularization by recombinant adeno-associated virus-polypyrimidine tract-binding protein-associated splicing factor intraocular injection in mice[J]. Chin J Ocul Fundus Dis, 2014, 30(5): 504-508. DOI: 10.3760/cma.j.issn.1005-1015.2014.05.019.
14.	Zeng A, Yin J, Li Y, et al. MiR-129-5p targets Wnt5a to block PKC/ERK/NF-κB and JNK pathways in glioblastoma[J]. Cell Death Dis, 2018, 9(3): 394. DOI: 10.1038/s41419-018-0343-1.
15.	Diao Y, Jin B, Huang L, et al. MiR-129-5p inhibits glioma cell progression in vitro and in vivo by targeting TGIF2[J]. J Cell Mol Med, 2018, 22(4): 2357-2367. DOI: 10.1111/jcmm.13529.
16.	Zhang P, Li J, Song Y, et al. MiR-129-5p inhibits proliferation and invasion of chondrosarcoma cells by regulating SOX4/Wnt/β-catenin signaling pathway[J]. Cell Physiol Biochem, 2017, 42(1): 242-253. DOI: 10.1159/000477323.
17.	Wang Y, Zeng X, Wang N, et al. Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma[J]. Mol Cancer, 2018, 17(1): 89. DOI: 10.1186/s12943-018-0837-6.
18.	Wei H, Tang QL, Zhang K, et al. MiR-532-5p is a prognostic marker and suppresses cells proliferation and invasion by targeting TWIST1 in epithelial ovarian cancer[J]. Eur Rev Med Pharmacol Sci, 2018, 22(18): 5842-5850. DOI: 10.26355/eurrev_201809_15911.
19.	Li T, Lai Q, Wang S, et al. MicroRNA-224 sustains Wnt/β-catenin signaling and promotes aggressive phenotype of colorectal cancer[J]. J Exp Clin Cancer Res, 2016, 35: 21. DOI: 10.1186/s13046-016-0287-1.
20.	Li M, Liu Q, Lei J, et al. MiR-362-3p inhibits the proliferation and migration of vascular smooth muscle cells in atherosclerosis by targeting ADAMTS1[J]. Biochem Biophys Res Commun, 2017, 493(1): 270-276. DOI: 10.1016/j.bbrc.2017.09.031.

1. Dong L, Nian H, Shao Y, et al. PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy[J]. Cell Tissue Res, 2015, 360(2): 233-243. DOI: 10.1007/s00441-014-2104-5.
2. Li W, Dong L, Ma M, et al. Preliminary in vitro and in vivo assessment of a new targeted inhibitor for choroidal neovascularization in age-related macular degeneration[J]. Drug Des Devel Ther, 2016, 10: 3415-3423. DOI: 10.2147/DDDT.S115801.
3. Shao Y, Dong LJ, Takahashi Y, et al. miRNA-451a regulates RPE function through promoting mitochondrial function in proliferative diabetic retinopathy[J/OL]. Am J Physiol Endocrinol Metab, 2019, 316(3): e443-452[2019-03-01]. https://pubmed.ncbi.nlm.nih.gov/30576241/. DOI: 10.1152/ajpendo.00360.2018.
4. Li C, Lie H, Sun W. Inhibitory effect of miR-182-5p on retinal neovascularization by targeting angiogenin and BDNF[J]. Mol Med Rep, 2022, 25(2): 61. DOI: 10.3892/mmr.2021.12577.
5. Chen X, Yao Y, Yuan F, et al. Overexpression of miR-181a-5p inhibits retinal neovascularization through endocan and the ERK1/2 signaling pathway[J]. J Cell Physiol, 2020, 235(12): 9323-9335. DOI: 10.1002/jcp.29733.
6. El-Deiry WS. p21(WAF1) mediates cell-cycle inhibition, relevant to cancer suppression and therapy[J]. Cancer Res, 2016, 76(18): 5189-5191. DOI: 10.1158/0008-5472.
7. 韩金栋, 袁志刚, 郑华宾, 等. 重组腺病毒介导p21对小鼠视网膜新生血管生成的抑制作用[J]. 中华眼底病杂志, 2012, 28(5): 493-497. DOI: 10.3760/cma.j.issn.1005-1015.2012.05.015.Han JD, Yuan ZG, Zheng HB, et al. Recombined adenovirus mediated delivery of p21 inhibits oxygen-induced retinal neovascularization in mice[J]. Chin J Ocul Fundus Dis, 2012, 28(5): 493-497. DOI: 10.3760/cma.j.issn.1005-1015.2012.05.015.
8. Han J, Yuan Z, Yan H. Inhibitory effect of adenoviral vector-mediated delivery of p21WAF1/CIP1 on retinal vascular endothelial cell proliferation and tube formation in cultured Rhesus monkey cells (RF/6A)[J]. Curr Eye Res, 2013, 38(6): 670-673. DOI: 10.3109/02713683.2012.746992.
9. Dong L, Li W, Lin T, et al. PSF functions as a repressor of hypoxia-induced angiogenesis by promoting mitochondrial function[J]. Cell Commun Signal, 2021, 19(1): 14. DOI: 10.1186/s12964-020-00684-w.
10. Xing X, Huang L, Lyu Y, et al. DL-3-N-butylphthalide protected retinal Müller cells dysfunction from oxidative stress[J]. Curr Eye Res, 2019, 44(10): 1112-1120. DOI: 10.1080/02713683.2019.1624777.
11. 牛瑞, 东莉洁, 马腾, 等. 结缔组织生长因子重组干扰载体慢病毒颗粒的构建及其对视网膜血管内皮细胞内源性结缔组织生长因子表达的抑制作用[J]. 中华眼底病杂志, 2018, 34(6): 580-585. DOI: 10.3760/cma.j.issn.1005-1015.2018.06.011.Niu R, Dong LJ, Ma T, et al. Construction of connective tissue growth factor recombinant interference vector lentiviral particle and its inhibitory effect on endogenous connective tissue growth factor expression in retinal vascular endothelial cells[J]. Chin J Ocul Fundus Dis, 2018, 34(6): 580-585. DOI: 10.3760/cma.j.issn.1005-1015.2018.06.011.
12. 张哲, 刘巨平, 东莉洁, 等. 高糖状态下视网膜血管内皮细胞基因表达谱的RNA-Seq分析[J]. 中华眼底病杂志, 2018, 34(4): 377-381. DOI: 10.3760/cma.j.issn.1005-1015.2018.04.014.Zhang Z, Liu JP, Dong LJ, et al. RNA-Seq analysis of gene expression profiling in retinal vascular endothelial cells under high glucose condition[J]. Chin J Ocul Fundus Dis, 2018, 34(4): 377-381. DOI: 10.3760/cma.j.issn.1005-1015.2018.04.014.
13. 田芳, 东莉洁, 周玉, 等. 重组腺相关病毒-多聚嘧啶序列结合蛋白相关剪接因子对氧诱导视网膜新生血管形成的抑制作用[J]. 中华眼底病杂志, 2014, 30(5): 504-508. DOI: 10.3760/cma.j.issn.1005-1015.2014.05.019.Tian F, Dong LJ, Zhou Y, et al. Inhibition of oxygen induced retinal neovascularization by recombinant adeno-associated virus-polypyrimidine tract-binding protein-associated splicing factor intraocular injection in mice[J]. Chin J Ocul Fundus Dis, 2014, 30(5): 504-508. DOI: 10.3760/cma.j.issn.1005-1015.2014.05.019.
14. Zeng A, Yin J, Li Y, et al. MiR-129-5p targets Wnt5a to block PKC/ERK/NF-κB and JNK pathways in glioblastoma[J]. Cell Death Dis, 2018, 9(3): 394. DOI: 10.1038/s41419-018-0343-1.
15. Diao Y, Jin B, Huang L, et al. MiR-129-5p inhibits glioma cell progression in vitro and in vivo by targeting TGIF2[J]. J Cell Mol Med, 2018, 22(4): 2357-2367. DOI: 10.1111/jcmm.13529.
16. Zhang P, Li J, Song Y, et al. MiR-129-5p inhibits proliferation and invasion of chondrosarcoma cells by regulating SOX4/Wnt/β-catenin signaling pathway[J]. Cell Physiol Biochem, 2017, 42(1): 242-253. DOI: 10.1159/000477323.
17. Wang Y, Zeng X, Wang N, et al. Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma[J]. Mol Cancer, 2018, 17(1): 89. DOI: 10.1186/s12943-018-0837-6.
18. Wei H, Tang QL, Zhang K, et al. MiR-532-5p is a prognostic marker and suppresses cells proliferation and invasion by targeting TWIST1 in epithelial ovarian cancer[J]. Eur Rev Med Pharmacol Sci, 2018, 22(18): 5842-5850. DOI: 10.26355/eurrev_201809_15911.
19. Li T, Lai Q, Wang S, et al. MicroRNA-224 sustains Wnt/β-catenin signaling and promotes aggressive phenotype of colorectal cancer[J]. J Exp Clin Cancer Res, 2016, 35: 21. DOI: 10.1186/s13046-016-0287-1.
20. Li M, Liu Q, Lei J, et al. MiR-362-3p inhibits the proliferation and migration of vascular smooth muscle cells in atherosclerosis by targeting ADAMTS1[J]. Biochem Biophys Res Commun, 2017, 493(1): 270-276. DOI: 10.1016/j.bbrc.2017.09.031.

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Study on the mechanism of miRNA expression profile and enrichment analysis on p21 in oxygen-induced retinopathy mice

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