miR-7 Reduces High Glucose Induced-damage Via HoxB3 and PI3K/AKT/mTOR Signaling Pathways in Retinal Pigment Epithelial Cells

Author(s): Zhongyi Yang, Hanying Hu, Yuling Zou, Wenbluo Luo, Lin Xie, Zhipeng You*

Journal Name: Current Molecular Medicine

Volume 20 , Issue 5 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor


Background: Diabetic retinopathy (DR) is a common complication of diabetes. This study investigated the effect of miR-7 in the regulation of cell proliferation via the HoxB3 gene and PI3K/AKT/mTOR signaling pathways in DR.

Methods: Human retinal pigment epithelial cell line (ARPE-19) cultured in normal medium (Control) and high glucose medium (25mM glucose, HG) was transfected with mimics NC (HG+ mimics NC), miR-7 mimics (HG+miR-7 mimics), inhibitor NC (HG+ inhibitor NC), and miR-inhibitor (HG+miR-7 inhibitor). The cells were assayed for viability, apoptosis, and expression of genes.

Results: HG reduced cell viability and increased apoptosis. However, miR-7 mimics reduced the apoptosis. PCR results showed that miR-7 was significantly upregulated after transfection with miR-7 mimics. The expression of Hoxb3, mTOR, p-PI3K, and p- AKT was significantly downregulated at mRNA and protein levels after miR-7 mimics transfection, while no difference was observed for PI3K and AKT expression.

Conclusion: Our findings demonstrate that miR-7 regulates the growth of retinal epithelial cells through various pathways and is a potential therapeutic target for the prevention and treatment of diabetic retinopathy.

Keywords: miR-7, HoxB3, DR, PI3K/AKT/mTOR signaling, retinopathy, celll proliferation.

Weng JP, Bi Y. Epidemiological status of chronic diabetic complications in china. Chin Med J 2015; 128(24): 3267-9.
[http://dx.doi.org/10.4103/0366-6999.171350] [PMID: 26668138]
Vujosevic S, Midena E. Diabetic retinopathy in italy: epidemiology data and telemedicine screening programs. J Diabetes Res 2016; 2016 3627465
[http://dx.doi.org/10.1155/2016/3627465] [PMID: 27990441]
Lorenzi GM, Braffett BH, Arends VL, et al. Quality control measures over 30 years in a multicenter clinical study: results from the diabetes control and complications trial / epidemiology of diabetes interventions and complications (DCCT/EDIC) study. PLoS One 2015; 10(11) e0141286
[http://dx.doi.org/10.1371/journal.pone.0141286] [PMID: 26529311]
Mottaghi S, Larijani B, Sharifi AM. Atorvastatin: an efficient step forward in mesenchymal stem cell therapy of diabetic retinopathy. Cytotherapy 2013; 15(3): 263-6.
[http://dx.doi.org/10.1016/j.jcyt.2012.11.002] [PMID: 23253439]
Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. eLife 2015; 4: 4.
[http://dx.doi.org/10.7554/eLife.05005] [PMID: 26267216]
Zhou X, Zhu W, Li H, et al. Diagnostic value of a plasma microRNA signature in gastric cancer: a microRNA expression analysis. Sci Rep 2015; 5: 11251.
[http://dx.doi.org/10.1038/srep11251] [PMID: 26059512]
Wu JH, Gao Y, Ren AJ, et al. Altered microRNA expression profiles in retinas with diabetic retinopathy. Ophthalmic Res 2012; 47(4): 195-201.
[http://dx.doi.org/10.1159/000331992] [PMID: 22156553]
Currie KW, Brown DD, Zhu S, et al. HOX gene complement and expression in the planarian Schmidtea mediterranea. Evodevo 2016; 7: 7.
[http://dx.doi.org/10.1186/s13227-016-0044-8] [PMID: 27034770]
Platais C, Hakami F, Darda L, Lambert DW, Morgan R, Hunter KD. The role of HOX genes in head and neck squamous cell carcinoma. J Oral Pathol Med 2016; 45(4): 239-47.
[http://dx.doi.org/10.1111/jop.12388] [PMID: 26661059]
Hutlet B, Theys N, Coste C, et al. Systematic expression analysis of Hox genes at adulthood reveals novel patterns in the central nervous system. Brain Struct Funct 2016; 221(3): 1223-43.
[http://dx.doi.org/10.1007/s00429-014-0965-8] [PMID: 25527350]
Li Q, Zhu F, Chen P. miR-7 and miR-218 epigenetically control tumor suppressor genes RASSF1A and Claudin-6 by targeting HoxB3 in breast cancer. Biochem Biophys Res Commun 2012; 424(1): 28-33.
[http://dx.doi.org/10.1016/j.bbrc.2012.06.028] [PMID: 22705304]
Li YZ, Wen L, Wei X, et al. Inhibition of miR-7 promotes angiogenesis in human umbilical vein endothelial cells by upregulating VEGF via KLF4. Oncol Rep 2016; 36(3): 1569-75.
[http://dx.doi.org/10.3892/or.2016.4912] [PMID: 27431648]
Wei LZ, Wang YQ, Chang YL, et al. Imbalance of a KLF4-miR-7 auto-regulatory feedback loop promotes prostate cancer cell growth by impairing microRNA processing. Am J Cancer Res 2018; 8(2): 226-44.
[PMID: 29511594]
Senthilkumari S, Sharmila R, Chidambaranathan G, Vanniarajan A. Epalrestat, an aldose reductase inhibitor prevents glucose-induced toxicity in human retinal pigment epithelial cells in vitro. J Ocul Pharmacol Ther 2017; 33(1): 34-41.
[http://dx.doi.org/10.1089/jop.2016.0103] [PMID: 27835059]
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25(4): 402-8.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
Shadrach KG, Rayborn ME, Hollyfield JG, Bonilha VL. Correction: DJ-1-dependent regulation of oxidative stress in the retinal pigment epithelium (RPE). PLoS One 2017; 12(10) e0185834
[http://dx.doi.org/10.1371/journal.pone.0185834] [PMID: 28968455]
Li KR, Yang SQ, Gong YQ, et al. 3H-1,2-dithiole-3-thione protects retinal pigment epithelium cells against Ultra-violet radiation via activation of Akt-mTORC1-dependent Nrf2-HO-1 signaling. Sci Rep 2016; 6: 25525.
[http://dx.doi.org/10.1038/srep25525] [PMID: 27151674]
Chen XL, Zhang XD, Li YY, Chen XM, Tang DR, Ran RJ. Involvement of HMGB1 mediated signalling pathway in diabetic retinopathy: evidence from type 2 diabetic rats and ARPE-19 cells under diabetic condition. Br J Ophthalmol 2013; 97(12): 1598-603.
[http://dx.doi.org/10.1136/bjophthalmol-2013-303736] [PMID: 24133029]
Oh JR, Han JW, Kim YK, Ohn YH, Park TK. The effects of anti-vascular endothelial growth factor agents on human retinal pigment epithelial cells under high glucose conditions. Int J Ophthalmol 2017; 10(2): 203-10.
[PMID: 28251077]
Takagi H, Tanihara H, Seino Y, Yoshimura N. Characterization of glucose transporter in cultured human retinal pigment epithelial cells: gene expression and effect of growth factors. Invest Ophthalmol Vis Sci 1994; 35(1): 170-7.
[PMID: 8300344]
Young TA, Wang H, Munk S, et al. Vascular endothelial growth factor expression and secretion by retinal pigment epithelial cells in high glucose and hypoxia is protein kinase C-dependent. Exp Eye Res 2005; 80(5): 651-62.
[http://dx.doi.org/10.1016/j.exer.2004.11.015] [PMID: 15862172]
Chen H, Fan Y, Xu W, et al. miR-10b inhibits apoptosis and promotes proliferation and invasion of endometrial cancer cells via targeting HOXB3. Cancer Biother Radiopharm 2016; 31(6): 225-31.
[http://dx.doi.org/10.1089/cbr.2016.1998] [PMID: 27447302]
Yang D, Yan R, Zhang X, et al. Deregulation of MicroRNA-375 inhibits cancer proliferation migration and chemosensitivity in pancreatic cancer through the association of HOXB3. Am J Transl Res 2016; 8(3): 1551-9.
[PMID: 27186281]
Arevalo JF, Liu TYA. Intravitreal bevacizumab in diabetic retinopathy. Recommendations from the pan-american collaborative retina study group (PACORES): The 2016 knobloch lecture. Asia Pac J Ophthalmol (Phila) 2018; 7(1): 36-9.
[PMID: 29280367]
Ma J, Wang J, Liu Y, et al. Comparisons of serum miRNA expression profiles in patients with diabetic retinopathy and type 2 diabetes mellitus. Clinics (São Paulo) 2017; 72(2): 111-5.
[http://dx.doi.org/10.6061/clinics/2017(02)08] [PMID: 28273235]
Choudhary GS, Al-Harbi S, Mazumder S, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis 2015; 6 e1593
[http://dx.doi.org/10.1038/cddis.2014.525] [PMID: 25590803]
Jacot JL, Sherris D. Potential therapeutic roles for inhibition of the PI3K/Akt/mTOR pathway in the pathophysiology of diabetic retinopathy. J Ophthalmol 2011; 2011 589813
[http://dx.doi.org/10.1155/2011/589813] [PMID: 22132311]
Xiong X, Wang P, Zhang Y, et al. Effects of traditional Chinese patent medicine on essential hypertension: a systematic review. Medicine (Baltimore) 2015; 94(5) e442
Chen X, Li J, Li M, et al. KH902 suppresses high glucose-induced migration and sprouting of human retinal endothelial cells by blocking VEGF and PIGF. Diabetes Obes Metab 2013; 15(3): 224-33.
[http://dx.doi.org/10.1111/dom.12008] [PMID: 22958404]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 27 April, 2020
Page: [372 - 378]
Pages: 7
DOI: 10.2174/1566524019666191023151137
Price: $65

Article Metrics

PDF: 16
PRC: 1