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Microrna-377 Participates in the Alzheimer's Disease by Regulating

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Microrna-377 Participates in the Alzheimer's Disease by Regulating European Review for Medical and Pharmacological Sciences 2018; 22: 2801-2808 Regulatory mechanism of microRNA-377 on CDH13 expression in the cell model of Alzheimer’s disease F.-F. LIU1,2, Z. ZHANG1, W. CHEN1, H.-Y. GU1, Q.-J. YAN2 1Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China 2Clinical Genomics Center, King Med Center for Clinical Laboratory Co., Ltd. Guangzhou, China Abstract. – OBJECTIVE: To explore whether mi- of the central nervous system. Epidemiological croRNA-377 could participate in the development researches1,2 have shown that AD mainly occurs of Alzheimer’s disease (AD) by regulating CDH13. in elderly over 65 years old, the incidence of whi- MATERIALS AND METHODS: In this research, ch increases with age. The pathogenesis of AD AD model was constructed by the SH-SY5Y cells. The expression levels of microRNA-377 is complicated and affected by multiple factors. and CDH13 in the AD model were detected by Many theories have been reported on the etiology quantitative Real-time polymerase chain reac- of AD, such as free radical injury, beta-amyloid tion (qRT-PCR). The cell viability and apoptosis (Aβ) cascade hypothesis, cholinergic theory, Tau after knockdown of microRNA-377 and CDH13 protein theory, calcium metabolism disorders were measured by cell counting kit-8 (CCK-8) and aluminum poisoning. However, Aβ cascade assay and flow cytometry, respectively. The reg- hypothesis and Tau protein theory are mostly of ulatory mechanism of microRNA-377 on CDH13 was confirmed by dual-luciferase reporter gene major concern to researchers. Establishment of an assay, qRT-PCR and Western blot. effective AD model is helpful to further study the RESULTS: Downregulated microRNA-377 and pathogenesis and treatment of AD on the cellular upregulated CDH13 were observed after suc- level. Since Aβ can mimic AD damage, it is com- cessful construction of the AD model. Cell via- monly used to induce the cell model of AD3. bility in the AD model group was significantly re- MicroRNAs are a class of small non-coding duced compared with that of the control group. Moreover, downregulated microRNA-377 could RNAs with 22 nucleotides (nt) in length. Mature further inhibit the cell viability, which was re- microRNAs are formed by the precursor tran- versed by CDH13 knockdown. Cell apoptosis script with a hairpin structure that is cut through in the AD model group was enhanced after mi- the Dicer enzyme4. In addition, mature miRNAs croRNA-377 knockdown, which was rescued by are complementarily bound to the 3’UTR se- decreasing the expression level of CDH13. Mi- quence of the target mRNA, leading to the regu- croRNA-377 was confirmed to regulate the ex- lation of the target gene5. MiRNAs are widely ex- pression level of CDH13 by dual-luciferase re- porter gene assay, qRT-PCR and Western blot. isted in all kinds of species and highly conserved CONCLUSIONS: MicroRNA-377 could regu- in evolution. It exerts a crucial role in regulating late the expression level of CDH13 by promoting gene expression and therefore has been well rec- cell proliferation and inhibiting cell apoptosis, ognized in recent years6,7. thus participating in the occurrence of the Alz- Studies have indicated that microRNA-377 can heimer’s disease. inhibit the proliferation and migration of gastric Key Words: cancer cells by inhibiting VEGFA expression, and MicroRNA-377, CDH13, Apoptosis, Alzheimer’s dis- eventually participates in the development of gas- ease. tric cancer8. Moreover, microRNA-377 has been proved to promote inflammation of white adipose Introduction tissues and reduce insulin sensitivity of obesity by inhibiting SIRT1 expression9. As to whether Alzheimer’s disease (AD), the most common microRNA-377 is involved in the occurrence of form of dementia, is known as a neurodegenera- AD still remain to be investigated. Therefore, we tive disease caused by the degenerative disorders aim to explore the effect of microRNA-377 on Corresponding Author: Huaiyu Gu, Ph.D; e-mail: [email protected] Qijiang Yan, Ph.D; e-mail: [email protected] 2801 F.-F. Liu, Z. Zhang, W. Chen, H.-Y. Gu, Q.-J. Yan cell viability and apoptosis by constructing the fected according to the instructions of Lipofect- cell model of AD, which provides new ideas for amine 2000 (Thermo Fisher Scientific, Waltham, exploring the AD pathogenesis. MA, USA). The microRNA-con, microRNA-337 mimics, anti-microRNA-337, si-CDH13 1 and si-CDH13 2 (Jima, Shanghai, China) were trans- Materials and Methods fected to the cells. Complete medium was re- placed 6 h after transfection. The interference Construction of the Cell Model of AD sequences were: microRNA-337 mimics (5’-AT- The SH-SY5Y cells were cultured in complete CACACAAAGGCAACTTTTGT-3’), anti-mi- Dulbecco’s Modified Eagle Medium (DMEM) croRNA-337 (F:5’-CGGGATCCGAATTCAC- high glucose medium supplemented with 10% fe- CAAGGGCAACCTCTTTTTTTAAGCTTGGG-3’, tal bovine serum (FBS) (Gibco, Rockville, MD, R:5’-CCCAAGCTTAAAAAAAGAGGTTGC- USA), 100 U/mL penicillin and 0.1 mg/mL strep- CCTTGGTGAATTCGGATCCCG-3’), si-CDH13 tomycin. Cells were maintained in an incubator (5’-CGGGCGCUUCUAGUCGGACAA-3’), si- with 5% CO2 and saturated humidity. After the CDH13 2 (5’-GGACCAGUCAAUUCUAAAC-3’). cells grew by the logarithmic growth phase, 25-35 μL of Aβ (final dose of 20 μmol/L) and 10% di- Cell Viability methyl sulfoxide (DMSO) were added in the AD 24 h after transfection, the cells were collect- model group and the control group, respectively. ed and seeded into 96-well plates at a dose of The cells were continually cultured for 48 h. 2×10 3/mL, with 6 replicates of each group. The cell viability was measured by cell counting kit- RNA Extraction and Quantitative 8 (CCK-8) assay (Dojindo, Kumamoto, Japan). Real-Time Polymerase Chain Reaction Briefly, 10 μL of CCK-8 solution were added (qRT-PCR) into each well. Cells were incubated at 37°C for Total RNA was extracted by TRIzol meth- 2 h in the dark. Absorbance (OD) values at the od (Invitrogen, Carlsbad, CA, USA) for re- wavelength of 450 nm were detected by the mi- verse transcription. Primers used in this study croplate reader. were as follows: CDH13 (F:5’-ACCAGCCT- GTCCTAAACTTGA-3’, R:5’-GTGTGGGCTT- Cell Apoptosis GAGACCTCG-3’), glyceraldehyde 3-phosphate Transfected cells in the logarithmic growth dehydrogenase (GAPDH) (F:5-’TGTGGGCAT- phase were seeded in 6-well plates at a density CAATGGATTTGG-3’, R:5’-ACACCATGTAT- of 1×10 5/mL. Cells were harvested after culturing TCCGGGTCAAT-3’). for 24 h. Annexin V-FITC (Invitrogen, Carlsbad, CA, USA) was used for cell staining for 15 min. Western Blotting Apoptosis was analyzed by a flow cytometer. Total proteins were extracted from cells by radio- Each experiment was repeated for three times and immunoprecipitation assay (RIPA) method (Beyo- the average value was taken. time, Shanghai, China) and then quantified using bi- cinchoninic acid (BCA) (Beyotime, Shanghai, China) Dual Luciferase Reporter Analysis based on manufacturer’s instructions. Proteins were The reporter plasmids containing the wild-type separated in a sodium dodecyl sulphate-polyacryl- (WT) and/or mutant (MUT) sequences of the amide gel electrophoresis (SDS-PAGE) gel and then 3’UTR of CDH13 were constructed. Cells were transferred to a polyvinylidene difluoride (PVDF) plated in 96-well plates overnight prior to trans- membrane (Millipore, Billerica, MA, USA). Mem- fection. 50 pmol/L microRNA-377 mimics or branes were blocked with 5% skimmed milk for 1 negative control and 80 ng CDH13 WT or MUT h, followed by the incubation of primary antibody plasmids were co-transfected to the cells. After overnight. Membranes were then incubated with the 48 h of transfection, luciferase activity was de- secondary antibody at room temperature for 1 h. Im- tected using the Dual Luciferase Reporter Assay munoreactive bands were exposed by enhanced che- System. miluminescence (ECL) method. Statistical Analysis Cell Transfection We used statistical product and service solu- The cells in the logarithmic growth phase were tions (SPSS 19.0, IBM Corp., Armonk, NY, USA) seeded into the 6-well plates, and were trans- software for statistical analysis. The quantitative 2802 MicroRNA-377 participates in the Alzheimer’s disease by regulating CDH13 data were represented as` x±s. Comparison be- detected by Western blot (Figure 1A). The pro- tween groups was done using One-way ANO- tein expressions of total Tau, Tau (S404) and Tau VA test followed by Least Significant Difference (T231) in the AD model group were remarkably (LSD). p<0.05 was considered statistically signif- increased in comparison with those of the con- icant (α=0.05). trol group (p<0.05), indicating the successful construction of the AD model. Additionally, reduced expression level of microRNA-377 in Results the AD model was observed (Figure 1B). Bio- informatics assay and functional analysis re- Construction of the Cell Model of AD and vealed that the target gene of microRNA-377 the Expression Level of microRNA-377 was CDH13. Therefore, the expression level of and CDH13 CDH13 in the AD model was detected. Our re- 48 h after successful construction of the AD sults demonstrated that the expression level of model, the protein expressions of total Tau, Tau CDH13 was remarkably increased in the AD cell (S404) and Tau (T231) in SH-SY5Y cells were model (Figure 1C). Figure 1. Construction of the AD cell model and the expression levels of microRNA-377 and CDH13. A, The expression levels and quantitative analysis of total Tau, Tau (S404) and Tau (T231) in SH-SY5Y cells. B, Compared with the control group, the expression level of microRNA-377 in the AD cell model group was significantly reduced. C, Compared with the control group, the expression level of CDH13 in the AD cell model group was significantly increased.
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