目的：探讨microRNA-139-5p（miR-139-5p）靶向调控S100钙结合蛋白A4（S100A4）基因介导Wnt信号通路对2型糖尿病（T2DM）大鼠胰岛β细胞凋亡的影响。方法：构建T2DM大鼠模型；通过组织和细胞实验证实糖尿病大鼠miR-195-5p/S100A4/Wnt通路相关因子表达失调；检测各组胰岛β细胞中GSK-3β、PDX-1以及凋亡相关因子（Bax、Bcl-2）的表达并检测各组细胞周期和凋亡情况。结果：过表达miR-139-5p或沉默S100A4能够抑制T2DM大鼠胰岛β细胞中Wnt通路相关因子表达，抑制GSK-3β、Bax表达，促进PDX-1、Bcl-2表达，G₀/G₁期细胞比例下降，S期细胞比例上升，抑制胰岛β细胞凋亡（均P<0.05）；miR-139-5p inhibitor组各项指标表达与miR-139-5p mimic组相反。结论：miR-139-5p能够靶向抑制S100A4基因，抑制Wnt信号通路激活，从而减少T2DM大鼠胰岛β细胞凋亡。

[1] DONG X,ZHAO S X,XU B Q,et al.Gynura divaricata ameliorates hepatic insulin resistance by modulating insulin signaling,maintaining glycolipid homeostasis and reducing inflammation in type 2 diabetic mice[J].Toxicol Res (Camb),2019,8(6):928-938.
[2] 邓琳玲,罗玲,林潭发,等.3C疗法对2型糖尿病患者血糖波动控制的效果研究[J].现代医学,2020,48(2):230-234.
[3] GUO R,YU Y,ZHANG Y J,et al.Overexpression of miR-297b-5p protects against stearic acid-induced pancreatic β-cell apoptosis by targeting LATS2[J].Am J Physiol Endocrinol Metab,2020,318(3):E430-E439.
[4] YAN C,LI J,FENG S,et al.Long noncoding RNA Gomafu upregulates Foxo1 expression to promote hepatic insulin resistance by sponging miR-139-5p[J].Cell Death Dis,2018,9(3):289.
[5] CHEN N,SATO D,SAIKI Y,et al.S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility[J].Biochem Biophys Res Commun,2014,447(3):459-464.
[6] YANG D,DU G,XU A,et al.Expression of miR-149-3p inhibits proliferation,migration,and invasion of bladder cancer by targeting S100A4[J].Am J Cancer Res,2017,7(11):2209-2219.
[7] GUO J,BIAN Y,WANG Y,et al.FAM107B is regulated by S100A4 and mediates the effect of S100A4 on the proliferation and migration of MGC803 gastric cancer cells[J].Cell Biol Int,2017,41(10):1103-1109.
[8] 闫锡秋.S100A4和OPN在糖尿病大鼠视网膜病变中表达的实验研究[J].中医临床研究,2018,10(4):37-39.
[9] 胡倩,周琼,李军,等.Wnt信号通路中DKK1、β-catenin基因在绝经后女性2型糖尿病患者中的表达及与骨代谢关系的研究[J].中国骨质疏松杂志,2018,24(11):64-68.
[10] ELEMEERY M N,MOHAMED M A,MADKOUR M A,et al.MicroRNA signature in patients with hepatocellular carcinoma associated with type 2 diabetes[J].World J Gastroenterol,2019,25:6322-6341.
[11] LI T,YANG G M,ZHU Y,et al.Diabetes and hyperlipidemia induce dysfunction of VSMCs:contribution of the metabolic inflammation/miRNA pathway[J].Am J Physiol Endocrinol Metab,2015,308(4):E257-E269.
[12] ZHANG K,YU M,HAO F,et al.Knockdown of S100A4 blocks growth and metastasis of anaplastic thyroid cancer cells in vitro and in vivo[J].Cancer Biomark,2016,17(3):281-291.
[13] LIU Y,GENG Y H,YANG H,et al.Extracellular ATP drives breast cancer cell migration and metastasis via S100A4 production by cancer cells and fibroblasts[J].Cancer Lett,2018,430:1-10.
[14] DONG N,SHI H,XU B,et al.Increased plasma S100A12 levels are associated with diabetic retinopathy and prognostic biomarkers of macrovascular events in type 2 diabetic patients[J].Invest Ophthalmol Vis Sci,2015,56(8):4177-4185.
[15] 王莉霞,罗晓红.S100A8/A9在2型糖尿病及其并发症中的作用及意义[J].华南国防医学杂志,2017,31(4):68-70.
[16] 岳温恒,厉娜,汪沁沁,等.S100A4基因沉默抑制晚期糖基化终产物诱导内皮细胞钙化的作用[J].上海交通大学学报(医学版),2016,36(7):974-979.
[17] WANG X Y,ZHANG X Z,LI F,et al.MiR-128-3p accelerates cardiovascular calcification and insulin resistance through ISL1-dependent Wnt pathway in type 2 diabetes mellitus rats[J].J Cell Physiol,2019,234(4):4997-5010.
[18] TIAN C Y,WANG Y,LA X J,et al.Spleen-kidney supplementing formula alleviates insulin resistance via regulating AKT/glycogen synthase kinase 3β pathway in rats with type 2 diabetic induced by high-fat diet[J].J Tradit Chin Med,2019,39(2):199-206.
[19] MARTINEZ G M,CRUZ V D E,MORENO C J,et al.Induction of nestin early expression as a hallmark for mesenchymal stem cells expression of PDX-1 as a pre-disposing factor for their conversion into insulin producing cells[J].Int J Stem Cells,2017,10(1):76-82.