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Volume 49 Issue 1
Jan.  2024
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Correlation between the expression levels of miRNA-16, circRNA-100679 and miRNA-124 and severity of depression

  • 1.

    Department of Psychiatry, Taixing People's Hospital, Taixing Jiangsu 225400

  • 2.

    Department of Psychiatry, Taixing Psychiatric Hospital, Taixing Jiangsu 225400, China

  • Corresponding author: JIANG Qing, 1060473190@qq.com
  • Received Date: 2020-09-18
    Accepted Date: 2021-05-01
  • ObjectiveTo know the correlation between the expression levels of microRNA(miRNA)-16, circular RNA(circRNA)-100679 and miRNA-124, and severity of depression.MethodsEighty-one patients diagnosed with depression for the first time and 80 healthy adults at the same time were divided into the observation group and control group, respectively.The relative RNA expression levels of miRNA-16, circRNA-100679 and miRNA-124 were compared between two groups.According to the changes of Hamilton depression scale version 17(HAMD-17), the observation group was subdivided into the A, B and C groups, the relative expression of RNA among three groups was compared, and the correlation of which was analyzed.ResultsAfter treatment, the relative expression levels of miRNA-16 and circRNA-100679 in the observation group increased compared with those before treatment, while the relative expression levels of miRNA-124 in the observation group decreased compared with that before treatment(P < 0.01), and the differences of which between two groups were statistically significant(P < 0.05).After treatment, the HAMD-17 scores in A, B and C groups decreased, the relative expression levels of miRNA-16 and circRNA-100679 increased, and the relative expression of miRNA-124 decreased compared with those before treatment(P < 0.01).The HAMD-17 scores and relative expression level of miRNA-124 in group A, group B and group C gradually increased in turn(P < 0.01), and the relative expression levels of miRNA-16 and circRNA-100679 in group A, group B and group C gradually decreased in turn(P < 0.01).The relative expression levels of miRNA-124 were positively correlated with the HAMD-17 score(r=0.557, P < 0.05), and the relative expression levels of miRNA-16 and circRNA-100679 were negatively correlated with the HAMD-17 score(r=-0.325, P < 0.01;r=0.453, P < 0.05).ConclusionsThe relative expression levels of miRNA-16, circRNA-100679 and miRNA-124 are correlated with the severity of depression.Regulating its expression level may provide a new idea for the treatment of depression.
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  • [1] 解瑞宁, 乔艺, 张跃兵, 等. 抑郁症发病危险因素分析[J]. 中国预防医学志, 2018, 19(5): 356.
    [2] 王睿, 黄树明. 抑郁症发病机制研究进展[J]. 医学研究生学报, 2014, 27(12): 1332.
    [3] LIU Q, SUN NN, WU ZZ, et al. Chaihu-Shugan-San exerts an antidepressive effect by downregulating miR-124 and releasing inhibition of the MAPK14 and Gria3 signaling pathways[J]. Neural Regen Res, 2018, 13(5): 837. doi: 10.4103/1673-5374.232478
    [4] 徐宁, 张广芬, 余海鹰, 等. 抑郁症的表观遗传学机制研究进展[J]. 医学研究生学报, 2016, 29(10): 1093.
    [5] 孔令明, 牛威, 姚高峰, 等. 外周血circRNA的差异表达及其与抑郁症严重程度的关系[J]. 解放军医学杂志, 2018, 43(6): 504.
    [6] 袁梅菊, 毕雪飞. 首发抑郁症患者外周血microRNA-124的变化及临床意义[J]. 精神医学杂志, 2018, 31(1): 27.
    [7] 徐俊冕. 抑郁症诊断与治疗进展[J]. 世界临床药物, 2006, 27(3): 158.
    [8] 邰传朕, 鲍纪雪, 许秀峰, 等. 首发抑郁症患者认知功能的影响因素[J]. 中国心理卫生杂志, 2018, 32(10): 808. doi: 10.3969/j.issn.1000-6729.2018.10.002
    [9] 刘婉婉, 董宪喆, 刘屏. MTHFR-C677T基因多态性-抑郁症治疗的新思路[J]. 中国药理学通报, 2015, 31(7): 915.
    [10] 王宏浩, 韩文静, 张燕军, 等. circRNA研究现状及展望[J]. 南方农业学报, 2018, 49(3): 431.
    [11] 胡煜, 王玲, 毕武, 等. miR-1246在疾病上的研究进展[J]. 生物技术通报, 2017, 33(3): 29.
    [12] LLORENS F, THUNE K, SANDRES-B, et al. Ferrer I. MicroRNA expression in the locus coeruleus, entorhinal cortex, and hippocampus at early and middle stages of braak neurofibrillary tangle pathology[J]. J Mol Neurosci, 2017, 63(2): 206. doi: 10.1007/s12031-017-0971-4
    [13] HIGUCHI F, UCHIDA S, YAMAGATA H, et al. Hippocampal microRNA-124 enhances chronic stress resilience in mice[J]. J Neurosci, 2016, 36(27): 7253. doi: 10.1523/JNEUROSCI.0319-16.2016
    [14] 余昊, 王刚, 孙备. 环状RNA和癌症[J]. 中国肿瘤生物治疗杂志, 2018, 25(9): 940.
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Correlation between the expression levels of miRNA-16, circRNA-100679 and miRNA-124 and severity of depression

    Corresponding author: JIANG Qing, 1060473190@qq.com
  • 1. Department of Psychiatry, Taixing People's Hospital, Taixing Jiangsu 225400
  • 2. Department of Psychiatry, Taixing Psychiatric Hospital, Taixing Jiangsu 225400, China
  • Received Date: 2020-09-18
  • Accepted Date: 2021-05-01
  • Available Online: 2024-01-15

Abstract: ObjectiveTo know the correlation between the expression levels of microRNA(miRNA)-16, circular RNA(circRNA)-100679 and miRNA-124, and severity of depression.MethodsEighty-one patients diagnosed with depression for the first time and 80 healthy adults at the same time were divided into the observation group and control group, respectively.The relative RNA expression levels of miRNA-16, circRNA-100679 and miRNA-124 were compared between two groups.According to the changes of Hamilton depression scale version 17(HAMD-17), the observation group was subdivided into the A, B and C groups, the relative expression of RNA among three groups was compared, and the correlation of which was analyzed.ResultsAfter treatment, the relative expression levels of miRNA-16 and circRNA-100679 in the observation group increased compared with those before treatment, while the relative expression levels of miRNA-124 in the observation group decreased compared with that before treatment(P < 0.01), and the differences of which between two groups were statistically significant(P < 0.05).After treatment, the HAMD-17 scores in A, B and C groups decreased, the relative expression levels of miRNA-16 and circRNA-100679 increased, and the relative expression of miRNA-124 decreased compared with those before treatment(P < 0.01).The HAMD-17 scores and relative expression level of miRNA-124 in group A, group B and group C gradually increased in turn(P < 0.01), and the relative expression levels of miRNA-16 and circRNA-100679 in group A, group B and group C gradually decreased in turn(P < 0.01).The relative expression levels of miRNA-124 were positively correlated with the HAMD-17 score(r=0.557, P < 0.05), and the relative expression levels of miRNA-16 and circRNA-100679 were negatively correlated with the HAMD-17 score(r=-0.325, P < 0.01;r=0.453, P < 0.05).ConclusionsThe relative expression levels of miRNA-16, circRNA-100679 and miRNA-124 are correlated with the severity of depression.Regulating its expression level may provide a new idea for the treatment of depression.

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  • 抑郁症属于精神系统疾病，病人可有思维缓慢、情绪低落、言语活动减少的表现，家庭收入、居住环境等均会影响其发生，目前在世界范围内，抑郁症所致疾病负担占居第四位[1]。从神经生化角度来讲，乙酰胆碱能神经元亢进、去甲肾上腺素表达量不足、5-羟色胺及其受体减少、多巴胺及其受体不足均是目前被广为接受的发病机制假说[2]。微小RNA(miRNA)直接调控重要蛋白表达进而参与疾病发生已经获得了共识，而近年来，人们认为各种非编码RNA(ncRNA)包括miRNA、环形RNA(circRNA)、长链非编码RNA(long non-coding RNA, lnc RNA)等也同样可以影响DNA的转录过程, 从而参与包括抑郁症在内的疾病发展[3]。有研究指出[4-6]，miRNA-16、circRNA-100679、miRNA-124均可参与抑郁症的发病进程，然而有关其与该病严重程度相关性的研究并不多见，为此，我们就以上问题进行了探究。

1.   资料与方法

    1.1.   一般资料

  • 将2015年1月至2018年7月于本地区首次确诊为抑郁症的81例病人定义为观察组，将同期于我院体检且结果提示无明显异常的80名健康成年人定义为对照组。观察组中男37例，女44例，年龄(42.87±5.15)岁；对照组中男35例，女45例，年龄(42.98±5.23)岁。2组性别、年龄差异无统计学意义，均具有可比性。本研究已经过伦理委员会审批。纳入标准: 观察组病人均符合单项抑郁症的诊断，并于我院接受抗抑郁治疗，对照组则均排除；签署知情同意书；资料完整；年龄在18周岁以上。排除标准: 合并严重的器质性病变；合并恶性肿瘤；符合其他类型抑郁症诊断标准者；有自杀倾向者；有酒精及药物滥用病史者。

    • 1.2.   方法

    1.2.1.   2组RNA相对表达量的检测

  • 分别于观察组病人治疗前(入组后)、治疗后次日清晨及对照组病人体检当日抽取其空腹肘静脉血约8 mL左右，采用抗凝采血管收集标本。2 h内于离心机中离心，3 500 r/min离心15 min获取血清，-80 ℃保存。用预冷的PBS缓冲液冲洗，加入TRIzol试剂1 mL，并将其转移至无RNA酶的离心管中。加200 μL的三氯甲烷，摇匀后离心(转速12 000×g，时间20 min, 温度4 ℃)，小心吸取上清，加入等体积的无水乙醇。将样品加入离心柱离心，并采用WB共洗涤3次。采用新的离心管收集，加50 μL的无RNA酶水，离心(转速10 000×g，时间3 min, 温度4 ℃)，共检测3次。采用Evolution分光光度计就样品RNA的A280、A260进行检测，使其在1.9~2.2，共检测3次。依次于新离心管中加入缓冲液10 μL，RNA模板2 μL，引物1.2 μL，逆转录酶0.2 μL及无RNA酶水至20 μL，进行逆转录(25 ℃ 30 min，42 ℃ 30 min，85 ℃ 5 min)。将10 μL的PCR试剂，上下游引物各3 μL(100 μmol/L)，cDNA 1 μL, 三蒸水3 μL加入小离心管中。采用Applied Biosystems Veriti PCR仪分析，参数设置: 95 ℃ 3 min, 95 ℃ 30 s，62 ℃ 40 s，循环数为40。过程结束后，将所获取数据保存，采用Excel软件计算RNA的相对表达量(2-△△Ct法)。

    • 1.2.2.   抑郁严重程度评估

  • 于观察组病人入组时及治疗疗程结束后采用汉密尔顿抑郁量表17版本(HAMD-17)进行评分，采用治疗前后评分差/治疗前评分得出减分率，得分在≥75%、25%~＜75%、＜25%范围内可分别定义为A、B、C 3组。HAMD-17评分较高者症状较重。

    • 1.3.   统计学方法

  • 采用t检验、单因素方差分析、q检验和Pearson相关分析。

2.   结果

    2.1.   2组RNA相对表达量比较

  • 治疗前，观察组miRNA-16、circRNA-100679相对表达量低于对照组(P＜0.01), miRNA-124相对表达量高于对照组(P＜0.01);治疗后，观察组miRNA-16、circRNA-100679相对表达量较治疗前升高(P＜0.01)，miRNA-124相对表达量较治疗前降低(P＜0.01)，但与对照组比较仍存在差异，观察组miRNA-16、circRNA-100679相对表达量低于对照组(P＜0.01)，miRNA-124相对表达量高于对照组(P＜0.01)(见表 1)。

    分组 n miRNA-16 circRNA-100679 miRNA-124
    治疗前
      观察组 81 0.21±0.04 9.67±1.22 15.73±2.82
      对照组 80 0.85±0.16 28.03±5.36 8.15±2.24
      t — 34.72* 29.88* 18.90*
      P — ＜0.01 ＜0.01 ＜0.01
    治疗后
      观察组 81 0.34±0.07## 15.70±2.15## 11.69±2.54##
      对照组 80 0.85±0.16 28.03±5.36 8.15±2.24
      t — 26.15* 19.11* 9.37
      P — ＜0.01 ＜0.01 ＜0.01
    *示t′值；组内配对t检

    • 2.2.   观察组不同分组间HAMD-17评分及RNA相对表达量比较

  • 治疗后，根据HAMD-17评分变化情况将观察组病人分为A组(18例)、B组(43例)和C组(20例)。治疗前，3组病人HAMD-17评分、miRNA-16、circRNA-100679、miRNA-124相对表达量差异均无统计学意义(P>0.05)；治疗后，3组病人HAMD-17评分下降，miRNA-16、circRNA-100679相对表达量较治疗前升高(P＜0.01), miRNA-124相对表达量较治疗前降低(P＜0.01)，3组HAMD-17评分、miRNA-124相对表达量比较: A组＜B组＜C组(P＜0.01)，3组miRNA-16、circRNA-100679相对表达量比较: A组>B组>C组(P＜0.01)(见表 2)。

    分组 n HAMD-17/分 miRNA-16 circRNA-100679 miRNA-124
    治疗前
      A组 18 25.12±2.39 0.22±0.06 9.51±1.34 15.58±2.74
      B组 43 25.47±2.60 0.21±0.05 9.60±1.47 15.75±2.59
      C组 20 25.33±2.81 0.22±0.05 9.71±1.29 15.69±2.20
      F — 0.12 0.37 0.10 0.03
      P — >0.05 >0.05 >0.05 >0.05
      MS组内 — 6.808 0.003 1.960 6.372
    治疗后
      A组 18 9.07±1.14▽▽ 0.45±0.16▽▽ 20.32±3.73▽▽ 5.42±1.05▽▽
      B组 43 14.93±2.45**▽▽ 0.36±0.07**▽▽ 16.81±2.35**▽▽ 10.20±2.38**▽▽
      C组 20 19.64±2.56**##▽▽ 0.30±0.05**##▽▽ 13.66±2.18**##▽▽ 13.35±2.13**##▽▽
      F — 103.70 12.21 29.33 68.61
      P — ＜0.01 ＜0.01 ＜0.01 ＜0.01
      MS组内 — 5.112 0.009 7.164 4.396
    q检验: 与A组比较**P＜0.01；与B组比较##P＜0.01；组内配对t检验: ▽▽P＜0.01验: ##P＜0.01

    • 2.3.   miRNA-16、circRNA-100679、miRNA-124相对表达量与抑郁症严重程度的相关性

  • 行Pearson相关分析后发现，miRNA-124相对表达量与HAMD-17评分呈正相关关系(r=0.557, P＜0.05)，miRNA-16、circRNA-100679相对表达量则与HAMD-17评分呈负相关关系(r=-0.325, P＜0.01；r=-0.453, P＜0.05)。

3.   讨论

  • 在全球范围内，抑郁症病人人数已超过3亿，而在近年内患病人数仍在不断增加，此类病人可伴有不同程度的认知功能异常，表现为注意力、记忆力等的减退，影响病人的社会功能，降低其生活质量[8]。因此，了解抑郁症的发生机制进而针对性干预就尤为重要。人们对抑郁症神经生化指标变化的研究包括多巴胺及其受体等已较为多见，近年来，人们对基因与抑郁症发生间的关系展开了探索，认为基因的多态性可能与抑郁症的发生有关，关键蛋白的基因突变可通过影响一些蛋白的表达水平, 从而影响正常的生化过程，进而参与抑郁症的发生[9]。circRNA具有序列保守性，在真核生物中广泛表达，且不容易被核酸酶降解，circRNA可以通过与miRNA竞争性结合从而发挥海绵效应，拮抗miRNA的生物活性[10]；miRNA则具有转录调节作用，可以影响细胞的正常代谢、基因的表达、疾病的发展[11]。为此，我们在既往研究的基础上，将miRNA-16、circRNA-100679、miRNA-124选为目的基因，探究了其与抑郁症发生及严重程度的关系。

    首先，我们对比了一般资料具有可比性的对照组及观察组病人的RNA相对表达水平，结果发现，观察组miRNA-16、circRNA-100679相对表达量低于对照组miRNA-124相对表达量高于对照组，且治疗后2组间数据差异减小。以上结果提示，miRNA-16、circRNA-100679、miRNA-124确实为差异基因。在此基础上，根据治疗后HAMD-17评分的变化将观察组病人分为A、B、C 3组，对比其RNA水平及HAMD-17评分后发现，A组HAMD-17评分、miRNA-124相对表达量低于B组，B组则低于C组，各组miRNA-16、circRNA-100679相对表达量则具有相反的变化趋势。进而行相关分析表明: miRNA-124相对表达量与HAMD-17评分呈正相关关系，miRNA-16、circRNA-100679相对表达量则与其呈负相关关系。说明miRNA-124具有促进抑郁症发生，而miRNA-16、circRNA-100679则对于抑郁症具有一定的抑制作用。

    有研究[12]指出，miRNA-124可以在发生脑损伤时在蓝斑区高表达，而蓝斑则是去甲肾上腺素产生的重要区域，去甲肾上腺素表达量不足被认为与抑郁症的发生有关。动物实验同样表明[13]，miRNA-124的表达可增强小鼠的慢性应激反应能力，从而造成神经可塑性失调及心境障碍性疾病的发生。miRNA-16在去甲肾上腺素及5-羟色胺能神经元中均可表达，而在前者中表达水平更高，miRNA-16在去甲肾上腺素能神经元中表达量下降时可促使5-羟色胺转运体的表达，推动抑郁症的发生[4]。circRNA在不同组织及细胞中的表达水平差异性较大，circRNA与miRNA的竞争性结合作用成为人们研究的热点，部分circRNA可具有多个miRNA结合位点[14]。本研究中，circRNA-100679可能通过竞争性与miRNA-124具有同样致抑郁症发生的miRNA而与miRNA-16共同发挥保护性作用。然而，有关详细作用机制尚需进一步的探究。

    综上所述，miRNA-16、circRNA-100679、miRNA-124均可参与抑郁症的发生，对以上基因的调控可能成为治疗抑郁症的新思路。

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