Skip to main content

Altered microRNA Expression in Peripheral Blood Mononuclear Cells from Young Patients with Schizophrenia

Journal of Molecular Neuroscience volume 56, pages 562–571 (2015)Cite this article

Abstract

Schizophrenia (SZ) is a debilitating psychotic disorder of unknown etiology, and the diagnosis is essentially based on clinical symptoms. So it is urgent to find an objective and feasible clinical diagnostic index for SZ. MicroRNA array was performed in peripheral blood mononuclear cells (PBMCs) obtained from young SZ patients and gender-, age-, and ethnicity-matched healthy controls. Then, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verify the top 10 microRNAs (miRNAs) with the highest fold change values in 55 SZ patients and 28 healthy controls, and 9 miRNAs demonstrate significant differences in expression levels (P < 0.01). Receiver operating characteristic (ROC) curve analysis showed that the combining area under the ROC curve (AUC) of the nine miRNAs was 0.973 (95 % confidence interval (CI): 0.945–1.000). miRNA target gene prediction and functional annotation analysis showed that there were significant enrichments in several gene ontology (GO) biological process and Kyoto encyclopedia of genes and genomes (KEGG) pathways associated with nervous system and brain functions, suggesting that the differentially expressed miRNAs may be involved in mechanism of SZ. We conclude that altered expression of miRNAs in PMBCs might be involved in young SZ pathogenesis and may serve as noninvasive biomarker for SZ diagnosis.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  • Ajit SK (2012) Circulating microRNAs as biomarkers, therapeutic targets, and signaling molecules. Sensors 12:3359–3369

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders. 5th ed. doi:10.1176/appi.books.9780890425596

  • Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, Feuerstein GZ (1997) Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke 28:1233–1244

    CAS  PubMed  Article  Google Scholar 

  • Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Bian S, Sun T (2011) Functions of noncoding RNAs in neural development and neurological diseases. Mol Neurobiol 44:359–373

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Buller B, Liu X, Wang X, Zhang RL, Zhang L, Hozeska-Solgot A, Chopp M, Zhang ZG (2010) MicroRNA-21 protects neurons from ischemic death. FEBS J 277:4299–4307

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Cattaneo A, Sesta A, Calabrese F, Nielsen G, Riva MA, Gennarelli M (2010) The expression of VGF is reduced in leukocytes of depressed patients and it is restored by effective antidepressant treatment. Neuropsychopharmacology 35:1423–1428

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Chen SY, Huang PH, Cheng HJ (2011) Disrupted-in-Schizophrenia 1-mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling. Proc Natl Acad Sci U S A 108:5861–5866

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Chertkow Y, Weinreb O, Youdim MB, Silver H (2007) Gene expression changes in peripheral mononuclear cells from schizophrenic patients treated with a combination of antipsychotic with fluvoxamine. Prog Neuropsychopharmacol Biol Psychiatry 31:1356–1362

    CAS  PubMed  Article  Google Scholar 

  • Duncan CE, Chetcuti AF, Schofield PR (2008) Coregulation of genes in the mouse brain following treatment with clozapine, haloperidol, or olanzapine implicates altered potassium channel subunit expression in the mechanism of antipsychotic drug action. Psychiatr Genet 18:226–239

    PubMed  Article  Google Scholar 

  • Earls LR, Fricke RG, Yu J, Berry RB, Baldwin LT, Zakharenko SS (2012) Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia. J Neurosci 32:14132–14144

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Fineberg AM, Ellman LM (2013) Inflammatory cytokines and neurological and neurocognitive alterations in the course of schizophrenia. Biol Psychiatry 73:951–966

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Fisar Z, Raboch J (2008) Depression, antidepressants, and peripheral blood components. Neuro Endocrinol Lett 29:17–28

    CAS  PubMed  Google Scholar 

  • Frydecka D, Misiak B, Beszlej JA, Karabon L, Pawlak-Adamska E, Tomkiewicz A, Partyka A, Jonkisz A, Kiejna A (2013) Genetic variants in transforming growth factor-beta gene (TGFB1) affect susceptibility to schizophrenia. Mol Biol Rep 40:5607–5614

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Griffon N, Jeanneteau F, Prieur F, Diaz J, Sokoloff P (2003) CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors. Brain Res Mol Brain Res 117:47–57

    CAS  PubMed  Article  Google Scholar 

  • Haller CS, Padmanabhan JL, Lizano P, Torous J, Keshavan M (2014) Recent advances in understanding schizophrenia. F1000prime reports 6:57. doi:10.12703/P6-57

  • Han Z, Chen F, Ge X, Tan J, Lei P, Zhang J (2014) miR-21 alleviated apoptosis of cortical neurons through promoting PTEN-Akt signaling pathway in vitro after experimental traumatic brain injury. Brain Res 1582:12–20

    CAS  PubMed  Article  Google Scholar 

  • Ikeda M et al (2013) Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population. Mol Psychiatry 18:636–638

    CAS  PubMed  Article  Google Scholar 

  • Iyengar BR, Choudhary A, Sarangdhar MA, Venkatesh KV, Gadgil CJ, Pillai B (2014) Non-coding RNA interact to regulate neuronal development and function. Front Cell Neurosci 8:47

    PubMed Central  PubMed  Article  Google Scholar 

  • Kalkman HO (2009) Altered growth factor signaling pathways as the basis of aberrant stem cell maturation in schizophrenia. Pharmacol Ther 121:115–122

    CAS  PubMed  Article  Google Scholar 

  • Kanaan Z, Rai SN, Eichenberger MR, Roberts H, Keskey B, Pan J, Galandiuk S (2012) Plasma miR-21: a potential diagnostic marker of colorectal cancer. Ann Surg 256:544–551

    PubMed  Article  Google Scholar 

  • Kerns D, Vong GS, Barley K, Dracheva S, Katsel P, Casaccia P, Haroutunian V, Byne W (2010) Gene expression abnormalities and oligodendrocyte deficits in the internal capsule in schizophrenia. Schizophr Res 120:150–158

    PubMed  Article  Google Scholar 

  • Lai C-Y, Yu S-L, Hsieh MH, Chen C-H, Chen H-Y, Wen C-C, Huang Y-H, Hsiao P-C, Hsiao CK, Liu C-M (2011) MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia. PLoS One 6:e21635

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Li BS, Zhao YL, Guo G, Li W, Zhu ED, Luo X, Mao XH, Zou QM, Yu PW, Zuo QF, Li N, Tang B, Liu KY, Xiao B (2012) Plasma microRNAs, miR-223, miR-21 and miR-218, as novel potential biomarkers for gastric cancer detection. PLoS One 7:e41629

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Liang Y, Ridzon D, Wong L, Chen C (2007) Characterization of microRNA expression profiles in normal human tissues. BMC Genomics 8:166

    PubMed Central  PubMed  Article  Google Scholar 

  • Ma X, Zhou J, Zhong Y, Jiang L, Mu P, Li Y, Singh N, Nagarkatti M, Nagarkatti P (2014) Expression, regulation and function of microRNAs in multiple sclerosis. Int J Med Sci 11:810–818

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Mar-Aguilar F, Mendoza-Ramirez JA, Malagon-Santiago I, Espino-Silva PK, Santuario-Facio SK, Ruiz-Flores P, Rodriguez-Padilla C, Resendez-Perez D (2013) Serum circulating microRNA profiling for identification of potential breast cancer biomarkers. Dis Markers 34:163–169

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Masana M, Santana N, Artigas F, Bortolozzi A (2012) Dopamine neurotransmission and atypical antipsychotics in prefrontal cortex: a critical review. Curr Top Med Chem 12:2357–2374

    CAS  PubMed  Article  Google Scholar 

  • Miller BH, Wahlestedt C (2010) MicroRNA dysregulation in psychiatric disease. Brain Res 1338:89–99

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B (2011) Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 70:663–671

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Miller BJ, Culpepper N, Rapaport MH, Buckley P (2013) Prenatal inflammation and neurodevelopment in schizophrenia: a review of human studies. Prog Neuropsychopharmacol Biol Psychiatry 42:92–100

    CAS  PubMed  Article  Google Scholar 

  • Montalban E, Mattugini N, Ciarapica R, Provenzano C, Savino M, Scagnoli F, Prosperini G, Carissimi C, Fulci V, Matrone C, Calissano P, Nasi S (2014) MiR-21 is an Ngf-modulated microRNA that supports Ngf signaling and regulates neuronal degeneration in PC12 cells. Neuromol Med 16:415–430

    CAS  Article  Google Scholar 

  • Moreno-Moya JM, Vilella F, Simon C (2014) MicroRNA: key gene expression regulators. Fertil Steril 101:1516–1523

    CAS  PubMed  Article  Google Scholar 

  • Munshi SU, Panda H, Holla P, Rewari BB, Jameel S (2014) MicroRNA-150 is a potential biomarker of HIV/AIDS disease progression and therapy. PLoS One 9:e95920

    PubMed Central  PubMed  Article  Google Scholar 

  • Nikkila HV, Muller K, Ahokas A, Rimon R, Andersson LC (2001) Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res 49:99–105

    CAS  PubMed  Article  Google Scholar 

  • Noren Hooten N, Abdelmohsen K, Gorospe M, Ejiogu N, Zonderman AB, Evans MK (2010) microRNA expression patterns reveal differential expression of target genes with age. PLoS One 5:e10724

    PubMed Central  PubMed  Article  Google Scholar 

  • Ohtsuki T, Horiuchi Y, Koga M, Ishiguro H, Inada T, Iwata N, Ozaki N, Ujike H, Watanabe Y, Someya T, Arinami T (2008) Association of polymorphisms in the haplotype block spanning the alternatively spliced exons of the NTNG1 gene at 1p13.3 with schizophrenia in Japanese populations. Neurosci Lett 435:194–197

    CAS  PubMed  Article  Google Scholar 

  • Pena-Chilet M, Martinez MT, Perez-Fidalgo JA, Peiro-Chova L, Oltra SS, Tormo E, Alonso-Yuste E, Martinez-Delgado B, Eroles P, Climent J, Burgues O, Ferrer-Lozano J, Bosch A, Lluch A, Ribas G (2014) MicroRNA profile in very young women with breast cancer. BMC Cancer 14:529

    PubMed Central  PubMed  Article  Google Scholar 

  • Peng Y, Xu Y, Cui D (2014) Wnt signaling pathway in schizophrenia. CNS Neurol Disord Drug Targets 13:755–764

    CAS  PubMed  Article  Google Scholar 

  • Ramachandra RK, Salem M, Gahr S, Rexroad CE 3rd, Yao J (2008) Cloning and characterization of microRNAs from rainbow trout (Oncorhynchus mykiss): their expression during early embryonic development. BMC Dev Biol 8:41

    PubMed Central  PubMed  Article  Google Scholar 

  • Saha S, Chant D, Welham J, McGrath J (2005) A systematic review of the prevalence of schizophrenia. PLoS Med 2:e141

    PubMed Central  PubMed  Article  Google Scholar 

  • Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108

    CAS  PubMed  Article  Google Scholar 

  • Singh KK (2013) An emerging role for Wnt and GSK3 signaling pathways in schizophrenia. Clin Genet 83:511–517

    CAS  PubMed  Article  Google Scholar 

  • Singh RK, Shi J, Zemaitaitis BW, Muma NA (2007) Olanzapine increases RGS7 protein expression via stimulation of the Janus tyrosine kinase-signal transducer and activator of transcription signaling cascade. J Pharmacol Exp Ther 322:133–140

    CAS  PubMed  Article  Google Scholar 

  • Smalheiser NR (2014) The RNA-centred view of the synapse: non-coding RNAs and synaptic plasticity. Philos Trans R Soc Lond Ser B Biol Sci 369(1652). doi:10.1098/rstb.2013.0504

  • Smigielska-Czepiel K, van den Berg A, Jellema P, Slezak-Prochazka I, Maat H, van den Bos H, van der Lei RJ, Kluiver J, Brouwer E, Boots AM, Kroesen BJ (2013) Dual role of miR-21 in CD4+ T-cells: activation-induced miR-21 supports survival of memory T-cells and regulates CCR7 expression in naive T-cells. PLoS One 8:e76217

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Song HT, Sun XY, Zhang L, Zhao L, Guo ZM, Fan HM, Zhong AF, Niu W, Dai YH, Zhang LY, Shi Z, Liu XP, Lu J (2014) A preliminary analysis of association between the down-regulation of microRNA-181b expression and symptomatology improvement in schizophrenia patients before and after antipsychotic treatment. J Psychiatr Res 54:134–140

    PubMed  Article  Google Scholar 

  • Sun XY, Lu J, Zhang L, Song HT, Zhao L, Fan HM, Zhong AF, Niu W, Guo ZM, Dai YH, Chen C, Ding YF, Zhang LY (2014) Aberrant microRNA expression in peripheral plasma and mononuclear cells as specific blood-based biomarkers in schizophrenia patients. J Clin Neurosci. doi:10.1016/j.jocn.2014.08.018

  • Tang D, Shen Y, Wang M, Yang R, Wang Z, Sui A, Jiao W, Wang Y (2013) Identification of plasma microRNAs as novel noninvasive biomarkers for early detection of lung cancer. Eur J Cancer Prev 22:540–548

    CAS  PubMed  Article  Google Scholar 

  • Vargas HE, Gama CS, Andreazza AC, Medeiros D, Stertz L, Fries G, Palha J, Cereser KM, Berk M, Kapczinski F, Belmonte-de-Abreu PS (2008) Decreased serum neurotrophin 3 in chronically medicated schizophrenic males. Neurosci Lett 440:197–201

    CAS  PubMed  Article  Google Scholar 

  • Wang Y, Gao X, Wei F, Zhang X, Yu J, Zhao H, Sun Q, Yan F, Yan C, Li H, Ren X (2014) Diagnostic and prognostic value of circulating miR-21 for cancer: a systematic review and meta-analysis. Gene 533:389–397

    CAS  PubMed  Article  Google Scholar 

  • Wilcox JA, Quadri S (2014) Replication of NTNG1 association in schizophrenia. Psychiatr Genet 24:266–268

    CAS  PubMed  Article  Google Scholar 

  • Wittmann J, Jäck H-M (2010) Serum microRNAs as powerful cancer biomarkers. Biochim Biophys Acta Rev Cancer 1806:200–207

    CAS  Article  Google Scholar 

  • Xu B, Karayiorgou M, Gogos JA (2010) MicroRNAs in psychiatric and neurodevelopmental disorders. Brain Res 1338:78–88

    CAS  PubMed  Article  Google Scholar 

  • Xu J, Zhao J, Evan G, Xiao C, Cheng Y, Xiao J (2012) Circulating microRNAs: novel biomarkers for cardiovascular diseases. J Mol Med 90:865–875

    CAS  PubMed  Article  Google Scholar 

  • Yao R, Ma Y, Du Y, Liao M, Li H, Liang W, Yuan J, Ma Z, Yu X, Xiao H, Liao Y (2011) The altered expression of inflammation-related microRNAs with microRNA-155 expression correlates with Th17 differentiation in patients with acute coronary syndrome. Cell Mol Immunol 8:486–495

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Zhang Z, Zha Y, Hu W, Huang Z, Gao Z, Zang Y, Chen J, Dong L, Zhang J (2013) The autoregulatory feedback loop of microRNA-21/programmed cell death protein 4/activation protein-1 (MiR-21/PDCD4/AP-1) as a driving force for hepatic fibrosis development. J Biol Chem 288:37082–37093

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Zhuo Y, Gao G, Shi JA, Zhou X, Wang X (2013) miRNAs: biogenesis, origin and evolution, functions on virus-host interaction. Cell Physiol Biochem 32:499–510

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Author notes

    Affiliations

    1. Cadre Ward, Chengdu Military General Hospital, Chengdu, Sichuan, 610083, People’s Republic of China

      Hui-min Fan

    2. Department of Psychology and Psychiatry, Second Military Medical University, Shanghai, 200433, People’s Republic of China

      Hui-min Fan & Xin-yang Sun

    3. Prevention and Treatment Center for Psychological Diseases, No.102 Hospital of Chinese People’s Liberation Army, North Peace Road 55, Changzhou, 213003, Jiangsu, People’s Republic of China

      Xin-yang Sun & Li-yi Zhang

    4. Department of Rehabilitation, No.102 Hospital of Chinese People’s Liberation Army, Changzhou, 213003, Jiangsu, People’s Republic of China

      Wei Niu

    5. Department of Psychiatry, Suzhou Psychiatric Hospital, Suzhou, 215008, Jiangsu, People’s Republic of China

      Lin Zhao

    6. Department of Neurology and Psychiatry, Postgraduate School, Xuzhou Medical College, Xuzhou, 221000, Jiangsu, People’s Republic of China

      Qiao-Li Zhang

    7. GoPath Diagnostic Laboratory Co. Ltd., No.801, Changwuzhong Road, Changzhou, 213164, Jiangsu, People’s Republic of China

      Wan-shuai Li & Jim Lu

    8. Department of Laboratory, No.102 Hospital of Chinese People’s Liberation Army, Changzhou, 213003, Jiangsu, People’s Republic of China

      Ai-fang Zhong

    9. GoPath Laboratories LLC, 1351 Barclay Blvd, Buffalo Grove, IL, 60089, USA

      Jim Lu

    Authors
    1. Hui-min Fan
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xin-yang Sun
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Wei Niu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Lin Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Qiao-Li Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Wan-shuai Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Ai-fang Zhong
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Li-yi Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Jim Lu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Li-yi Zhang or Jim Lu.

    Additional information

    Hui-min Fan, Xin-yang Sun, and Wei Niu agreed to share the first authorship position together.

    Hui-min Fan, Xin-yang Sun and Wei Niu contributed equally to this work.

    Rights and permissions

    Reprints and Permissions

    About this article

    Verify currency and authenticity via CrossMark

    Cite this article

    Fan, Hm., Sun, Xy., Niu, W. et al. Altered microRNA Expression in Peripheral Blood Mononuclear Cells from Young Patients with Schizophrenia. J Mol Neurosci 56, 562–571 (2015). https://doi.org/10.1007/s12031-015-0503-z

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12031-015-0503-z

    Keywords

    • Schizophrenia
    • microRNA
    • Peripheral blood mononuclear cells
    • microRNA array
    • Target gene prediction
    • Functional annotation analysis