Schizophrenia plausible protective effect of microRNA-137 is potentially related to estrogen and prolactin in female patients

Qian Peng; Zhun Dai; Jingwen Yin; Dong Lv; Xudong Luo; Susu Xiong; Zhijiang Yang; Guangmin Chen; Yaxue Wei; Ying Wang; Dandan Zhang; Lulu Wang; Debo Yu; Yusheng Zhao; Dele Lin; Zhiyu Liao; Yongxi Zhong; Zhixiong Lin; Juda Lin

doi:10.3389/fpsyt.2023.1187111

Schizophrenia plausible protective effect of microRNA-137 is potentially related to estrogen and prolactin in female patients

Front Psychiatry. 2023 Aug 23:14:1187111. doi: 10.3389/fpsyt.2023.1187111. eCollection 2023.

Authors

Qian Peng^#¹, Zhun Dai^#¹, Jingwen Yin¹, Dong Lv¹, Xudong Luo¹, Susu Xiong¹, Zhijiang Yang¹, Guangmin Chen¹, Yaxue Wei¹, Ying Wang¹, Dandan Zhang¹, Lulu Wang¹, Debo Yu¹, Yusheng Zhao¹, Dele Lin¹, Zhiyu Liao¹, Yongxi Zhong¹, Zhixiong Lin¹, Juda Lin¹

Affiliation

¹ Department of Psychiatry, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.

^# Contributed equally.

Abstract

Background: Schizophrenia (SCZ) is a serious chronic mental disorder. Our previous case-control genetic association study has shown that microRNA-137 (miR-137) may only protect females against SCZ. Since estrogen, an important female sex hormone, exerts neuroprotective effects, the relationship between estrogen and miR-137 in the pathophysiology of SCZ was further studied in this study.

Methods: Genotyping of single-nucleotide polymorphism rs1625579 of miR-137 gene in 1,004 SCZ patients and 896 healthy controls was conducted using the iMLDR assay. The effect of estradiol (E2) on the miR-137 expression was evaluated on the human mammary adenocarcinoma cell line (MCF-7) and the mouse hippocampal neuron cell line (HT22). The relationships between serum E2, prolactin (PRL), and peripheral blood miR-137 were investigated in 41 SCZ patients and 43 healthy controls. The miR-137 and other reference miRNAs were detected by real-time fluorescent quantitative reverse transcription-PCR.

Results: Based on the well-known SNP rs1625579, the distributions of protective genotypes and alleles of the miR-137 gene were not different between patients and healthy controls but were marginally significantly lower in female patients. E2 upregulated the expression of miR-137 to 2.83 and 1.81 times in MCF-7 and HT22 cells, respectively. Both serum E2 and blood miR-137 were significantly decreased or downregulated in SCZ patients, but they lacked expected positive correlations with each other in both patients and controls. When stratified by sex, blood miR-137 was negatively correlated with serum E2 in female patients. On the other hand, serum PRL was significantly increased in SCZ patients, and the female patients had the highest serum PRL level and a negative correlation between serum PRL and blood miR-137.

Conclusion: The plausible SCZ-protective effect of miR-137 may be female specific, of which the underlying mechanism may be that E2 upregulates the expression of miR-137. This protective mechanism may also be abrogated by elevated PRL in female patients. These preliminary findings suggest a new genetic/environmental interaction mechanism for E2/miR-137 to protect normal females against SCZ and a novel E2/PRL/miR-137-related pathophysiology of female SCZ, implying some new antipsychotic ways for female patients in future.

Keywords: estrogen; gene expression in vitro; genetic association; miR-137; prolactin; schizophrenia; single nucleotide polymorphisms.

Grants and funding

This study was supported by the National Nature Science Foundation of China (81670252 and 81770034) and the Guangdong Basic and Applied Basic Research Foundation (2019A1515011306).