Upregulation of miR-29a suppressed the migration and invasion of trophoblasts by directly targeting LOXL2 in preeclampsia

Abstract

Objective: Preeclampsia is a pregnancy-specific disorder that is a major cause of maternal and foetal morbidity and mortality, with a prevalence of 6-8% of pregnancies. Although the downregulation of lysyl oxidase (LOX) and LOX-like protein 2 (LOXL2), which leads to reduced trophoblast cell migration and invasion through activation of the TGF-b1/Smad3/collagen pathway, is relevant to preeclampsia, the mechanisms regulating differences in the gene expression of LOX and LOXL2 in placentas are not yet understood. This study aimed to investigate the mechanisms regulating differences in the gene expression of LOX and LOXL2 in placentas. Methods:The expression of miRNAs, LOX and LOXL2 in preeclamptic placentas and control placentas was analysed by qPCR. Localisation of miR29a and LOXL2 in preeclamptic placentas was performed by RNA-Fluorescence in-situ hybridization assay. The direct regulation of LOXL2 by miR-29a was assessed by dualluciferase reporter assays in human extravillous trophoblast cells (HTR8/SVneo). Cell migration and invasion were evaluated by Transwell assays in HTR8/SVneo cells.Results: miR-29a expression was upregulated in preeclamptic placentas and negatively correlated with LOXL2 mRNA expression levels. RNA-Fluorescence in-situ hybridization assay revealed a clear overlap between miR-29a and LOXL2 in the placentas of preeclampic women. LOXL2 was a direct target gene of miR-29a, as confirmed by a dual-luciferase reporter assay in HTR8/SVneo trophoblast cells. miR-29a suppressed HTR8/SVneo trophoblast cell migration and invasion. LOXL2 overexpression reversed the inhibitory effects of miR-29a on HTR8/SVneo trophoblast cell migration and invasion. Conclusion:Our results suggest that the upregulation of miR-29a suppresses the migration and invasion of HTR8/ SVneo trophoblast cells by directly targeting LOXL2 in preeclampsia.

Vascular Endothelial Growth Factor Receptor 2: Molecular Mechanism and Therapeutic Potential in Preeclampsia Comorbidity with Human Immunodeficiency Virus and Severe Acute Respiratory Syndrome Coronavirus 2 Infections

“…MicroRNAs have been implicated in the progression of normal physiological processes such as pregnancy, as well as in pathological conditions such as cardiovascular diseases, cancer, viral infections, and PE. MicroRNAs post-transcriptionally regulate the expression of VEGFR-2 in normal and pathological conditions [ 18 , 111 ]. Figure 3 explores microRNA regulation of VEGFR-2 in PE, HIV, and SARS-CoV-2 infection.…”

“…MiR-15b, miR-126, miR-29a, and miR-16 are dysregulated in PE, HIV infection, and COVID-19 and influence VEGFR-2 mRNA both directly and indirectly ( Table 1 ) [ 18 , 19 , 111 , 112 , 113 , 114 ]. It was reported that miR-15b is downregulated in PE and HIV but upregulated in COVID-19 [ 18 , 112 ].…”

“…The nucleocapsid of SARS-CoV-2 is a target of miR-126, making miR-126 an anti-viral host miRNA [ 117 ]. MiR-29a was reported to be upregulated in PE but downregulated in HIV infection and COVID-19 [ 111 , 113 ]. Xu et al reported that the upregulation of miR-29a in PE suppresses the migration and invasion of trophoblasts by directly targeting the LOXL2 (lysyl oxidase homolog 2) mRNA; hence, showing a negative correlation between miR-29a and trophoblastic migration and invasion [ 111 ].…”