miR-146b-5p downregulates IRAK1 and ADAM19 to suppress trophoblast proliferation, invasion, and migration in miscarriage

Abstract

A large proportion of miscarriages are classified as unexplained miscarriages (UM) since no cause is identified. No reliable biomarkers or treatments are available for these pregnancy losses. While our transcriptomic sequencing has revealed substantial upregulation of miR-146b-5p in UM villous tissues, its role and associated molecular processes have yet to be fully characterized. Our work revealed that relative to samples from normal pregnancy (NP), miR-146b-5p was significantly elevated in villous tissues from UM patients and displayed promising diagnostic potential. Moreover, miR-146b-5p agomir contributed to higher rates of embryonic resorption in ICR mice. When overexpressed in HTR-8/SVneo cells, miR-146b-5p attenuated the proliferative, invasive, and migratory activity of these cells while suppressing the expression of MMP9 and immune inflammation-associated cytokines, including IL1B, IL11, CXCL1, CXCL8, and CXCL12. Conversely, inhibition of its expression enhanced proliferation, migration, and invasion abilities. Mechanistically, IRAK1 (IL-1 receptor-associated kinase-1) and ADAM19 (a disintegrin and metalloproteinase 19) were identified as miR-146b-5p targets regulating trophoblast function, and silencing IRAK1 had similar effects as miR-146b-5p overexpression, while IRAK1 overexpression could partially reverse the inhibitory impact of this miRNA on trophoblasts. miR-146b-5p may inhibit trophoblast proliferation, migration, invasion, and implantation-associated inflammation by downregulating IRAK1 and ADAM19, participating in the pathogenesis of miscarriage and providing a critical biomarker and a promising therapeutic target for UM.