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

Author:

Zhang Xiaoli1,Li Xueyu12,Tan Xuemei1,Deng Lingjie1,Zhong Linlin1,Wei Changqiang1,Ruan Heyun1,Lu Yebin1,Pang Lihong13

Affiliation:

1. First Affiliated Hospital of Guangxi Medical University Department of Prenatal Diagnosis and Genetic Diseases, , Nanning, Guangxi , China

2. Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Reproductive Medicine Center, , Nanning, Guangxi , China

3. Guangxi Medical University, Ministry of Education Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor, , Nanning, Guangxi , China

Abstract

Abstract A large proportion of miscarriages are classified as unexplained miscarriages 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 unexplained miscarriage villous tissues, its role and associated molecular processes have yet to be fully characterized. Our work revealed that relative to samples from normal pregnancy, miR-146b-5p was significantly elevated in villous tissues from unexplained miscarriage 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, IL-1 receptor-associated kinase-1 and a disintegrin and metalloproteinase 19 were identified as miR-146b-5p targets regulating trophoblast function, and silencing IL-1 receptor-associated kinase-1 had similar effects as miR-146b-5p overexpression, while IL-1 receptor-associated kinase-1 overexpression could partially reverse the inhibitory impact of this microRNA on trophoblasts. miR-146b-5p may inhibit trophoblast proliferation, migration, invasion, and implantation-associated inflammation by downregulating IL-1 receptor-associated kinase-1 and a disintegrin and metalloproteinase 19, participating in the pathogenesis of miscarriage and providing a critical biomarker and a promising therapeutic target for unexplained miscarriage.

Funder

Guangxi Key R&D Program

First Affiliated Hospital of Guangxi Medical University

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,General Medicine,Reproductive Medicine

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