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STAT3 Mediates Trophoblast Cell Damage and Insulin Resistance in Gestational Diabetes Mellitus by Regulating LITAF
Vol 37, Issue 8, 2023
Abstract
Background: Gestational diabetes mellitus (GDM) has emerged as a social health issue that threatens pregnancy outcomes. Insulin resistance (IR) is considered to be a critical factor contributing to the development of GDM. It has been reported that signal transducer and activator of transcription 3 (STAT3) and IR are related. This study aimed to investigate the role of STAT3 in the modulation of IR in GDM. Methods: Ten cases of normal placenta and ten cases of GDM placenta were collected. The phosphorylation of STAT3 and lipopolysaccharide-induced TNF-α factor (LITAF) expression was measured by Western blot and immunohistochemistry. Trophoblast cells were treated with glucosamine to establish an IR cell model. Cell viability was detected by Cell Counting Kit-8 assay. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining. STAT3 effect on the LITAF promoter was explored by chromatin immunoprecipitation and dual-luciferase reporter assay. Trophoblast cells were treated with STAT3 inhibitors and transfected with LITAF overexpression plasmids to explore STAT3 and LITAF effect on IR and cellular activity in trophoblast cells. Insulin receptor substrate-1 (IRS-1), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and its phosphorylated proteins and glucose transporter 4 (GLUT4) protein expression were evaluated by Western blot. Results: LITAF and phosphorylation of STAT3 were increased in GDM placental tissue and IR cells (p < 0.05). Meanwhile, cell proliferation decreased, and phosphorylation levels of insulin signaling factors IRS-1, PI3K and AKT were reduced in GDM placentas, but cell apoptosis was increased (p < 0.05). STAT3 could target LITAF promoter, and STAT3 activation could increase LITAF expression (p < 0.05). STAT3 inhibitor treatment increased cell viability and reduced apoptosis and IR in glucosamine-treated trophoblast cells (p < 0.05). Overexpression of LITAF counteracted the action of STAT3 on trophoblast cells (p < 0.05). Conclusions: STAT3 inhibition suppressed trophoblast cell damage and IR in gestational diabetes by downregulating LITAF expression.
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Copyright (c) 2023 Ruizhen Li, Wen Wu, Chunxia Cheng, Jiajing Liu, Xinli Liu, Chunmei Mi, Mailian Long
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy