Integrated cervical secretion proteome and metabolome reveal key elements and regulatory pathways in patients with cervical insufficiency

Abstract Background : Cervical insufficiency (CI) is when the cervix appears progressively and painlessly shortened, dilated and funnel-shaped before a full-term pregnancy. This could be attributed to various reasons that hinder the carrying of pregnancy to term and cause abortion or premature birth in the middle and late trimesters of pregnancy. However, its potential pathogenesis remains unclear. Therefore, we aimed to explore the possible pathogenesis of CI through the changes of proteins and metabolites in cervical secretions. Methods : In this study, cervical secretions from pregnant women with CI (n=6) and normal pregnant women (n=6) in the second trimester were collected. The changes of proteins and metabolites in cervical secretions were identified by LC-MS/MS, and the differential proteins and metabolites were further analyzed. Results : Compared with the normal pregnant women, 95 differential proteins and 117 differential metabolites were detected in patients with CI.The proteomic results showed that 26S proteasomes family members (e.g. PSMC1, PSMC4, PSMC6, PSMD4, etc.) were down-regulated in the CI group, and were widely involved in inflammatory response and Wnt signaling pathway. Increased expression of fructose-1, 6-biphosphatase 1 (FBP1), a key enzyme of gluconeogenesis, and decreased expression of phosphoglycerate mutase 1 (PGAM1), an important enzyme of glycolysis, were also observed in the CI group. Additionally, our metabolomic analysis revealed high expression of sugars and gluconeogenic substrates (S-isopentene-L-cysteine and ketones) in the CI group. Conclusions : The inflammatory response and EMT regulated by 26S proteasome and other differential proteins may involved in the occurrence and development of CI by destroying the barrier of cervical epithelium. At the same time, enhanced gluconeogenesis could provide energy for both processes. These findings could help improve pregnancy outcomes in women with cervical insufficiency.