Hypoxia‐induced SPOP attenuates the mobility of trophoblast cells through inhibition of the PI3K/AKT/GSK3β pathway

Abstract

Placental hypoxia has been implicated in pregnancy pathologies such as pre‐eclampsia and intrauterine growth restriction. However, the underlying mechanism by which the trophoblasts respond to hypoxia remains unclear. Speckle‑type POZ protein (SPOP), an E3 ubiquitin ligase adapter, was previously reported to play important roles in various physiological and pathological processes. This study aims to investigate the expression and biological functions of SPOP after exposure to cobalt chloride (CoCl2)‐mimicked hypoxia conditions using human trophoblast‐derived choriocarcinoma cell lines and extravillous cytotrophoblast. These data showed that SPOP protein was directly induced by CoCl2‐mimicked hypoxia and regulated by HIF‐1α at the posttranscription level. CoCl2 treatment could dramatically influence the localization of SPOP in trophoblasts, especially the accumulation of SPOP into the nucleus. In addition, both CoCl2‐mimicked hypoxia and induction of endogenous SPOP expression by lentivirus transfection attenuated the migration and invasion abilities of trophoblasts. Furthermore, we demonstrated that SPOP was involved in CoCl2‐induced the inhibition of the PI3K/AKT/GSK3β pathway in placental trophoblasts. Taken together, these data indicate that accumulation of HIF‐1α augments the expression of SPOP in trophoblasts, which impairs trophoblastic mobility by targeting the PI3K/AKT/GSK3β pathway. This potentially leads to insufficient uterine spiral artery remodeling and suboptimal placental perfusion, and thus the development of pregnancy‐related complication.

Research progress of E3 ubiquitin ligase regulating biological behavior of human placental trophoblast cells

“…The above results indicate that CUL3 can regulate the invasion and migration of trophoblast cells, and the disorder of its expression and regulation may also lead to the occurrence of PE (9). One possible explanation is that hypoxia stimulates the production of large amounts of HIF-1 a, HIF-1 a Accumulation increases the expression of speckle-type POZ protein(SPOP) in trophoblast (14). As the connector protein of cullin3, SPOP targets PI3K/AKT/GSK3 and damage the mobility of trophoblast (15).…”

“…One possible explanation is that hypoxia stimulates the production of large amounts of HIF-1 α, HIF-1 α Accumulation increases the expression of speckle-type POZ protein(SPOP) in trophoblast ( 14 ). As the connector protein of cullin3, SPOP targets PI3K/AKT/GSK3 and damage the mobility of trophoblast ( 15 ).…”

The Molecular Biology of Prostate Cancer Stem Cells: From the Past to the Future

“…Usually, ligand bound membrane receptors such as G protein-coupled receptors (GPCR) or tyrosine kinase receptor (RTK) mediated PI3K activation results in the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3), which binds to AKT at the plasma membrane and leads to AKT phosphorylation by phosphoinositide-dependent kinase 1 (PDK1). Phosphorylated AKT is activated and exerts its biological functions via regulating a variety of downstream molecules such as tuberous sclerosis protein 2 (TSC2), forkhead box transcription factors of the class O (FOXO) and glycogen synthase kinase 3b (GSK3b) [141][142][143][144].…”

Tumor-suppressive function and mechanism of miR-873-5p in glioblastoma: evidence based on bioinformatics analysis and experimental validation

“…SPOP encodes an E3 ubiquitin ligase component, and in clear cell renal cell carcinoma, it is a transcriptional target of HIFs [ 15 ]. SPOP exerts essential roles in physiological and pathological processes [ 16 ]. Notably, a previous study has suggested SPOP as a tumor suppressor in glioma to inhibit cell viability, migration, and invasion in vitro [ 17 ].…”