Shp2 regulates the trophoblast cell cycle progression through p53-p21 pathway modulation

Normal trophoblast cells proliferation and migration are crucial for placental development. Dysfunction in these processes is closely linked to pregnancy-related diseases, such as preeclampsia (PE) and fetal growth restriction (FGR). This study aimed to explore the role of Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp2) in regulating trophoblast cell HTR-8/SVneo (HTR8) functions and its underlying mechanisms. By using a specific Shp2 inhibitor (SHP099) and lentivirus-mediated Shp2 knockdown combined with transcriptome sequencing, we found that Shp2 inactivation significantly inhibited HTR8 proliferation by inducing G₀/G₁ cell cycle arrest and reduced migratory/invasive capacities. The transcriptomic study revealed that Shp2 knockdown in HTR8 cells significantly upregulated p53 pathway downstream genes (CDKN1A, MDM2, etc.). Western blot results showed that Shp2 downregulation increased p21 protein levels, suggesting that Shp2 probably maintains cell cycle progression by suppressing the p53-p21 axis. Both pharmacological inhibition and genetic knockdown of Shp2 modulated Erk1/2 and Akt activities, indicating its roles in trophoblast functions through MAPK and PI3K-Akt signaling. This study provides new insights into the molecular mechanisms governing trophoblast biology and potential therapeutic targets for placental disorders.