Tumor metastasis is the primary cause of poor survival in gastric cancer (GC) patients. PVT1 and EIF4A1 have been shown to synergistically promote GC metastasis and invasion. However, the underlying mechanism remains unclear. The binding site between PVT1 and EIF4A1 was identified by RNA-binding protein immunoprecipitation (RIP). 4D-DIA proteomics combined with mass spectrometry was used to identify downstream proteins regulated by PVT1 and EIF4A1. From the differentially expressed proteins, Stanniocalcin-1 ( STC1) expression was validated in GC tissues, cell lines, and animal metastatic tumor samples. Following STC1 knockdown, cell proliferation and migration were assessed using MTT, colony formation, wound healing, and Transwell assays. Epithelial-mesenchymal transition (EMT) and Notch1 signaling were also evaluated. PVT1 bound to EIF4A1 through its N-terminal domain (NTD). Proteomic analysis revealed that PVT1 and EIF4A1 jointly upregulate STC1 expression. Immunohistochemistry (IHC) on a tissue microarray containing 183 GC samples, 128 adjacent normal tissues, and animal metastatic lesions demonstrated that STC1 was significantly upregulated in GC and correlated with metastasis, histological type, and tumor stage. Inhibition of EIF4A1 reduced STC1 expression, suggesting that STC1 is a key downstream target of the PVT1/EIF4A1 axis. Knockdown of STC1 attenuated GC cell migration and proliferation, and suppressed both EMT and the Notch1 signaling pathway. STC1 acts as a critical downstream effector of PVT1 and EIF4A1, promoting GC cell metastasis and proliferation, thereby driving malignant progression. This mechanism involves the regulation of the Notch1 signaling pathway and the EMT process.
Cao et al. (Thu,) studied this question.
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