SRPK1 Activation Facilitates Gli3^S664 Phosphorylation and Promotes Metastasis in Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) stands out as one of the most malignant digestive tumors, with its prognosis marred by frequent metastasis and recurrence. However, the mechanism behind ESCC metastasis remains elusive, impeding therapeutic advancements. SRPK1 emerges as an independent prognostic marker for ESCC patients. Our research illuminates the consequential role of SRPK1, where its genetic knockout led to decreased levels of transcription factors Snail and Slug, concomitant with an enhanced expression of the cell-to-cell adhesion protein E-cadherin. Conversely, reintroducing an overexpression of SRPK1 reversed the effects, highlighting its essential role in ESCC metastasis. Through bioinformatics analysis, we identified a correlation between SRPK1 and Gli3. Furthermore, increased levels of Gli3 and its phosphorylated form, p-Gli3^S664, were detected in ESCC tissues, which are implicated in promoting ESCC metastasis. Notably, our research confirmed that SRPK1 promotes migration, invasion, and epithelial-mesenchymal transition (EMT) of ESCC cells through phosphorylates Gli3 at ser 664. Additional investigations reveal that dihydroartemisinin (DHA) effectively impedes ESCC cell metastasis by suppressing SRPK1-mediated phosphorylation of Gli3^S664 both in vitro and in vivo. Consequently, our study underscores the pivotal role of the SRPK1-p-Gli3^S664 axis in ESCC metastasis and suggests DHA as a promising candidate for preventing ESCC metastasis by targeting this axis.