SPI1 mediates CST2 transcription to promote the proliferation, metastasis, and angiogenesis of esophageal cancer.

Esophageal cancer (ESCA) is a common gastrointestinal tumor with high incidence and metastatic potential. Cystatin 2 (CST2) has been identified as a carcinogenic factor that regulates the progression of esophageal squamous cell carcinoma (ESCC). However, its role in ESCA progression and the underlying molecular mechanisms require further investigation. Data from several databases were analyzed to examine gene expression and correlations, to confirm the correlation of gene expression with clinical pathological parameters and prognosis of ESCA patients, and to screen for transcription factors. CST2 and Spi-1 proto-oncogene (SPI1) expression was detected by quantitative real-time PCR (qRT-PCR) and Western blot. Cell functions were assessed using cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) staining, colony formation, flow cytometry, wound healing, transwell, and tube formation assays. In vivo, xenograft tumor models were established to investigate the effect of CST2 knockdown on ESCA tumor growth. Mechanically, the binding between SPI1 and the CST2 promoter was confirmed by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. CST2 was up-regulated in ESCA cells and tissues, and its expression was associated with clinical pathological features. Knockdown of CST2 inhibited ESCA cell proliferation, migration, invasion, and angiogenesis, while inducing apoptosis. In vivo, CST2 down-regulation suppressed ESCA tumor growth. Moreover, SPI1 was identified as an upstream transcription factor of CST2, and its expression was positively correlated with CST2 expression. Clinically, the expression of SPI1 was also correlated with clinical pathological features in ESCA patients. Mechanically, SPI1 promoted ESCA malignant progression by transcriptionally activating CST2. In conclusion, SPI1 transcriptionally activates CST2 to promote ESCA cell proliferation, metastasis and angiogenesis. Moreover, the SPI1/CST2 axis is associated with aggressive clinical pathological features and poor prognosis in ESCA patients, highlighting its potential as a prognostic biomarker and therapeutic target for this malignancy.