Hypermethylation‑induced silencing of ITGA4 promotes oral squamous cell carcinoma progression through SNX5 upregulation

Epigenetic modifications, especially DNA methylation, play an increasingly important role in oral cancer. However, their specific contributions to the progression of oral squamous cell carcinoma (OSCC) remain unclear. The present study used the Shiny Methylation Analysis Resource Tool (SMART) database (https: //smart. embl. de/smart/changeₘode. cgi) to identify methylation‑driven genes associated with OSCC. Among the identified candidates, integrin subunit α4 (ITGA4) exhibited significantly elevated methylation levels in head and neck cancers. A methylation‑specific PCR assay showed that ITGA4 is highly methylated in OSCC cells compared with normal immortalized human normal oral keratinocyte (iNOK) cells. Additionally, the mRNA expression levels of ITGA4 were significantly lower in OSCC cell lines compared with normal iNOK cells. ITGA4 overexpression markedly inhibited the cell proliferation, migratory ability and capacity of colony formation and induced apoptosis in FaDu and YD‑15 cells. In proteomic analysis, ITGA4 suppressed the expression of Sorting Nexin 5 (SNX5), a protein linked to cancer progression. siRNA‑mediated knockdown of SNX5 importantly inhibited cell proliferation, migration, and colony formation in FaDu and YD‑15 cells. Moreover, in a chick chorioallantoic membrane xenograft model, overexpression of ITGA4 or small interfering SNX5 significantly inhibited OSCC tumor growth and angiogenesis in vivo. Collectively, these findings demonstrated that ITGA4 acts as a tumor suppressor in OSCC by downregulating SNX5 and suggested that ITGA4 may serve as a valuable prognostic biomarker and potential therapeutic target for OSCC.