Study on the effect of molecular regulation on oxaliplatin resistance and macrophage polarization in esophageal squamous cell carcinoma based on the multiomics bioinformatic analysis and experimental verification

Oxaliplatin (OHP) resistance remains a major therapeutic challenge in esophageal squamous cell carcinoma (ESCC). While Wnt1 inducible signaling pathway protein 1 (WISP1) has been implicated in tumor progression, its role in chemotherapy resistance and tumor microenvironment modulation remains unexplored in ESCC. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) to detect mRNA expression levels of WISP1. Western blotting was used to analyze protein expression of WISP1 and WT1 associated protein (WTAP). Cell viability, proliferation, apoptosis, migration, and invasion were assessed using cell counting kit-8 (CCK-8) assay, cell colony formation assay, flow cytometry, and transwell assays, respectively. The sensitivity of tumor cells to oxaliplatin (OHP) was evaluated by CCK-8 assay. The expression of CD11b and CD206-positive cells was quantified by flow cytometry. The interaction between WTAP and WISP1 was investigated using m 6 A RNA immunoprecipitation, RNA immunoprecipitation, and actinomycin D assays. WISP1 expression was upregulated in ESCC tissues and cells. Silencing WISP1 significantly improved OHP sensitivity and induced cell apoptosis, whereas inhibiting ESCC cell proliferation, migration, and invasion. Furthermore, WISP1 knockdown suppressed M2 macrophage polarization and inactivated the PI3K/AKT pathway. WTAP was shown to maintain the mRNA stability of WISP1 in KYSE-30 and KYSE-150 cells. Overexpression of WISP1 reversed the effects of WTAP knockdown on ESCC cell proliferation, migration, invasion, apoptosis, and OHP sensitivity. Additionally, WTAP knockdown inhibited M2 macrophage polarization by decreasing WISP1 expression. WTAP-induced stabilization of WISP1 inhibited OHP sensitivity and promoted the malignant progression of ESCC. These findings position WTAP-WISP1 as a promising therapeutic target for overcoming platinum resistance in esophageal cancer.