Identification and validation of the role of ZNF281 in 5-fluorouracil chemotherapy of gastric cancer

Abstract

Abstract Background The early diagnosis of gastric cancer (GC) and overcoming chemotherapy resistance is challenging. The aberrant expression of zinc finger protein 281 (ZNF281) and the over-activation of the Wnt/β-catenin pathway are oncogenic factors and confer tumor chemoresistance. ZNF281 modulates the Wnt/β-catenin pathway to influence malignant tumor behavior. However, the role of ZNF281 in GC chemotherapy and the relationship with the Wnt/β-catenin pathway have not been elucidated by researchers. Methods We explored differences in ZNF281 expression in Pan-cancer and normal tissues, the effect of its expression on prognosis of patients treated with 5-fluorouracil (5-FU). Cox regression was utilized to determine whether ZNF281 is an independent prognostic factor. Enrichment analysis was performed to explore the mechanism underlying ZNF281’s role in 5-FU treatment. We assessed the relationship between ZNF281 and the tumour microenvironment (TME) and combined bulk-RNA and single-cell RNA data to analyse the relationship between ZNF281 and immune infiltration. In vitro experiments verified the effects of ZNF281 knockdown on proliferation, invasion, migration, apoptosis, DNA damage of GC cells with 5-FU treated and the Wnt/β-catenin pathway proteins. Results ZNF281 was highly expressed in seven cancers and correlates with the prognosis. It is an independent prognostic factor in 5-FU treatment. ZNF281 correlates with TME score, CD8T cell abundance. ZNF281 is primarily associated with DNA repair and the Wnt/β-catenin pathway. ZNF281 knockdown enhanced the effect of 5-FU on phenotypes of GC cells. Conclusion We identified and verified ZNF281 as one of the potential influencing factors of 5-FU treatment in GC and may be associated with the Wnt/β-catenin pathway. Low ZNF281 may contribute to improved 5-FU sensitivity in GC patients.