Integrated bioinformatic multi-omics analysis and experimental verification reveal the oncogenic role of WDHD1 and its underlying mechanism in gastric cancer progression.

backgroundGastric cancer (GC) is one of the most common malignancies worldwide. WD repeat and HMG-box DNA-binding protein 1 (WDHD1) has been identified as an oncogenic factor involved in the progression of hepatocellular carcinoma, lung adenocarcinoma, nasopharyngeal carcinoma, and several other cancers. However, its role in GC remains insufficiently explored in the existing literature.

methodsIn this study, TCGA, GTEx, and GEO datasets were used to evaluate differences in WDHD1 expression between GC tissues and normal gastric tissues, and to analyze its associations with patient prognosis and clinicopathological characteristics. The CCLE database was used to assess WDHD1 expression levels in GC cell lines. The GDSC and CTRP pharmacogenomic databases were used to investigate the potential relationship between WDHD1 expression and sensitivity to antitumor agents. In addition, the TISCH2 single-cell database was used to analyze the distribution of WDHD1 expression across different cell populations in the GC tumor microenvironment and to preliminarily explore its association with the immune microenvironment. Subsequently, EdU, CCK-8, and colony formation assays were performed to evaluate the effect of WDHD1 on the proliferative capacity of GC cells, and a nude mouse xenograft tumor model was used to validate the regulatory role of WDHD1 in tumor growth in vivo. To further explore the potential underlying mechanisms, comparative proteomic analysis and cell-cycle flow cytometry were performed in WDHD1 knockdown cells and control cells, thereby preliminarily revealing the possible molecular mechanisms by which WDHD1 contributes to GC progression.

resultsWDHD1 was significantly overexpressed in GC, and its high expression was associated with poor prognosis and showed favorable diagnostic value. Functional enrichment analysis indicated that high WDHD1 expression was mainly associated with enrichment of pathways related to the cell cycle, DNA replication, and cell proliferation. In GC, WDHD1 downregulation exerted tumor-suppressive effects, inhibited DNA synthesis, and induced cell-cycle redistribution.

conclusionWDHD1, as a key factor regulating DNA replication and cell cycle progression during GC progression, may serve as a potential molecular target for diagnosis, prognostic assessment, and therapeutic intervention in GC.