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. 2024 Jun 16;150(6):307.
doi: 10.1007/s00432-024-05838-8.

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

Yifan Li  1 , Chengying Zhou  1 , Guoxu Wang  1 , Huiru Xin  1 , Yafei Xiao  1 , Changjiang Qin  2   3
Affiliations

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

Yifan Li et al. J Cancer Res Clin Oncol. .

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.

Keywords: 5-fluorouracil; DNA repair; Gastric cancer; Wnt/β-catenin pathway; ZNF281.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Flow chart of this study
Fig. 2
Fig. 2
Analysis and validation of the differential expression of ZNF281: (A) Differential expression of ZNF281 in pan-cancer. (B) Differential expression (left) and ROC curve (right) of ZNF281 in the TCGA-STAD cohort. (C) Differential expression(left) and ROC curve(right) of ZNF281 in the GSE13911 cohort. (D). Differential expression of ZNF281 in GC cells and normal cell
Fig. 3
Fig. 3
Relationship between expression of ZNF281 and prognosis (A) ZNF281 expression correlated with survival in eight cancers. (B) In the 5-FU cohort, patients with low ZNF281 expression showed a better prognosis. (C) Univariate and multivariate Cox regression analyses identified ZNF281 as an independent influence on prognosis in patients treated with 5-FU chemotherapy. (D) Low expression of ZNF281 associated with better prognosis in GSE15459 validation data
Fig. 4
Fig. 4
Relationship between ZNF281 and TME (A) TME score (5-FU cohort) differences between high and low ZNF281 expression groups. (B) Correlation between ZNF281 expression and immune infiltration score (5-FU cohort). (C) The GSE134520 dataset was annotated into nine cell clusters (left), and the distribution of ZNF281 in each cluster. (D) ZNF281 is highly expressed in CD8T cells. (E) The GSE167297 dataset was annotated into nine cell clusters (left), and the distribution of ZNF281 in each cluster. (F) ZNF281 is highly expressed in CD8T cells
Fig. 5
Fig. 5
Identification and validation of the relationship between ZNF281 and the Wnt/β-catenin pathway (A) GO enrichment analysis of genes positively associated with the expression of ZNF281. (B) Selection of highest efficiency siRNAs for AGS (left) and HGC-27 cell (right). (C) Knockdown of ZNF281 expression inhibits c-Myc and β-catenin protein expression in AGS (left) and HGC-27 cells (right)
Fig. 6
Fig. 6
Cell proliferation assay (A)Knockdown of ZNF281 enhances the inhibition of AGS cell proliferation by 5-FU. (B) Knockdown of ZNF281 enhances the inhibition of HGC-27 cell proliferation by 5-FU
Fig. 7
Fig. 7
Cell migration assay (A)Knockdown of ZNF281 enhances the inhibition of AGS cell migration by 5-FU. (B) Knockdown of ZNF281 enhances the inhibition of HGC-27 cell migration by 5-FU
Fig. 8
Fig. 8
Cell invasion assay (A) Knockdown of ZNF281 enhances the invasion of AGS cell migration by 5-FU. (B) Knockdown of ZNF281 enhances the inhibition of HGC-27 cell invasion by 5-FU
Fig. 9
Fig. 9
Apoptosis immunofluorescence assay(A) Knockdown of ZNF281 enhances 5-FU-induced apoptosis in AGS cells. (B) Knockdown of ZNF281 enhances 5-FU-induced apoptosis in HGC-27 cells
Fig. 10
Fig. 10
γH2AX immunofluorescence assay (A) Knockdown of ZNF281 enhances 5-FU-induced DNA damage in AGS cells. (B) Knockdown of ZNF281 enhances 5-FU-induced DNA damage in HGC-27 cells
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