Overexpression and clinicopathological significance of zinc finger protein 71 in hepatocellular carcinoma

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive forms of liver cancer, with high morbidity and poor prognosis due to late diagnosis and limited treatment options. Despite advances in understanding its molecular mechanisms, effective biomarkers for early detection and targeted therapy remain scarce. Zinc finger protein 71 (ZNF71), a zinc-finger protein, has been implicated in various cancers, yet its role in HCC remains largely unexplored. This gap in knowledge underscores the need for further investigation into the ZNF71 of potential as a diagnostic or therapeutic target in HCC.

AIM

To explore the expression levels, clinical relevance, and molecular mechanisms of ZNF71 in the progression of HCC.

METHODS

The study evaluated ZNF71 expression in 235 HCC specimens and 13 noncancerous liver tissue samples using immunohistochemistry. High-throughput datasets were employed to assess the differential expression of ZNF71 in HCC and its association with clinical and pathological features. The impact of ZNF71 on HCC cell line growth was examined through clustered regularly interspaced short palindromic repeat knockout screens. Co-expressed genes were identified and analyzed for enrichment using LinkedOmics and Sangerbox 3.0, focusing on significant correlations (P < 0.01, correlation coefficient ≥ 0.3). Furthermore, the relationship between ZNF71 expression and immune cell infiltration was quantified using TIMER2.0.

RESULTS

ZNF71 showed higher expression in HCC tissues vs non-tumorous tissues, with a significant statistical difference (P < 0.05). Data from the UALCAN platform indicated increased ZNF71 levels across early to mid-stage HCC, correlating with disease severity (P < 0.05). High-throughput analysis presented a standardized mean difference in ZNF71 expression of 0.55 (95% confidence interval [CI]: 0.34-0.75). The efficiency of ZNF71 mRNA was evaluated, yielding an area under the curve of 0.78 (95%CI: 0.75-0.82), a sensitivity of 0.63 (95%CI: 0.53-0.72), and a specificity of 0.82 (95%CI: 0.73-0.89). Diagnostic likelihood ratios were positive at 3.61 (95%CI: 2.41-5.41) and negative at 0.45 (95%CI: 0.36-0.56). LinkedOmics analysis identified strong positive correlations of ZNF71 with genes such as ZNF470, ZNF256, and ZNF285. Pathway enrichment analyses highlighted associations with herpes simplex virus type 1 infection, the cell cycle, and DNA replication. Negative correlations involved metabolic pathways, peroxisomes, and fatty acid degradation. TIMER2.0 analysis demonstrated positive correlations of high ZNF71 expression with various immune cell types, including CD4⁺ T cells, B cells, regulatory T cells, monocytes, macrophages, and myeloid dendritic cells.

CONCLUSION

ZNF71 is significantly upregulated in HCC, correlating with the disease’s clinical and pathological stages. It appears to promote HCC progression through mechanisms involving the cell cycle and metabolism and is associated with immune cell infiltration. These findings suggest that ZNF71 could be a novel target for diagnosing and treating HCC.

Keywords: Hepatocellular carcinoma; Zinc finger protein 71; Immunohistochemistry; Enrichment analysis; Immune infiltration

Core Tip: This study identified zinc finger protein 71 (ZNF71) as a key marker significantly upregulated in hepatocellular carcinoma (HCC), linking its elevated levels to increased disease severity. Employing a comprehensive methodology, including immunohistochemistry, high-throughput analysis, and single-cell sequencing, we demonstrated the involvement of ZNF71 in promoting HCC progression through cell cycle and metabolic pathways. Our findings underscore the potential of ZNF71 as a therapeutic target, especially given its association with immune cell infiltration, highlighting its role in the tumor microenvironment.