Background: Cleavage stimulation factor 2 (CSTF2) encodes a nuclear protein that is implicated in the development of various cancers. However, the role of CSTF2 in hepatocellular carcinoma (HCC) has not been understood. This study aims to explore the function of CSTF2 in HCC.
Methods: The expression, diagnostic capability, prognostic value, and immune cell effect of CSTF2 in HCC were explored using various databases. The expression level of CSTF2 were validated in our cell lines. The effect of CSTF2 on hepatocarcinogenesis was explored by CSTF2 silencing.
Results: CSTF2 expression was significantly elevated in HCC and correlated with multiple clinicopathological characteristics. CSTF2 exhibited good diagnostic capability in discriminating HCC samples from nontumorous samples. High CSTF2 expression was significantly related to poor overall survival. Univariate and multivariate Cox regression analyses suggested that CSTF2 expression was an independent risk factor for HCC. These results were validated in ICGC cohorts. In addition, the nomogram based on CSTF2 showed better predictive performance than the AJCC staging system in TCGA and ICGC cohorts. Functional enrichment analysis revealed that CSTF2-related genes were involved in DNA/RNA processing and the cell cycle. In addition, we found that CSTF2 expression was closely related to the levels of various infiltrating immune cells, especially neutrophils. Moreover, some immune checkpoints had positive relationships with CSTF2 expression. CSTF2 silencing inhibited proliferation, invasion and migration, and promoted apoptosis in HepG2 cells. Western blotting analysis revealed that CSTF2 silencing inactivated the Wnt/β-catenin signaling pathway.
Conclusion: High CSTF2 expression not only correlates with unfavorable outcomes but also affects immune cell infiltration and immune checkpoint expression in HCC. CSTF2 silencing can alleviate the malignant phenotypes of hepatic cancer cell by inactivating the Wnt/β-catenin signaling pathway. These results indicate that CSTF2 can serve as a promising prognostic marker and therapeutic target for HCC patients.
Keywords: hepatocellular carcinoma, CSTF2, immune infiltration, prognosis, biomarker