Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the fourth leading cause of cancer-related mortality worldwide. The slow development of HCC involves the accumulation of genetic mutations and dysregulated gene expression over time. CircRNAs play essential roles in various physiological processes and involves in many diseases, in particular cancer. Global downregulation of circRNA expression has been observed in HCC in many studies. To explore the circRNA biogenesis in HCC, we focused on the role of CPSF4, for 3’ end formation and cleavage, in circRNA formation.
In this study, clinical research has shown that CPSF4 expression is upregulated in HCC and that high expression of CPSF4 is associated with poor prognosis in HCC patients. Mechanistic studies have demonstrated that CPSF4 reduces the levels of circRNAs, which possess a polyadenylation signal sequence and this decrease in circRNAs reduces the accumulation of miRNA and disrupts the miRNA-mediated gene silencing in HCC. Experiments in cell culture and xenograft mouse models showed that CPSF4 promotes the proliferation of HCC cells and enhances tumorigenicity. Moreover, CPSF4 antagonizes the tumor suppressor effect of its downstream circRNA in HCC.
In summary, the increase in CPSF4 enhances the recognition of PAS signals and the cleavage of circRNAs, which leads to a global decrease in circRNAs in HCC. Due to the prolonged absence of sponge circRNA storage pools, miRNAs are no longer protected and are degraded, enabling oncogenes to evade miRNA regulation and, thus, induce HCC tumorigenesis and metastasis.