Upregulation of FEN1 Is Associated with the Tumor Progression and Prognosis of Hepatocellular Carcinoma

Abstract

Background. Studies show that patients with hepatocellular carcinoma (HCC) have poor prognosis, particularly when patients are diagnosed at late stages of the disease development. The flap endonuclease 1 (FEN1) gene is overexpressed in multiple malignant tumors and may promote tumor aggressiveness. However, its expression profile and functional roles in HCC are still unclear. Here, we evaluated the molecular mechanisms of FEN1 in HCC. Methods. The expression of FEN1 in HCC was evaluated using HCC mRNA expression data from TCGA and GEO databases. The expression of FEN1 was also confirmed by immunohistochemistry (IHC) using a tissue microarray (TMA) cohort with a total of 396 HCC patients. Kaplan-Meier analysis and univariate and multivariate Cox regression analyses were used to determine the correlation between FEN1 expression and survival rate of HCC patients. The molecular mechanism and biological functions of FEN1 in HCC were predicted using functional and pathway enrichment analysis in vitro experiments. Results. FEN1 was overexpressed in multiple HCC cohorts at both mRNA and protein levels. The receiver operating characteristic (ROC) curve showed that FEN1 can serve as a diagnostic predictor of HCC. Meanwhile, patients with high FEN1 expression levels showed lower overall survival (OS) and relapse-free survival (RFS) rates than those with low FEN1 expression. More importantly, we found that FEN1 elevation was an independent prognostic factor for OS and RFS in HCC patients based on univariate and multivariate analyses, indicating that FEN1 might be a potential prognostic marker in HCC. Furthermore, knocking down FEN1 resulted in suppressed cell proliferation and migration in vitro. This could have been due to regulation expressions of c-Myc, survivin, and cyclin D1 genes, indicating that FEN1 may function as an oncogene through its role in the cell cycle and DNA replication pathway. Conclusion. Our study indicated that high FEN1 expression might function as a biomarker for diagnosis and prognosis. In addition, the study confirms that FEN1 is an oncogene in HCC progression.

Functional regulation of the structure-specific endonuclease FEN1 by the human cytomegalovirus protein IE1 suggests a role for the re-initiation of stalled viral replication forks

“…So far, knowledge on the utilization of the structure-specific endonuclease FEN1 during viral infections is limited. Only recently FEN1 was recognized as a key enzyme for hepatitis B virus cccDNA formation and as a marker for hepatitis B virus-associated hepatocellular carcinoma [45][46][47][48][49]. This emphasizes that blocking enzymatic activities of DNA repair proteins such as FEN1 may represent novel therapeutic opportunities for the treatment of viral diseases [50].…”

The Clinical Significance of the Expression of FEN1 in Primary Osteosarcoma

“…For example, Zhang et al demonstrated that in hepatocellular carcinoma, FEN1 expression was positively correlated with cell cycle and DNA replication pathway-related genes such as c-Myc, survivin, and cyclin D1, silencing FEN1 could inhibit cell proliferation and migration by regulating expression of these genes. 29 Becker et al reported that flap endonuclease overexpression was a driver of genome instability in yeast and human cells that impairs DNA replication in a manner dependent on its interaction with PCNA. 22 Wang et al demonstrated that the FEN1 protein level was tightly controlled by sequential phosphorylation, SUMOylation, and ubiquitination in a cell cycle-dependent manner in breast cancer.…”

Long Noncoding RNA AC007639.1 Promotes the Pathogenesis and Progression of Hepatocellular Carcinoma Through Inhibiting Apoptosis and Stimulating Chemotherapeutic Resistance

“…LncRNAs and endonuclease ( 15 ) are involved in the pathogenesis of liver cancer. Most lncRNAs promote the proliferation of HCC through microRNAs ( 16 ).…”