The fidelity of DNA replication is usually closely related to the progression of cancer, including liver cancer. The strict regulation of cell cycle growth signals controls the proliferation of normal cells. DNA damage repair and loss of checkpoint function can lead to genome instability, causing cancer cells to proliferate out of control. RFC is involved in DNA damage repair and checkpoint control during the cell cycle, and has been showed to be an important regulator of the malignant progression of many cancers(Cui et al. 2004; Koch et al. 2007; Xiong et al. 2011). Among them, RFC2 has been proven to promote a variety of tumor proliferation(Xiong et al. 2011) (Cui et al. 2004) (Gupte 2018). However, the biological function of RFC2 in HCC has not been explored. In this study, the expression, function, interaction pathway and prognostic value of RFC2 in HCC were analyzed for the first time to guide the future research of liver cancer.
Existing studies have shown that RFC2 is significantly upregulated in some tumors, such as nasopharyngeal carcinoma(Xiong et al. 2011), choriocarcinoma(Cui et al. 2004), and colorectal cancer(Hu et al. 2020). Our results found that RFC2 is overexpressed in HCC, which is consistent with previous studies. In addition, the protein expression level of RFC2 was further checked through the HPA database. The immunohistochemical staining intensity of tumor samples is much higher, which is consistent with mRNA expression.
Previous studies have shown that RFC2 is related to the progression and metastasis of breast cancer and can be used as a prognostic indicator for breast cancer patients. CRC patients with higher RFC2 levels showed poor clinicopathological symptom(Hu et al. 2020). In this study, the expression of RFC2 mRNA is significantly related to the clinical stage and tumor grade of liver cancer. Patients with advanced cancer and high tumor grade tend to express higher RFC2 mRNA. Further survival analysis showed that higher expression of RFC2 mRNA was associated with poor overall survival (OS) and disease-free survival (DFS).
Previous studies have found that the inhibition of RFC2 can enhance the cytotoxicity of temozolomide to glioblastoma(Ho et al. 2020). This article analyzed the functions and pathways of 50 similar genes of RFC2 in HCC patients. We found that DNA replication is the most significant functional enrichment term. In terms of protein interaction, the PPI network composed of proteins associated with the DNA replication origin was most affected (these proteins included: MCM2, MCM3, MCM4, MCM6, MCM7, MCM10, CDC6, CDK2, CDT1, CLSPND, DBF4 and ORC1).
Some limitations exist in our research. First, all the data in our study comes from online databases. In vivo and in vitro tests including larger sample sizes are needed to verify the findings in this article and explore the clinical application of RFC2 in the treatment of liver cancer. Secondly, the potential diagnostic and therapeutic role of RFC2 in liver cancer has not been evaluated, so further studies are needed to explore whether RFC2 can be used as a diagnostic marker or therapeutic target. Finally, although the possible pathways are analyzed in this article, further research is needed to explore the direct mechanism of RFC2 on HCC in the future.