The development of cancer often involved complicated regulatory networks, and many studies have shown that DNA methylation in malignant tumor cells is abnormal. Chang et al found that the degree of methylation of p15 and p16 in body fluids and tumor tissues of HNSCC patients were significantly higher than these of healthy group (16). The methylation level of p15 in HNSCC tissues of patients with long-term smoking or drinking was higher than non-smoking or non-drinking patients, indicating that the abnormal DNA methylation is significantly correlated with clinical high-risk factors of HNSCC (17). Besides, Sanchez-Cespedes’s group have detected the methylation level of p16,6-oxomethylguanine-DNA methyltransferase, a death-related protein kinase in HNSCC tissues, suggesting that DNA methylation existed in all pathological stages of tumor tissues (Sanchez-Cespedes, 2000). In this study, we developed a prognostic model for HNSCC that analyzed the transcriptomes and DNA methylation data of 493 HNSCC samples. The results showed that prognostic signature was significantly associated with overall survival in HNSCC patients, and patients with higher model scores tended to have poorer survival. 8 genes were identified as stable and reliable characteristic genes in SIS model, including HS3ST1, TOMM34, RPL26L1, MTHFD2, ORC1, MYOSLID, UHRF1, and AL357033.3.
It was found that the methylation level of UHRF1 showed a significant related with the gene expression level, and the expression level of the gene TOMM34 was significant different between high-risk and low-risk groups. In the present study, it had been reported that Ubiquitin-like PHD and Ring Finger domain 1 (UHRF1) genes were newly discovered nuclear protein genes closely related to cell growth, and it played an important role in regulating biological processes such as DNA damage repair, cell proliferation, cell cycle, and apoptosis (18, 19). Furthermore, UHRF1 is also an important epigenetic regulator maintaining DNA methylation and histone code in the cell, involving in the regulation of tumorigenesis and progression (20, 21). Several studies have suggested UHRF1 as a potential universal biomarker for cancers (22–25). Translocase of the outer mitochondrial membrane 34 (TOMM34) gene transcript as one of the tops differentially expressed gene, have been proven to be associated with features of aggressive behavior including higher tumor grade, advanced nodal stage, larger tumor size and lymphovascular invasion (26). The prognostic value of TOMM34 has been reported in colorectal cancer (27, 28).
Moreover, folate metabolism was central to cell proliferation and a target of commonly used cancer chemotherapeutics. In particular, the mitochondrial folate-coupled metabolism was thought to be important for proliferating cancer cells (29). The mitochondrial enzymes bifunctional methylenetetrahydrofolate dehydrogenase / cyclohydrolase (MTHFD2) in this pathway was highly expressed in human tumors, and broadly required in survival of cancer cells. Philip M et al revealed that overexpression of MTHFD2 was associated with both high proliferation rates and c-MYC overexpression (30). It has been reported that the overexpression of MTHFD2 was associated with poor prognosis of breast cancer patients and with an increased rate of invasion and metastasis (31). As MTHFD2 is over expressed in rapidly replicating tumor cells but not in adult tissue, it is suitable as a therapeutic target for selective cancer treatment (32).
In summary, the above reports on the functions of our characteristic genes were consistent with our finding, however, some genes were shown to be related with the cardiovascular disease, such as HS3ST1 and MYOSLID, and other genes had been less studied. Thus, we would verify the relationship between these genes and HNSCC as well as the role of genes in the signaling pathway in the future study. In addition, we should expand the clinical data in further investigate to better assess the survival of HNSCC and obtain the prognostic model.