Studies have shown that mitochondria were the key to almost all aspects of tumor progression, not just the main source of AT [12, 13]. The role of mitochondria in tumors has gradually been given proper recognition. However, the expression of mitochondrial-related genes in HNSCC was still controversial [14, 15]. In the present study, we identified a Mito-RGs signature and evaluated the integrated roles of Mito-RGs in the progression of HNSCC patients. A prognosis-related 13 Mito-RGs signature (FSTL4, SAR1A, PNPLA4, LPAR2, PGM3, CAMK2B, DPM1, PER3, POLR2J, B4GALT7, MEF2A, SKAP2, PTPRC ) was constructed for establishing risk stratification and predicting clinical outcomes. In the internal and external validation queues, Mito-RGs characteristics performed well in predicting the progress of HNSCC patients. It supported that the Mito-RGs signature was repeatable and utility for the prognosis of HNSCC overall survival. Moreover, the Mito-RGs signature was also significantly related to specific clinical characteristics of HNSCC, which would help clinicians to manage patients and choose treatment. Additionally, a valuable predictive nomogram model with Mito-RGs signature and other prognosis factors was established to predict the survival of HNSCC patients.
The identified 13 Mito-RGs were risk-associated and highly expressed in the high-risk group. Most of them played an important role in the oncogenesis and progression of tumors.
B4GALT7 encodes beta-1,4-galactosyltransferase, which catalyzes the addition of galactose to xylose in the tetrasaccharide linkage region of proteoglycans. This enzyme is critical for the O-linked glycosylation-mediated functions of proteoglycans, a major component of the extracellular matrix.
LPAR2 belongs to the EDG family and contains 351 amino acids [16]. Some studies have shown that LPAR2 expression plays a crucial role in the occurrence and development of cancer, which may promote gene transcription and cell proliferation in tumor microenvironment[17–19]. In the HNSC immune cell subgroup, the high expression of LPAR2 was significantly correlated with various immune markers. LPAR2 could act as a valuable prognostic biomarker for HNSC [20].
DPM1 was a mainly catalytic component of Dolichol phosphate mannose synthase (DPMS)[21]. The lack of DPMS activity led to cell cycle arrest and apoptosis induction of capillary endothelial cells treated with carbamycins [22]. Studies have reported that DPM1 could be a potential prognostic biomarker for the survivals of HCC patients[23].
The PER3 gene was the most important member of the human period gene family[24]. Research have shown that the PER3 gene participates in the process of tumor development by regulating cell proliferation and apoptosis, participating in DNA damage repair pathways, and maintaining genome stability[25, 26].
POLR2J gene could encode RNA polymerase II. The researchers found that there may be a relationship between the POLR2J gene family and several human hRPB11 proteins [27, 28].
Src kinase associated phosphoprotein 2 (SKAP2) was a substrate of Src family kinases (SFK), which played a vital role during cancer progression. SKAP2-dependent macrophage invasion promoted the infiltration of macrophages into tumors and further enhanced tumor growth and metastatic spread[29].
Protein tyrosine phosphatase receptor type C (PTPRC) was a transmembrane glycoprotein. It was expressed on almost all hematopoietic cells except for mature erythrocytes and was an essential regulator of T and B cell antigen receptor-mediated activation. The disrupted equilibrium between protein tyrosine kinase and phosphatase activity could lead to immunodeficiency, autoimmunity, or malignancy[30].
MEF2A played an essential role in embryonic development, controlling cytotrophoblast invasion, differentiation, B-cell development, and cardiogenesis. The studies demonstrated that a higher level of MEF2A may cause shorter survival time and promote distant metastases in colorectal cancer[31].
The N-Acetylglucosamine-phosphate Mutase (PGM3) could catalyze the conversion of N-Acetylglucosamine-6-phosphate (GlcNAc-6-P) into N-Acetylglucosamine-1-phosphate (GlcNAc-1-P). It was reported that PGM3 inhibition in breast cancer cells led to cell death by inducing endoplasmic reticulum (ER) stress and reactive oxygen species (ROS)[32, 33].
CAMK2B belongs to the serine/threonine protein kinase family and the Ca(2+)/calmodulin-dependent protein kinase subfamily. It has been reported that overexpression of CAMK2B could inhibit the proliferation and tumor interstitial cell infiltration of papillary renal cell carcinoma [34].
Glycolysis was considered the main metabolic process for cancer cells to generate energy and grow through anabolism [35]. Like most aggressive tumors, HNSCC exhibit a high rate of glycolysis to meet their metabolic demands. Studies have reported that glycolysis regulation was associated with the alteration in oncogenes, tumor suppressor genes, overexpression of glycolytic enzymes, and glucose transporter in HNSCC[36].
In our study, we discovered that high-risk HNSCC patients had higher activity of the glycolysis pathway than did low-risk patients. Furthermore, the glycolysis pathway declined, leading to a favorable prognosis, indicating that activation of the glycolysis pathway may serve as a prognosis biomarker in HNSCC. The role and mechanism of glycolysis pathway in the progress and prognosis of HNSCC needed further experimental verification.
The idea of immune promotion or tumor suppression has been widely accepted, and immune checkpoint therapy is one of the most influential anticancer therapies developed in recent years. Our results showed that there were significant differences in immune cells and functions between low-risk and high-risk HNSCC patients, including DCs, CD8 + T cells, Treg, APC_co_inhibition, HLA, et al. In our research, the infiltration of CD8 + T cells accounted for the most obvious difference in the two risk groups, indicating that patients in the low-risk group were more sensitive to immune checkpoint inhibitors[37]. Regulatory T cells (Tregs) could accumulate aberrantly in some types of the tumor to suppress antitumor immunity and support the establishment of immunological hypo-responsiveness microenvironment[38]. We also found the Tregs were higher in the low-risk group, Consistent with the results of Lukesova et al. reported that HNSC patients with elevated Treg levels had significantly better overall survival[39]. In our study, the immune cells were all negatively associated with a risk score. It was necessary to conduct more research on the above results.
There were some limitations in this study. More HNSCC cohorts and prospective samples were obtained to build a sufficient dataset to validate our prognostic signature. After all, only two cohorts consisting of 761 samples were included. The biological mechanisms behind identified Mito-RGs-based were not very clear; large-scale, multi-center studies were needed to provide more critical information for further understanding of their functional roles in the HNSCC.