Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker

Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by high rates of mortality and treatment-related morbidity, underscoring the urgent need for innovative and safe treatment strategies and diagnosis practices. Mitochondrial dysfunction is a hallmark of cancer and can lead to the accumulation of tricarboxylic acid cycle intermediates, such as succinate, which function as oncometabolites. In addition to its role in cancer development through epigenetic events, succinate is an extracellular signal transducer that modulates immune response, angiogenesis and cell invasion by activating its cognate receptor SUCNR1. Here, we explored the potential value of the circulating succinate and related genes in HNSCC diagnosis and prognosis. We determined the succinate levels in the serum of 66 pathologically confirmed, untreated patients with HNSCC and 20 healthy controls. We also surveyed the expression of the genes related to succinate metabolism and signaling in tumoral and nontumoral adjacent tissue and in normal mucosa from 50 patients. Finally, we performed immunohistochemical analysis of SUCNR1 in mucosal samples. The results showed that the circulating levels of succinate were higher in patients with HNSCC than in the healthy controls. Additionally, the expression of SUCNR1, HIF-1α, succinate dehydrogenase (SDH) A, and SDHB was higher in the tumor tissue than in the matched normal mucosa. Consistent with this, immunohistochemical analysis revealed an increase in SUCNR1 protein expression in tumoral and nontumoral adjacent tissue. High SUCNR1 and SDHA expression levels were associated with poor locoregional control, and the locoregional recurrence-free survival rate was significantly lower in patients with high SUCNR1 and SDHA expression than in their peers with lower levels (77.1% [95% CI: 48.9–100.0] vs. 16.7% [95% CI: 0.0–44.4], p = 0.018). Thus, the circulating succinate levels are elevated in HNSCC and high SUCNR1/SDHA expression predicts poor locoregional disease-free survival, identifying this oncometabolite as a potentially valuable noninvasive biomarker for HNSCC diagnosis and prognosis.

Cancer-derived extracellular succinate: a driver of cancer metastasis

“…They further reported that serum succinate level is increased in patients with non-small cell lung carcinoma and that serum succinate has the potential to be a biomarker of lung cancer [ 48 ]. A recent report reveals that serum succinate is a biomarker of human head and neck squamous carcinoma [ 107 ]. Taken together, these findings suggest that cancer cell secrete succinate into circulating blood to raise the blood level of succinate.…”

TCA-phospholipid-glycolysis targeted triple therapy effectively suppresses ATP production and tumor growth in glioblastoma

“…To decrease this inflammatory response, macrophages tend to use itaconate to inhibit SDH function and the proinflammatory responses 52 . In head and neck squamous cell carcinoma (HNSCC), the expression of SDHA is higher in the tumor tissues than in the tissue-matched normal mucosa, predicting a higher locoregional recurrence 53 . Our study showed that the increased ATF3 level could repress the TCA cycle-related gene SDHA 's expression, leading to a reduced mitochondrial respiration rate and ATP contents.…”

Oncometabolites—A Link between Cancer Cells and Tumor Microenvironment

“…GPR91 expression also correlated with that of other receptors for inhibitory pathways, such as PD-L1, PD-L2, CD48, CD80, and CD86. GPR91 is not only highly expressed in ovarian cancer cells, so we may extrapolate that succinate exerts similar immune effects in other cancers, such as head and neck squamous cell carcinoma [ 79 ]. A recent study [ 76 ] also shows that succinate stimulates TAM marker gene expression, including Arg1 , Fizz1 , Mgl1 , and Mgl2, and is responsible for the upregulation of vascular cell adhesion molecule 1 (VCAM1) and CD11c on the surface of TAMs.…”