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

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.

Circulating microRNAs modulating glycolysis as non-invasive prognostic biomarkers of HNSCC.

BACKGROUND: The identification of prognostic non-invasive biomarkers is a priority for cancer patients' care. Circulating microRNA (miRNAs) have been described in numerous human malignancies as diagnostic, prognostic, and therapeutic cancer biomarkers. The aim of our study was to analyze the expression profile of a set of miRNAs, involved in the modulation of the glycolytic pathway, as prognostic factors in human head and neck squamous cell carcinomas (HNSCC). METHODS: Serum samples of 54 patients with untreated HNSCC were obtained at the time of diagnosis. The prognostic value of circulating miR-26b, miR-124, miR-155 and miR-375 was evaluated towards disease-free survival. RESULTS: We found that there were optimal miRNAs cut-off values for lower risk of recurrence in HNSCC patients. Kaplan-Meier curves showed that higher levels of miR-26b and lower levels of miR-155 were associated with better disease-free survival rates. In the multivariate analysis, patients with serum miR-26b > 0.062 and miR-155 < 0.159 presented more than 2.9 times lower risk of poor outcome. CONCLUSION: Our results suggest that two miRNAs that modulate the glycolytic pathway, miR-26b and miR-155, are independently associated with the risk of recurrence in patients with HNSCC. The overall results in this study supports the evidence that the glucose homeostasis may be a target to improve the outcomes for patients with HNSCC. LEVEL OF EVIDENCE: Individual retrospective cohort study (2b).

Prognostic relevance of insulin resistance on disease-free survival in head and neck squamous cell carcinomas: Preliminary results.

BACKGROUND: The primary purpose of this study was to investigate the significance of pretreatment glycemic parameters in the prognosis of head and neck squamous cell carcinoma (HNSCC). METHODS: Plasma samples of 71 patients with untreated HNSCC were obtained at the time of diagnosis. The prognostic value of fasting insulin, glucose, glycosylated hemoglobin levels, and the homeostatic model of risk assessment-insulin resistance (HOMA-IR) was evaluated toward disease-free survival. RESULTS: High HOMA-IR levels were associated with poor disease-free survival in intermediate-advanced stage tumors. Kaplan-Meier curves showed lower disease-free survival rates in patients with high HOMA-IR than in patients with low levels. In patients with intermediate-advanced stage tumors, multivariate analysis revealed that those with an HOMA-IR >2.974 presented a 2.7 times higher risk of poor outcome (95% confidence interval [CI] 1.023-7.341; P = .045). CONCLUSION: The HOMA-IR is independently associated with disease-free survival in patients with HNSCC. We found an optimal HOMA-IR cutoff value for disease-free survival in patients with intermediate-advanced HNSCC.

External validation of sTWEAK as a prognostic noninvasive biomarker for head and neck squamous cell carcinoma.

BACKGROUND: The main purpose of this study was to validate the prognostic significance of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) in head and neck squamous cell carcinoma (HNSCC) using an independent cohort. METHODS: Data were evaluated from 153 patients with HNSCC in stages III to IV, who received radiotherapy (RT) or chemoradiotherapy. We quantified soluble TWEAK (sTWEAK) in pretreatment samples using enzyme-linked immunosorbent assay. RESULTS: The classification tree revealed a cutoff value of 322 pg/mL for sTWEAK to be ideal for discriminating between patients' disease control. Kaplan-Meier curves indicate that the disease-free survival rate in patients with high sTWEAK was significantly higher than in patients with low levels (p = .006, log-rank test). An independent link was identified between low sTWEAK and poor clinical outcome in Cox regression multivariate analysis (hazard ratio = 1.866; 95% confidence interval [CI] = 1.114-3.125; p = .001). CONCLUSION: Our study highlights the significance of this noninvasive biomarker in the discrimination according to the disease control achieved by patients who received a nonsurgical organ-preservation treatment. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1358-E1363, 2016.

Low blood levels of sTWEAK are related to locoregional failure in head and neck cancer.

Identifying serum pre-treatment molecular markers that can predict response to therapy is of great interest in head and neck oncology and is required to develop personalized treatments that maximize survival while minimizing morbidity. The main aim was to investigate the potential prognostic significance of tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and its receptors, fibroblast growth factor-inducible 14 (Fn14) and CD163, in head and neck squamous cell carcinoma (HNSCC). The study comprised 37 consecutive patients with pathologically confirmed, untreated HNSCC. Serum and tissue samples from these patients were available for study. We determined sTWEAK and sCD163 levels in serum from 37 HNSCC patients by ELISA. TWEAK, CD163, Fn14 and TNF-α gene expression were detected by real-time RT-PCR in 111 matched tissue samples (tumoral, adjacent and distal/normal mucosa). Our results showed a significant relationship between low sTWEAK levels and poor locoregional control of the disease. Kaplan-Meier curves indicated that the locoregional recurrence-free survival rate in patients with low sTWEAK circulating levels was significantly lower than in patients with high levels, and that high CD136/TWEAK expression ratio in tumors was also related to poor prognosis. sTWEAK pre-treatment serum levels might be used as prognostic non-invasive biomarkers for locoregional control in patients with HNSCC. Future investigations are warranted to determine the potential prognostic significance of this non-invasive biomarker in the rapid discrimination according to the locoregional control achieved in patients who received a non-surgical organ preservation treatment.