Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker
1
MoBioFood Research Group, Biochemistry and Biotechnology Department, Universitat Rovira i Virgili, Campus Sescel·lades, 43007 Tarragona, Spain
2
Department of Endocrinology and Nutrition, Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Universitari de Tarragona Joan XXIII, 43005 Tarragona, Spain
3
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (CIBERDEM), 28029 Madrid, Spain
4
Otorhinolaryngology Head-Neck Surgery Department, Hospital Universitari de Tarragona Joan XXIII, Insitut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, 43005 Tarragona, Spain
5
School of Medicine, Universitat Rovira i Virgili, 43201 Reus, Spain
6
Pathology Department, Plataforma de Estudios Histológicos, Citológicos y de Digitalización, Hospital de Tortosa Verge de la Cinta, Institut d’Investigació Sanitària Pere Virgili (IISPV), URV, 43500 Tortosa, Spain
7
Pathology Department, Hospital Clínic de Barcelona, IDIBAPS, 08036 Barcelona, Spain
8
Otorhinolaryngology Head-Neck Surgery Department, Hospital de la Santa Creu i Sant Pau and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN, MICINN, ISCIII), Universitat Autònoma de Barcelona, 08041 Barcelona, Spain
9
Radiation Oncology Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
10
Oncology Department, IDIBAPS, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
11
Maxillofacial Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
12
Oncology Department, Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Sant Joan de Reus, 43204 Reus, Spain
13
Otorhinolaryngology Department, UB, IDIBAPS, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
14
Head Neck Clínic, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), 2017-SGR-01581 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
†
Two authors contributed equally to this work.
‡
Current address: Unitat de Recerca, Institut d’Investigació Sanitària Pere Virgili, Hospital Universitari de Tarragona Joan XXIII, C/Mallafré Guasch 4, 43007 Tarragona, Spain.
Academic Editor: Patrick J. Schuler
Cancers 2021, 13(7), 1653; https://doi.org/10.3390/cancers13071653
Received: 18 February 2021
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Revised: 23 March 2021
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Accepted: 24 March 2021
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Published: 1 April 2021
(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)
Simple Summary
Emerging evidence points to succinate as an important oncometabolite in cancer development; however, the contribution of the succinate-SUCNR1 axis to cancer progression remains unclear. Head and neck squamous cell carcinoma (HNSCC) is associated with disease and treatment-related morbidity so there is an urgent need for innovation in treatment and diagnosis practices. Our aim was to evaluate the potential of the succinate-related pathway as a diagnostic and prognostic biomarker in HNSCC. The circulating succinate levels are increased in HNSCC, being a potential noninvasive biomarker for HNSCC diagnosis. Moreover, the succinate receptor (SUCNR1) and genes related to succinate metabolism, which are predominantly expressed in the tumoral mucosa as compared with healthy tissue, are positively associated with plasma succinate. Remarkably, we found that SUCNR1 and SDHA expression levels predict prognosis.
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.
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Keywords:
oncometabolite; succinate; succinate receptor; metabolism; head and neck cancer; treatment; prognosis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Terra, X.; Ceperuelo-Mallafré, V.; Merma, C.; Benaiges, E.; Bosch, R.; Castillo, P.; Flores, J.C.; León, X.; Valduvieco, I.; Basté, N.; Cámara, M.; Lejeune, M.; Gumà, J.; Vendrell, J.; Vilaseca, I.; Fernández-Veledo, S.; Avilés-Jurado, F.X. Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker. Cancers 2021, 13, 1653. https://doi.org/10.3390/cancers13071653
AMA Style
Terra X, Ceperuelo-Mallafré V, Merma C, Benaiges E, Bosch R, Castillo P, Flores JC, León X, Valduvieco I, Basté N, Cámara M, Lejeune M, Gumà J, Vendrell J, Vilaseca I, Fernández-Veledo S, Avilés-Jurado FX. Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker. Cancers. 2021; 13(7):1653. https://doi.org/10.3390/cancers13071653
Chicago/Turabian StyleTerra, Ximena, Victoria Ceperuelo-Mallafré, Carla Merma, Ester Benaiges, Ramon Bosch, Paola Castillo, Joan C. Flores, Xavier León, Izaskun Valduvieco, Neus Basté, Marina Cámara, Marylène Lejeune, Josep Gumà, Joan Vendrell, Isabel Vilaseca, Sonia Fernández-Veledo, and Francesc X. Avilés-Jurado. 2021. "Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker" Cancers 13, no. 7: 1653. https://doi.org/10.3390/cancers13071653
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